CA2001389C - Pyrimidinedione derivative compounds, method of producing the same and antiarrythmic agents containing the same - Google Patents
Pyrimidinedione derivative compounds, method of producing the same and antiarrythmic agents containing the sameInfo
- Publication number
- CA2001389C CA2001389C CA 2001389 CA2001389A CA2001389C CA 2001389 C CA2001389 C CA 2001389C CA 2001389 CA2001389 CA 2001389 CA 2001389 A CA2001389 A CA 2001389A CA 2001389 C CA2001389 C CA 2001389C
- Authority
- CA
- Canada
- Prior art keywords
- group
- substituted
- compound
- lower alkyl
- alkyloxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compounds of formula (1) are provided which are useful as Class III type antiarrythmic agents improving cardiac dysfunction, cardiac insufficiency and provide positive inotropic action. The compounds of this invention are embodied by formula (1).
(see fig.I) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, (see fig.II) or (see fig.III);
B represents an oxygen or a sulfur atom, (see fig.IV), (see fig V) or (see fig. VI);
D represents (see fig.VII), (see fig. VIII) or (see fig.IX);
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group or a lower alkyl group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected from the group consisting of a hydroxy group; a lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or R1 and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
- 424a -R3 and R4 each independently represent a hydrogen atom, or a lower alkyl group;
X1 and x2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl group, a carboxy group, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring;
n represents an integral number 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
(see fig.I) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, (see fig.II) or (see fig.III);
B represents an oxygen or a sulfur atom, (see fig.IV), (see fig V) or (see fig. VI);
D represents (see fig.VII), (see fig. VIII) or (see fig.IX);
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group or a lower alkyl group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected from the group consisting of a hydroxy group; a lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or R1 and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
- 424a -R3 and R4 each independently represent a hydrogen atom, or a lower alkyl group;
X1 and x2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl group, a carboxy group, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring;
n represents an integral number 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
Description
2~1389 SPECIFICATION
TITLE OF THE INYENTION
PYRIMIDINEDiONE DERIVATIVE COMPOUNDS, METHOD OF PRODUCING
THE SAME AND ANTIARRYTHMIC AGENTS CONTAINING THE SAME
BACKGROUND OF THE IN~ENTiON
1. Field of the Invention This invention relates to novel pyrimidinedione derivatives and acid addition salts thereof, to methods of L' producing the same and to pharmaceutical agents containing the same, which are effective for the treatment of cardiac dysfunctions such as arrhythmia and cardiac insufficiency.
2. Description of the Prior Art The mechanism of the occurrence of arrhythmia is camplicated. Abnormalities in stimulation production and disorders in the conducting system or combinations thereof are considered to be responsible.
As to disorders in excitation conduction, the re-entry theory is representative.
One of the conditions of occurrence of arrhyttlmia is irregularity in thc refractory period in various parts of the heart. In addition, one-directional block, shortened refractory period, delay in conduction, the presence of circus movement are complicatedly involved.
Conventionally, varieties of antiarrythmic agents have been used for the treatment of arrhythmia.
The antiarrythmic agents are classified into four 2~ 389 groups according to their mode of action.
Namely, E. M. Vaughan Williams (Vaughan Williams E. M.;
"Advances in dtulg research, vol. 9"; ed. by Harper N. J., Simmonds A. B., Academic Press, London, 1974; pages 69~
classified the antiarrythmic agents into the following four groups according to their action against the action potential of cardiac muscle or against the ionic current which generates the action potential.
Class 1: Sodium channel depressors These agents are efficacious ;n repressing a sodium current. However, these agents have no or only minute effects on the retention time of the normal action potential and decrease the maximum rising velocity (YmaX) of the sodium current. The antiarrythmic agents which belong to this IS class have a high antiarrythmic activity but at the same time strongly repress cardiac functions. Careful consideration is required in administering to patients with cardiac failure or hypotension.
Class 1l: Beta-blocking agents The agents in this class, represented by propranolol, are efficacious in the beta-blocking action and are useful in treating patients with arrhythmia in which the sympathetic nerve is involved. However, the care must be taken for use since these agents have side-effects caused by the beta-blocking action, such a.s depression of card;ac fllnctions, induction of bronchial asthmatic attach and _ 3 _ 20~''1389 hypoglycemic seizures.
Class III: Pharmaceutical agents for prolonging the retention time of the action current.
These agents are efficacious in remarkably prolonging the retention time of the action current of the cardiac muscle and in prolonging an effective refractory period. Re-entry arrhythmia is considered to be suppressed by the action of the pharmaceutical agents of Class III. The medicaments of this Class III include amiodarone and bretylium. However, all the agents have severe side effects; therefore, careful consideration is required for use.
Class IV: Calcium antagonists These agents control a calcium channel and suppress arrhythmia due to automatic sthenia of sinoatrial nodes and to ventricular tachycardia in which atrial nodes are contained the re-entry cycle.
Among these antiarrythmic agents, pharmaceutical agents of the Class III type are considered to be particularly important and the most efficacious, and known to be effective on ventricular arrhythmia, the most fatal of all symptoms.
SUMMARY OF THE INVENTION
An object of an aspect of the present invention is to provide a novel compound which is useful as a Class III type antiarrythmic agent and to provide a process for producing the same.
Another object of an aspect of the present invention is to provide a novel compound which is effective in improving cardiac dysfunction such as cardiac insufficiency and a process for the preparation of the same.
Another object of an aspect of the present invention is to provide a pharmaceutical agent, which contains the novel compound as an effective component, for the treatment of cardiac dysfunctions such as arrythmic and cardiac insufficiency.
Accordingly, an aspect of the invention provides compounds of the general formula (1) shown below and acid addition salts thereof, along with their pharmacological properties. These compounds have pharmacological characteristics to markedly prolong the retention time of the action potential of cardiomuscular cells and to markedly prolong the ventricular refractory period.
Furthermore, the compounds of this invention have a positive inotropic action and are useful as therapeutic agents for cardiac insufficiency.
According to another aspect of the invention, compounds of the invention are represented by Formula (1):
N0z R' RZ ~ 0 X ~ A-N-(CH2) n - N ~ ~N-R4 (1) X2 R3 ~
in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1 ~ -N3 or -NHCH2CH-CH2-;
OH
B represents an oxygen or a sulfur atom, -N-, -CNH- or -CO-;
O OH O
Il l 11 D represents -NHC-, -CH- or -C-;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group or a lower alkyl group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected from the group consisting of a hydroxy group; a .. ~
_ ~ - 5 ~ 2 ~ ~ ~ 3 8 9 lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom, or a lower alkyl group;
X1 and x2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl group, a carboxy group, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring;
n represents an integral number 2 or 3; m represents an integral number, O, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and l represents an integral number, O, 1, 2, 3 or 4.
2 0 û ~ 3 8 9 -5a-DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Compounds according to the present invention is those of the general formula (1) shown below and acid addition salts thereof. More specifically, the compounds are described in Examples thereinafter as preferred embodiments.
N02 A-N-(CH2) n - N ~ -R~ .. ~1 X2 R3' ~
In the formula. A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-. -N ~ OI -NHCH2CH-CH~-;
OH
~5 O O
11 ll B represents an oxygen or a sulfur atom, -N-, -CNH- or -CO-;
o OH ~
Il l 11 D represents -NHC-, -CH- or -C-;
Rl and R2 each independently represent a hydrogen atom~ a lower alkyloxycarbonyl graup, an unsaturated lower alkyl - group or a lower alky1 group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected from the group consisting of a hydroxy group; a lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group; a benzoylvxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or Rl and R2 may be so linked as to form an alkylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
xl and X~ ea~h independently represent a hydrogen atom, -CO-Rfi, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl, groupacarboxylgroup, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group. a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to form an alkylene 2~ 89 chain and thus form a heterqcyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups independently selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring;
n represents an integral number 2 or 3: m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number. 0, 1, 2, 3 or 4.
In the above formula (1), examples of the unsaturated lower alkyl group include vinyl, allyl and propargyl groups.
Examples of the lower alkyl group include linear- or branched-alkyl groups having 1 - 5 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary-butyl and secondary-butyl groups.
Examples of the lower alkyl group substituted by a hydroxyl group include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyprqpyl and 4-hydroxy-butyl groups.
Examples of the lower alkyl group substituted by a lower monoalkylamino group include 2-(methylamino)ethyl, 3-(methylamino)propyl and 2-(ethylamino3ethyl groups.
Examples of the lower alkyl group substituted by a lower dialkylamino group include 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl and 3-(dimethylamino)propyl groups.
An example of the lower alkyloxy group is an oxygen - 8 - ~ 0 ~ ~ ~ 8 ~
atom substituted by a lower alkyl group described above.
Examples of the lower alkanoyloxy group include acetyloxy, propionyloxy, ~L~loxy~isobutyryloxY and pivaloyloxy groups.
Examples of the lower alkyl group substituted by a benzoyloxy group include 2-benzoyloxYethyl~ 3-benzoyloxypropyl, ~-benzoyloxypropyl and 2-benzoyloxy-1-methylethyl groups.
Examples of the lower alkyl group substituted by a phenyl group include benzyl, 2-phenylethyl and 3-phenylpropyl groups.
An example of the lower alkyl group in the lower alkyloxycarbonyl group is that identical with the lower alkyl group described above.
Examples of the halogen atom include fluorine, chlorine, bromine and iqdine atoms.
No limitation is required of substitution sites in the halogen-substituted lower alkyl group; the lower alkyl group substituted by a substituting group selected from the group consisting of the lower alkyloxy group. the lower alkanoyloxy group. the benzoyloxy group substituted by a halogen atom or a lower alkyloxy group, the phenyl group substituted by a halogen atom or a lower alkyloxy group and the lower alkyloxycarbonyl group; the benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; and the phenyl group substituted bY a halogen atom or a lower .... .
-2~ 389 alkyloxy group.
Examples of the lower alkylthio group include sulfur atoms substituted by the lower alkyl group mentioned above.
Examples of the lower alkanoylamino group include acetylamino and propionylamino groups.
Examples of the lower alkylsulfonamido group include methanesulfonamido and ethanesulfonamido groups.
Examples of the mono- or di-lower alkylamino group include methylamino, ethylamino, dimethylamino and diethylamino groups.
Examples of the phenyl group-substituted lower alkylamino group include the above-mentioned alkylamino groups which are further substituted by phenyl group. No limitation is required in this substitution.
~xamples of the unsaturated lower alkyloxy group include vinyloxy, allyloxy and propargyloxy groups.
Examples of the alkyl chain to link Rl and R2 or ~1 and R5 include ethylene and propylene chains.
Examples of the lower alkanoyl group include formyl, acetyl, propionyl and butyryl and pivaloyl groups.
Examples of the lower alkylsulfonyl group include methanesulfonyl and ethanesulfonyl g~oups.
Examples of the cycloalkyl group include cyclopentyl and cyclohexyl groups.
Examples of the heterocyclic group as ~6 include pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl Z~89 gI-O UpS .
No limitation is required of the substitution sites in the phenyl grqup substituted by a substituting group in R6.
The expression "pharmaceutically acceptable" as used to describe the pharmaceutically acceptable acid addition salts in the compounds of the general formula (1) described above means not to have remarkable side effects or absence of toxicity and not to reduce the pharmaceutical activities, when administered to man. These acid addition salts can be produced by neutralization of the corresponding free bases.
~ xamples of the acids from which these pharmaceutically acceptalbe salts can be prepared include organic acids or inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, .
methanesulfonic acid, maleic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, lactic acid. and benzenesulfonic acid.
The concrete examples of the compounds of the general formula (1) include the following compounds.
2~1389 1. I,3-dimethyl-6-[2-~4-nitrqanilino~ethylamino]-2,~-(lH,3H)-p~rimidinedione 2. 1,3-dimethyl-6-[3-(~-nitroanilino)propylamino]-2,4(1H,3H)-pyrimidineditne 3. 1,3-dimethyl-6-[4-(4-nitrophenyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione . 1,3-dimethyl-fi-[N-ethyl-2-(4-nitroanilino)ethyl-amino~-2,~(1H,3H')-pyrimidinedione .~. 1,3-dimethyl-6-[2-(N-meth~ nitroanilino~ethyl-amino)]-2.~1H.3H'-pyrimidinedione 6. 1,3-dimethyl-6-~ 4-nltrophenyl!homo~ipera~in-]-yl~-2.4(1H.3HI-pyrimidinedione 7. 1,3-dimethyl-6-~2-(4-nitro~enzylamino~ethyl-amino]-2,4~1H,3H)-pyrimidinedlone 8. 1,3-dimethyl-6-~3-(~-nitrobenzylamino)Dr.)~yl-amino)]-2,~(1H,3H)-p~rimidinedione . 1,3-dimethyl-6-[4-(4-nittlobenzyl)piperazin-1-yl]-2,~(1H,3H)-pyrimidinedione 10. 1,3-dimethyl-6-[N-propyl-2-;1-nitrobenzylamino)-ethYlamino~-2.4(lH~3H~-pyrimidinedione 11. 1,3-dimethyl-6-[2-~N-ethvl-4-nitr-)benzylamino)-ethylamino)~ llH.3H~-pyl-imidinedione 12. 1,3-dimethyl-6-~-[~ 2-hYdro-x~ethy~
nitroben7.ylamino~ethylamino'~-2.~1H.3H!-pyrimidinedione 13. 1.3-dimethyl-fi-~2-~J--.~-nitrophenvl)ethylamino~-Z~1389 ethylamino~-2,~(1H,3H)-pyrimidinedione 14. 1,3-dimethyl-6-~3-t2-14-nitrophenyl)eth~laminn~-propylamino}-2,~(1H,3H)-pyrimidinedione 15. 1,3-dimethy]-6-{N-(2-hydroxyethyl)-2-t2-~4-nitrophenyl)ethylamino]ethylamino~-2,~(1H,3H)-pyrimidinedione 16. 1,3-dimethyl-6-~2-tN-ethyl-2-(4-nitrophenYl)-ethylamino]ethylamino~-2~4(1H.3H!-pyrimidinedione, 17. 1.3-dimethyl-Ç-~2-~N-(2-hydroxyethyl)-2-(~-nitro-phenyl)ethylamino]ethylamino~-2,4~1H.3H)-pyrimidinedione 18. 1.3-dimethyl-6-{~-[2-~4-nitl-ophenyl'~ethyl]-piperazin-l-yl~-2.~(IH.3H)-~yrimidinedione 19 . 1, 3-d i methyl -6- ~4- t2- ( 4-ni tl-ophenyl !ethyl ] -hnmopiperazin-l-yl~-2?4(1H,~H)-pyrimidinedinne 20. 1,3-dimethyl-6-~2-[N-~'2-acetoxyethyl)-5-l~-nitl(,-phenyl~ethylamino]ethylamino~-2,~(IH,3H)-pyrimidinedione 21. 1,3-dimethyl-6-{2-~N-1'3-hydroxypropyl)-2-~nitrophenyl)ethY]amino]ethylamino'~-2.~(]H.3H!-pyrimidinedione 22. 1.~-dimethyl-6-~2-~N-~'3-benzoyloxypropyl!-2-(~-nitrophenyl~ethylamino~ethylamino~-2.~(1H.3H)-pyrimidinedlone 23. 1.3-dimethyl-6-~-[2-~3-nitro~henvl~eth piperazin-l-yl ~-2.4~1H.3H!-pYr~ idinedione 2~1389 2~. 1,3-dimethyl-6-{~-~2-~2-nitrophenyl)ethY
piperazin-1-yll-2,1(1H,~H~-pylimidinedione 25. 3-methyl-6-~-t2-(4-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedinne 26. 1-methyl-6-~-t2-(~-nitrophenyl)ethyl~piperazin-I-yl3-2,4(1H,3H~-pyrimidinedione 27. 1,3-diethyl-6-~2-[N-~'2-hydroxvethvl)-2-~4-nitrophenyl!ethylaminc~ethylaminc,'~ 'lH.3H~-pyrimidinedione 28. 1.3-diisopropyl-G-~2-rN-~'2-hYdrc,xyethYl!-2-~-nitrophenyl)ethylaminn]ethylamin~ IH.3H~-pyrimidinedione 29. 1,3-dimethyl-fi-{2-t3-(4-nitr-)phenyl~propylamino~-ethylamino~-2~4(1H.3H)-pyrimidinedione 30. 1,3-dimethyl-6-~3-~3-(~-nitroDhenyl)proipylamino]-propylamino~-2.4(1H.3H)-pyrimidlnedione 31. 1,3-dimethyl-6-{N-methyl-2-t3-(~-nitrophenyl)-propylamino~ethylamino'~ ('lH.3H)-pyrimidinedione 3~. l,3-dimethyl-~-{~-ethyl-~-~3-~-nitro~henYl)-propy]amino~ethylamino~ (1H.3H!-pyrimidinedione 33. I,3-dimethyl-fi-i~'-pro~yl-~-t3-~-nitriphenvl)-propylamino~ethylamin-,~ ]H.3H!-pyrimidinedi-Jne 3~. I.3-dimethyl-fi-~N-~3-hYdro-x~ethVl~-'-t3-~-nitrophenyl?propylamln~ ethylamincl~ (lH~3H?-pyrlmidinedion~
3~. I,3-dimethyl-6-~N-~ hYdroxypl~-3py~ - t3- ( ~-2~1~1389 nitr~iphenyl)propylamino]ethylamino~-7,~IH.3H~-pylimidinedione 36. I~3-dimethyl-6-{N-(~2-hydroxy-I-methylethyl~-2-t3-(4-nitrophenyl)prnpylamino~ethylamino~-~7,4-(IHs3H)-pyrimidinedione 3~. 1,3-dimethyl-6-~N-~2-acetoxyethyl)-2-[3-(~- -nitrnr3henyl)r3ropylamino~ethylamino'~-2.~-~IH.3H~-pyrimidinedione 38. 1.3-dimethyl-6-{~-methoxycarbonylmethyl-2-t3-~l-nitrophenyl~proDylamino~eth~lamln~-2.1~lH.3H!-pyrimidinedione 39. I,3-dimethyl-6-{~-''2-phenylethyl)-2-~3-'~-nitro-phenyl)pl~opylamino]ethylamino~-2,4-(1H,3H)-pyrimidinedi~ne 40. 3,3-dimethyl-6-~2-~N-methy]-3-~-nitrophenyl)-propylamino]ethylamino~-2,~1H,3H~-pyrimidinedi(lne ~1. 1,3-dimethyl-6-{2-<N'-ethyl-N-t3-~-nitror3henyl!-propyl]amino>ethylamino~-2,~('IH.3H)-pyrimidinedi-3ne ~'7. 113-dimethyl-6-~2-[N-propyl-3-~4-nitl~oDhenyl~-propylaminr33ethylamin-3~-2.~1H.3H)--7yrimidinedil~ne ~3. 1.3-dimethyl-6-~- r~- (l-meth~]ethyl!-3-(~-nitrophenyl)propylamlnolethylamino'~ lHt3H)-pyrimidinedi-ne . 1,3-dimethyl-~ -tN-butyl-3-'4-nitrophenyl)-propylamino~ethvlamin()l-~ '2.~(1H.3H)-pyrimidinedi-~ne 20~1389 , 5 15. 1,3-dimethyl-fi-~2-t~ tert-butyl~-3(~-nitrnphenyl)-propylamino]ethylamino~ ,1(1H,3H~-pyrimidinedione ~6. 1,3-dimethyl-6-{2-<N-(2-hydroxyethyl)-N-[3-~nitrophenyl)pl-cpyl~amino>ethy1amina~-2.4(~H~3H~-pyrimidinedione 4~ . 1 ,3-dimethyl-6-~ ~-rN-~3-hydl-oxypr~pyl !-3-(~-nitrophen~l)propylamino]ethylaminll~-2~/1H.3H)-pyrimidinedione . 1.3-dimethyl-6-~'2-[N-.~-hv~roxy-l-meth~lethyl)-3-('4-nitrophenyllplopylamina~ethyl~mino'~
~~1H,3H)-~yrimidinedione ~9. 1.3-dimethyl-6-~-[~-(2-hydroxypropyl--3-('4-nitrophenyl)pro~ylamino]ethylamino}-2.~(1H.3H'-pyrimidinedione 5~. 1,3-dimethyl-6-~2-~ -hydroxybutyl)-3-(~-nitrophenyl)propylamincl~ethylamino'~ lH.3h' -pyrimidinedione 51. 1,3-dimethyl-6-~ -acetoxyethylj-3-~.l-nitl-o-pheny]!~ropylamino]ethylamin-J'~-2~1H.3H~-pyrimidinedi.-,n~
. 1.3-dimethYl-6-~ N-(2-f~llmylc!x'~ t~lyl !-;~-~4-nitronhenyl~ranylamino]ethylamino~-~J.~(lH.3H)-pyrimidinedione ~3. 1.~-dimethyl-6-~-[N-(2-~ropionylaxyethyl)-3-'~-nitrophenvl )pr(pylamina~ethylamincl~-J.~IH,3H!-pyrimidinedinne 2~1389 .~4. 1 3-dimethyl-6-~-[N-(2-isobutyryldxyethyl3-3 ~-nitrophenyl~propylamino~ethylamino~-2.4(IH 3H'-pyrimidinedione ~5. I 3-dimethyl-6-~2-[N-(2-pival~yloxyethyl~ (4-nitrophenyl)propylaminn]ethylamino~-2 ~(lH.3H~-pyrimidinedione 56. 1.3-dimethyl-6-~2-~N-~2-acetoxypr~pyl)-3-(4-nitrophenyl)propylamino3ethylaminc~ .4(lH~3H!
pyrimidinedi-ne 57. 1 3-dimethyl-6-~2-tN-.2-acetoxy-1-methylethyl)-3-(4-nitrophenyl~propylamino~ethylamino~-2.~(IH.3H)-pyrimidinedione 58. ] 3-dimethyl-6-~-tN-~2-benzoyloxyethyl)-3-(4-nitrophenyl)propy1amino]ethylamino~-2 1(1H.~H~-pyrimidinedione ~9. l,3-d.imethyl-t~-{2-<~ -('4-fluo~ benzovlnxY~-ethyl]-3-(~-nitrophenyl-pro~ylamincl>ethylamirlol-~.4'1H,3H)-pvrimidinedion-?
fiO. I~3-dimethYl-fi-~-<N-[2(4-methoxybenzoylf!xy!eth~l3 3- 4-nitl-oDhen~ propylaminl)~ethvlamino~-2.~(IH.3H~-pylimi~inedi-1ne 61. l.3-dimethyl-fi-~2-<N-~ hlorobenzoyloxv)ethyl ]-3-(~-nitroDhenyl~pl~cpylamino>ethylamino~-2.4-~1H 3H)-pyrimid.inedione G2. I 3-dimethyl-6-~2-<N-[2-(3~-dimethoxybenzoyloxY!-ethyl~-3-(~-nitrophenyl)prnpylamino>ethylamin-~-Xg~13~39 2,4(1H,3H)-pyrimidinedione 63. 1,3-dimethYl-6-~2-<N-[2-~3~4-dibromobenzoyloxy)-ethyl~-3-(4-nitrophenyl)propylamino>ethylamino~- -2,1(1H,3H)-pyrimidinedione 6~. 1,3-dimethyl-6-{2-tN-(2-methoxyethyl)-3-(~-nitrophenyl)propylamino]ethylamino~-2.4(1H.3Hl-pyrimidinedione 63 . 1,3-dimethyl-6-~ '-(2-propyloxyethyli-3-~-nitrophenyl~propylamino]ethylamino'~-2,4~'1H.3H~-pyrimidinedidne 66. 1,3-dimethyl-6-~-[h~-benzYl-3-(~4-nitJophenYl' propylamino~ethylamino~-~,4~1H~3H~-pyrimidinedione 67. 1,3-dimethyl-6-~2-~-(4-methoxybenzyl)-3-(~-nitro-phenyl~propylamino~ethylamino~-2,4tlH,3H)-pyrimidinedione fi8. 1,3-dimethyl-6-~2-[N-(3.1.~-trimethoxybenzyli-3-(4-nitrophenyl)prflpylamino~ethylamino~-2.4~lH.3H~-pyrimidined.inne 69. l.3-dimethyl-6-{,-rN-( r -chloroben,vl ! -;i- ~ ~-nitrophenyl)proDylamindlethylamino'~ lH.3H~-pyl~imidined~one 7(). 1.3-dimethyl-6-~2-~ henylethyl)-3-/l-nitrf.~phenyl )prnpylamino]ethylaminn~-2.~(1H.3H)-pyrimidinedione 71 1,3-dimethyl-6-~2-rN-vinyl-3-~'l-nitl-nphenyl)-propylamino]ethylamino~-2,~(1H.3H)-pyrimidinedione 72. 1~3-dimethyl-6-~2-rN-allYl-3-~4-nitrophenyl !-propylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione 73. l,3-dimethyl-6-{2-t~-propar~Yl-3-(4-nitrophenyl ! -propylamino]ethylamino~-2.~1H.3H~-pyrimidinedi~ne 7~ 3-dimethyl-6-~2-[N-etho~ycarb~n~lmethyl-~-(l- -nitrophenyl)propylamino]ethylamino~-2.~IH.3H)-p~rimidinedione 5. l,3-dimethYl-~-t2-~N-tert-but~xycal-bonylmethyl-3-(4-nitrophenyl)propylamino~ethylamino~-~.4(lH.3H~-pyrinidinedinne 76. 1,3-dimethyl-6-t2-[N-~2-methoxycarbonylethyl)-3-(~-nitrophenyl~propylamino~ethylamino~-2,411Hl3H)-.. .
pyrimidinedione 7I. ],3-dimethyl-6-tN-methy]-2-tN-methyl-3-(~-nitrophenyl~propylamino]ethylaminn~-2,i(1H.3H~-pyrimidinedione 78. 1,3-dimethyl-6-tN-ethyl-2~N-''2-hydr~xYethyli-3-(~-nitl-ophenyl3prc~pylamin~1~ethylamino}
~IH,3H3-Dyrimidinedi~-)ne 7~. l.3-dimethyl-6-t2-<~-ethy~ 3-(;~-nitrophenvl)-pr~lpyl]aminn>ethylamin-!~-2.~;H.3Hl-pyrimidinedione 80. 1,3-dimethYI-~-~'2-~N-methnxycatbnnvl-3--~-nitl-ophenYl)Dl-opylamino~ethylamino~-2 (IH,3H)-pylimidinedione 81. 1,3-dimethyl-6-i2-[N-~tert-butoxycarbonyl)-3-(4-nitrophenyl)propylamino]ethylamino~-~.1-(IH.3H)-pyrimidinedione 82. l,3-dimethyl-6-~2-<N-~2-('N-methylamino?ethyl]-3-(4-nitrophenyl)propylamino>ethylaminQ~-2.~-(lH,3H)-py~imidinedione 83. 1~3-dimethyl-6-~2-~r~-t2-(N.N-dimethyl~mino)ethvl]
3-(4-nitrophenyl')propylamino~ethylamino'~-7.~-~IH.3H)-pyrimidinedione 8~. 1,3-dimethyl-6-{~-<N-t2-(N.N-diethylamino)-ethyl3-3-(2-nitrophenyl'~propylamino>ethyl-amino~-2,4(1H,~H)-pyrimidinedinne 85. 1,3-dimethyl-6-{-7-rN-(2-hydroxyethyl~-3-s7-nitrophenyl)propylamino~ethylamino'~-2,~1H.3H)-pyrimidinedione 86. 1,3-dimethyl-6-{~-[3-(~-nitrophenyl)pl-opyl~-piperazin-l-yl'~-2.~slH.3H)-pyrimidinedinne 8~. l,3-dimeth~rl-6-~-t3-(1-nitroDheny]~pl-op~
homopiperazin-l-yl~-2.~1lH.3H)-pyrimidlnedione 88. 3-methyl-6-~-r~ -nitl-ophenyl~pl-opyll-~ipera7in-l-vl'~-2.~(1H.3H)-pvrlmidinedlone 89. 1-propyl-6-{2-tN-~2-hydroxyethyl?-3-(~-nitrophenyl)propylamino]ethylamino~-2.~-(lH,3H)-pyrimidinedione 9~. 6-~2-tN-ethyl-3-(~-nitrophenyl)propylamino]-ethylamino~-].3,3-tl-imethyl-'~ ~lH,3H'~-2~2~-89 pynimidinedione 91. 6-{2-[N-(2-hydroxYethy~ nitrophenyl~-- proprlamino3eth~1amino~-].3.~-trimethyl-~.4-(lH.3H)-pyrimidinedione 92. 1.3-dimethy]-6-~?-[~'-(ethyl-3-('4-nitrophenyl!-proDylamino3ethylamino~-5-nltro-2.~(lH.3H)-pyrimidinedione 93. 1.3-dimethYl-6-{2-~-(Z-hYdroxyethyl)-3-~4-nitrophenyl~propylamino]ethylamino~-5-nitro-2,4(1H,3H~-pyrimidinedione 9~. 1,3-dimethyl-6-{2-~N-~methoxycal-bonylmethyl ! -3- ( 4-nitrophenyl)propylamino]ethylamino3-5-cyano-2,~(1H,3H)-pyrimid.inedione ' 95. 1,3-dimethyl-6-f2-~N-~2-hydroxyethyl)-3-(~-nitrophenyl)propylamino3ethylamino~-v-cyano-2.~(lH.3H)-pyrimidinedi~ne 96. 1.3-dimethyl-6-~2-~ -nitlophenyl!hutylamin~
ethylamino~-2.~1H.3H)-pyrimidin~dione g~. 6-(~i-ethyl-~i<~-[~-(4-nitrophenyl)butylam~no3-ethyl>amino3-1.3-dimethvl-2.~1H.3H,-pyrimidinedione 98. l.3-dimethyl-6-s~'-(2-hydroxyethYl)-2 ~-nitrophen~l)butylamino3ethYlamino~-2.
IlH,3H)-pyrimidinedione 99. l,3-dimethyl-6-~'-methoxycarbonylmethyl-2-~ -nitrophenyl)~utylamino]ethylamino~-2.~'1H.3H!-pyrimidinedione 100. 1.3-dim~thvl-~-~2-[N-ethY~ -nitrophen~
butylamino]ethylamino)-~2.i(~1H~3H!-pyl-imidinedione 101. l,3-dimethyl-6-(2-[N-(tert-butyl)-4-(4-nitrQphenyl)-butylamino~ethylamino~-2~4(lH.3H!-pyl-imidinedinne 102. 1,3-dimethyl-6-~2-[N-i2-hydroxyethyl)-4-(4-nitrophenyl)butylamino~ethylamino'~-2~4(1H,3H)-pyrimidinedione 103. 1,3-dimethyl-6-{2-tN-('3-hrdroxypropyl~-4-~4-nitrophenyl)butylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione 104. 1,3-dimethyl-6-{2-CN-~'2-acetnxyethyl')-4-(4-nitrophenyhl'~butylamino]ethylamino~-2.~(1H.3H!-pyrimidinedione 10~. 1.3-dimethyl-6-~2-[r3-~2-methoxyethy]~-4-(4-nitrnDhenvl)hutylamino~ethylamino'~-7.4tlH.:~H)-pyrimidinedione 106. 1~3-dimethyl-6-~2-tN-benzyl-4-(4-nitr-~)phen-il~-butylamino]ethylamino~-2~4~1H~3H!-pyrimidinedione 107. 1,3-dimethyl-6-~2-rl~-allyl-4-('4-nitrophenyl)-butylamino]ethylamino~-2,4<'IH,3H)-pyrimidinedione 108. 1,3-dimethyl-6-~2-[N-ethoxycarbonylmethyl-4-(4-nitrophenyl)blltylamino]ethylamino~-2.4-(IH,3H)-pyrimidinedi-~ne 109 . I .3-dimethYl-6-~i-methyl-2-tN-methy~
nitr~phenyl!butylamino~ethyl~mino~ .4-slH~3H)-pyrimidinedione 1l~). 1,3-dimethyl-6-{2-CN-t~-('N.~-d iethylamino~ethyl~-4-(4-nitrophenyl)butylamino>ethylamino~-2.4(IH~3H)-pyrimidinedione 111. 1,3-dimethyl-6-{4-t4-(4-nitrophenyl')butyl]-piperazin-l-yl~-2,4(1H,3H)-pyrimidinedione 112. 6-{2-tN-ethyl-4-14-nitrophenyl)butylamino]-ethylamino~-1,3,5-tlimethyl-2,4(1H,3H~-pyrimidinedione 113. 1,3-dimethyl-6-(2-t2-('4-nitrophenoxy!-ethylamino]ethylamino-~.~(IH.3H)-pyrimidinedione . l,3-dimethyl-6-~-ethyl-~-t2-(~-nitroiphenoxy~-ethylamino~ethylamino'~-2.4t;H~3H~-pvl-imidinedinne 11~. 1.3-dimethy]-6-t4-t2-(4-nitl-ophenoxy!ethyl3-piperazin-1-vl'~-7~/lH.;lHj-pvrimidinedlone l16. 1.3-dimethyl-6-{2-[3-(~-nltroDhenox~!propYl-amino]ethylamino~-2~/lH,3H~-pyrimidinedione 11/. 1,3-dimethyl-6-~ thyl- -t3-~4-nitroPhen~xv ! -propylamino]ethylamino~-2,~l1H,3H~-pyrimidinedione 118. 1,3-dimethyl-6-{2-tN-ethyl-3-(~-nitrophenoxy)-propylamino]ethylamino~ (lH,3H)-pyrimidinedione 119. 1,3-dimethyl-6-{2-[.N-(2-hydroxyethyl)-3-(4-nitrophenoxy)~ropYlamino]ethylaminh~-2~ H~3H) pyrimidinedione -Z~1389 -?(~ dimethvl-6-~ J-~c~t~ xY~thyl ~
nitrophen(xy~propylamino~thYlamin("-J ~;IH.1H!-pyrimidinedione 121. 1.3-dimethyl-6-~N-methyl-2-[N-methyl-3-~-nitrophenoxy~propylamino]ethylamino~-2.~(IH,3H)-pyrimidinedione 122. I,3-dimethyl-6-~-t3-~4-nitrophenboxy)proeyl]-piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione 123. 3-methyl-6-{~-[3-(4-nitrophenoxy)propyl]-piperazin-1-yl~-2,~(1H.-3H)-pyrimidinedjone 12~. 1,3-dimethyl-6-~4-[3-('3-nitrophenoxy)propyl~-piperazin-l-yl~-,.4~1H.3H!-~yrimidinedione 125. 1.3-dimethyl-6-~4-~3-~2-nitrophenoxY~propyl]-piperazin-l-~ -2.~(1H,~ -pyrimldlnedione I26. 1.3-dimethyl-6-~2-~t-~-nitrophennxy)bllt l~mino3 ethylalr,ino~-c.~(~]H~3H!-pyrilr,idine(iione 127. 1.3-dimethyl-~-~N'-methyl-2~N-methvl-~-(~-nitrophenoxy!buty]aminc!~ethvlaminc~ 5~(1H.3H~-pyrimidinedione 128. 1,3-dimethyl-6-{~-~4-(4-nitrophenoxv~butyl~-piperazin-I-yl~-2,~(IH,3H)-pyrimidinedione 129. ~,3-dimethyl-6-~2-[N-ethyl-2-(4-nitr-)phenylthic~-ethylamino]ethylamino'~-2,~(IH,3H)-pyrimidinedione 130. 1,3-dimethyl-6-~2-~N-(2-hYdrox~ethyl)-3-l~-nitrophenylthio)proDylamino]ethylamino~-2.~-~H..~H~-pyrimidinedione Z~ 89 131. 1,~-dimethyl-6-i4-[3-~4-nitl-o~henYlthio)DIop~l]-piperazin-l-yl~-2,~1H.3H'-pyrimidinedinne 132. 1.3-dimethyl-6-{N-methyl-'~-t~i-methvl-~-(4-nitrophenylthioibutylamino]ethYl~min 2,~( 1H.3H~-pyrimid.inedinne 133. 1,3-dimethy]-6-t~-(4-nitrophenacyl)piperazin-1-y1~- -2,~(1H,3H)-pyrimidinedi d ne 134. 1,3-dimethyl-6-~-r5-~4-nitrobenzoyl~ethyl]-Diperazin-1-yl~ (lH,3H)-pYrimidinedione 135. 1,3-dimethyl-6-{N-methyl-5- tN-methYl-4-(4-nitrophenylthio~butylamino]ethvlaminn~-2.4-(lH,3H)-pyrimidinedione 136. 1,3-dimethyl-6-{4-t.5-hydroxy-2-(~-nitrophenyl)-ethyl]piperazin-l-yl~-2,~1H.3H~-pyrimidinedione 13~. 1,3-dimethyl-6-{1-t2--~-nitrnbenzoyl.~xy~ethvl3-piperazin-l-yl3-2.~(1H~3H~-p~l~imidinedione 138. 1,3-dimethyl-fi-~2-[N-ethvl-~ -nitrQbenzoylnxy)-propylamino~ethylamin~ .4(~H~3H?-pyl-in,idinedinne 139. 1.3-dimethyl-6-t2-~-ni t ioben~o~laminn)-ethylaminn~-2.4~1H.;~H ! -p~rimidinedione 140. 1,3-dimethyl-6-{4-[~-~4-nitrobenzoylaminoi-ethy]~piperazin-1-yl~-2.4('1H.3H)-pyrimidinedione 1~1. 1,3-dimethyl-6-~4-tN-~4-nitroDhenyl)carbamoyl-methyl~piperazin-1-yl}-2 4(1H,3H)-pyrimidinedione 142. 1,3-dimethyl-fi-{4-t~-(4-nitrophenyl~-carhamoylethyl~homopipel-azin-1-yl~ (lH.3H!-ZCli~)~3~9 pvrimidinedione 1~3. 1,3-dimethyl-~ -[3-~-nitroanilino~-2-hydroxypropyl~piperazin-1-yl~-2.4(1H.3H!-pyrimidinedione ]44. ~,3-dimethyl-6-~4-<4-tN-(~-nitrophenyl)-carbamoyl]butyl>piperazin-l-yl~-2,~(lH.3H)- -pyrimidinedione 145. 1,3-dimethyl-6-~N-methyl-2-[N-methyl-2-(4-nitroanilino)ethylamino~ethylamino~-2.~(1H,3H)-pyrimidinedione 146. 1 ,-.~-dimethyl-6-~ lethyl-'~-rN-~2-hyd~ xyet~yl !-2-~-nitroanillno~ethvlamino]ethylamin 2.4~1H.3H)-pyrimidinedic~ne -; li7. 1.3-dimethyl-6-~-[~-eth 1-2-~-nitroanilino)-ethylaminc~ethylamin-,i-2.4~1H.3H!-p.vrimidinedi-,ne l~x. 1,3-dimethyl-6-~.3-[N-propyl-2-1~-nitroanilino'j-ethylamino~propylamincl}-2.4~1H.3H~-pyrimidinediclne 1~9. 1,3-dimethyl-6-~-methvl-2-[~'-methyl-2-(N-methyl-4-nitroanilino)ethy]aminc]ethylamino'~-- 2,~11H,3H)-pyrimidinedione 15~ 3-dimethyl-6-~N-methYl-3-tN-methyl-2-(4-nitroanilino')ethylamino~propylamino~-2,~-(1H,3H)-pyrimidinedione 151. 1,3-dimethyl-6-~2-t.N-ethYl-3-~-nitroanilino)-propylamino]ethYlamino~-2~ H.;:;Hl-ovl imidinedi-~ne 1.-,2. 1.3-dimethyl-fi-~2-[.N-~2-hdvrox-~ethyl~-;3~
2~3~1389 nitroanilino)propylamino]propylamino~-2.4(1H.3H)-pyl-imidinedione 1.~3. 1,3-dimethyl-6-{2-tN-methoxycarbonylmethyl-3-(4-nitroanilino)propylamino~ethYlamino~-2~4(lH~3H!
pyrimidinedione 154. '1,3-dimethyl-6-~4-[3-(4-nitroanilino')propyl]- --piperazin-l-yl~-2,4('1H,3H)-pyrimidinedione 15~. 1,3-dimethyl-6-{4-t3-(N-methyl-4-nitroanilino~-propyl]piperazin-1-yl~-2,4(1H,3H~-pyrimidinedione 156. 1,3-dimethyl-6-{4-t3-(N-propyl-4-nitroanilinc~-propyl]piperazin-l-yl)-~s4(IH,3H)-pyrimid.inedione 1~. 1,3-dimethyl-6-{4-[3-('N-methanesulfonyl-4-nitro-anilino~propyl]piperazin-l-Yl~-2~4(lH~3H) pyrimidinedione 1~8. 1.3-dimethyl-6-~4-[3-iN-ethaneslllfonYl-4-nitroanilinn'.~Dropyl]piperazin-1-vl-~-2.~(1H.3H!-pyrimidinedione 1~. l,3-dim~thyl-6-~-t3-(N-acetyl-~-nitroanilino!-propyl]piperazin-1-yl~-~.4~1H.3H)-pyl-imidinedione 160. I,3-d.imethyl-6-~4-[3-lN-propionyl-~-nitroanilino)-propyl~piperazin-l-yl~-2,4('1Ht3H3-pyrimidinedic)ne Ifil. 1,3-dimethyl-6-~2-<[1-(4-nitrophenyl)piperidine-~-yl ]amino>ethylamino~-2,4('1H,~H)-pyl-imidinedione 162 1,3-dimethyl-6-~.2-t4-(~-nitrophenylJpiperazin-]-yl ]eth,vlamino~-2,~(1H.3H!-Dyrimidinedione - 2~13~39 163. 1,3-dimethYl-6-{3-[~ -nitr()Dhenyl)piperazin yl ]propylamino~-2,4(1H,3H3-pYrimidinedione 164. 1,3-dimethyl-6-~N-(2-hydroxyethyl)-~(4-nitrophenyl)piperazin-1-yl~-ethylamino~-2,4(1H,3H)-pyrimidinedione 165. 1,3-dimethyl-6-~N-methyl-2-[4-(~-nitroDhenyl)-piperazin-l-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione 166. 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrnphenyl)-propyl]piperazin-1-yl~-2.~]H.3H)-~Yrimidinedic!ne I67. 1~3-dlmethyl-6-~-tN-eth~ -benz~vl-i-nitrnphenyl!ethylamino~ethylaminoJ-2~4(1H,3H!-pyrimidinedione 168. 1,3-dimethyl-6-t4-(3-acetyl-1-nitroiDhenyl~-piperazin-l-yl]-~2,J~lH,3H~-pyrimidinedione 169. 1,3-dimethyl-6-{4-t1-~-acetyl-~-nitrophenoxy)-butyl]piperazin-l-yl~-2,i~lH,3H)-~yrimidinedione 170. 1-methyl-6-~4-[3-(2-acetyl-4-nitrophenoxy~-propyl]piperazin-l-yl~-2,~(1H,3H~-pyrimidinedione 1~1. 1,3-dimethyl-6-{~-<3-t2-nitro-4-( -pyridinecarbonyl)phennxy]propyl>piperazin-l-yl~-2.~1H.3H!-pyrimidinedi~ne 172. 1.3-dimethyl-6-(~-[N-~2-hdvrnxyethyl)-3-~4-benzoyl-2-nitl-~phenoxy~pl(lpyl~min(~
ethylamin~-2.~1H.3H)-Dvrimidinedlnne 173. 1 3-dimethyl-6-~-[3-~ cetYi-~-nitroanilin 2~13~39 propyl]piperazin-l-yl}-2,~(1H.3H)-pyrimidinedione 174. 1,3-dimethyl-6-{~-~3-('2-cyclopentanecarbonyl-4-nitroanilino)propyl]piperazin-l-yl~-2.~(1H,3H)-pyrimidinedione 175~ 1,3-dimethyl-6-~4-<3-~2-~2-chlorobenzoyl)-4-nitroanilino]propyl>piperazin-1-yl~-~.4- -(IH,3H)-pyrimidinedione 176. 1.3-dimethyl-6-~4-<3-[2-(~-~yridinecarbonyl !-4-nitroanilino~propyl>piperazin-l-yl~-2~ H.3H) pyrimidinedione 1~7. 1.3-dimethyl-6-~4-<3-~2-'~-pvridinecarb~nyl)-4-nitroanilino3propyl>pipel-azin-1-vl~-2,~1H,3H)-pyrimidinedione 1~8~ 1,3-dimethyl-6-~4-[3-14-acetyl-~-nitroanilino3-propyl]piperazin-l-yl~-2,~lH.3H)-pYrimidinedione 179. 1,3-dimethyl-6-~4-t3-(4-propanoyl-~-nitroanilino~propyl]piperazin-l-yl'~-2~-(1H,3H)-pyrimidinedione 18~. 1,3-dimethyl-6-~1-t3-~4-benzoyl-2-nitroanilino)-propyl~piperazin-1-yl~-~.1(1H.3H'I-nyl-imidinedione 181. 1,3-dimethyl-6-i~-~3-~'3-acetyl-~-nitroanilino~-propyl]piperazin-l-yl~ (1H.3H~-~yt~imidinedione 182. 1.3-dimethyl-6-~-[3-~-acetyl-~-nitroanilinoj-propylamino~ethylaminc~-2.~(1H.3H;-pvrimidinedione 183. l~3-dimethyl-6-~3-~N-'''-h-~dr-lxvethyl)-3-~-propanoyl-~-nitl-nanilino!nl-nDylamln(~-2~C)1;~89 pro~ylamino~-2.~1H.3H)-Dyrimidinedione l84. l.3-dimethyl-6-~4-t3-(2-ben,oyl-~-nitro~nilino~-propyl]piDerazin-l-yl~-~,4~1H.-3H~-~yrimidinedione 18~. 3-methyl-6-~4-t3-(2-benzoyl-~-ni troani ] ino!-propyl~piperazin-1-yl~-~,451H.3Hl-pyrimidinedione J86. 1t3-dimethyl-6-{N-ethy]-2-t3-(~-fol-myl-~-nitroanilino~propylamino]ethylamino~-2.~1H,3H)-pyrimidinedicne 187. 1,3-dimethyl-6-{~-[3-~3-fluoro-~-nitrophenoxy~-propyl~piperazin-l-yl~-2.~(lH~3H!-pyl-imidinedione 188 . I, 3-dimethyl-~-{~-[3-(3-fluoro-~-nitroanilino)-propy]~piperazin-1-yl~-2,1(1H.3H~-pyrimidinedione 189. 1,3-dimethyl-6-~4-t3-(3,5-difluoro-~-nitroDhenoxy)-; propyl]piperazin-l-yl~-2,~1H.3H)-pyrimidinedione 190. It3-dimethyl-6-~4-[3-~3.5-difluol-(?-~-nitr-lanilino)-propyl~niperazin-]-yli-2.~1H.3H~-D~.t~ ]dinedione 191. 1.3-dimethyl-6-~-t3~ -fluorn-~-nltroanilino~-propyl~piperazin-l-yl~-2.~(lH.~H!-Dyl-imidinedione 19~. 1,3-dimethyl-6-1~-[3-~2-methl-1xy-~-ni troDhenoxy~-propylamino~ethylamino~-2.~1H.3H.-Dyl-imidinedione 193. 1.3-dimethyl-6-~3-[~-ethyl-3-(3-tl-ifluoromethyl-~-nitroanilino)propylamino~pl-opylamino~-2~4(lH.3H) pyrimidinedione 194. ~,3-dimethyl-6-~2-t4-(2-acetyloxy-4-nitro-phenoxy)butylamino]ethylamino~ (IH,3H)-pyrimidinedione 2~)1389 195. 1,3-dimethyl-6-{4-~3-(2-dimethylamino-~-nitroanilino)propyl~homopiperazin-1-yl}-2,~(1H,3H)-pyrimidinedione 196. ],3-dimethyl-6-~2-[2-(2-diethylamino-4-nit anilino)ethylamino]ethylamino~-2,4(lH,3H)-pyrimidinedione 197. 3-methyl-6-~2-[3-~'2-hydroxy-4-nitrophenoxy)-propylamino~ethylamino~-2~4~1H,3H?-pyrimidinedione 1~8. l-ethYl-6-i4-[3-(2-brtmo-~-nitroanilino !-propyl~piperazin-1-yl~ 1H.3H)-pyrimidinedione I99. 6-{4-[2-{2-ethyl-~-nitroanilino)ethylamino]-piperazin-1-yl~-5,~1H,3H)-pyrimidinedione 200. 1,3-dimethyl-6-{~-[N-t3-fllloro-4-nitroiphenyl)-carbamoylmelthyl~piperazin-l-yl'~-2,4(1H,3H)--pyrimidinedione 1. I,3-dimethyl-6-{2-[3-t~-ethoxy-~-nitroDhenylthio~-propylamino~ethylamino}-2,~(1H.~H ! -pyl- i diminediorle . I,3-dimethyl-6-i~-t3-'2-ethaneslllfonamldo-4-nitrophenox~)propyl3piperazin-~-yl'~ -(1H.3H?-~yrimidinedione 203. 1,3-dimethyl-6-i4-[2-~'3-fluolc!-~-nitrophenYl~-ethyl]piperazin-l-yI'~ tlH.3H)-pyrimidinedione 20~. 1,3-dimethyl-6-~2-[N-ethyl-3-(3-fluoro-~-nitrophenyl)propYlamino]ethylamino}-~
2~8~389 ('lH.3H!-pyrimidinedione 205. 1.3-dimethYl-~-f3-~N-~?-hvdr-~xyethyl3-~-~3..~-dif]uaro-~-nitronhenyl!pl-opylamino~-propylamino~-2.~lH.3H)-pvrimidinedione 206. l.3-dimethyl-6-~2-rN-(~?-acetoxyethrl~-3-(2-dimethylamino-~-nitrophenyl)propylamino]-ethylamino~-2,4(1H,3H)-oyrimidinedione 207. 1,3-dimethyl-6-{2-[N-ethyl-3-~2-ethoxy-~-nitrnphenyl)propylamino]ethylamino}-2,4-(lH,3H)-pyrimidinedione 208. 1,3-dimethyl-6-~3- rN- (2-acetyloxrethyl !-3-(2-ethanesulfonamido-~-nitrophenyl)-proDylamino]proDylamino~-2.~(lH.3H~-pyrimidinedione .~
2~9. l,3-dimethyl-6-~ 3-methyl-~-nitrnbenzyl)-piperazin-1-y]]-2.~(1H.3H~-Dyl-imidinedione 210. 1,3-dimethyl-6-~J-[~ -hy~roxyethv~ /3-methoxy-~-nitrophen~ pl-oDYl~min~]ethylamino~-2,4-(lH,3H)-pyrimidinedione 21~. 1.3-dimethyl-6-~2-t.~-(3-ben~oyloxypl-opyl~-3-(2-ethoxycarbonyl-~-nitrophenyl;propylamino]-ethylamino~-2,~(~H ! 3H)-pyrimidinedione 212. 1,3-dimethyl-6-~-[3-(2-acetyl-~-nitrophenoxy)-propyl]piperazin-l-yl~-2,i~H.3H)-prrimidinedione 213. 1,3-dimethyl-6-~-[3-(~-acetyl-2-nitrophenoxy)-propyl~pipera7jn-1-yl}-2,~(1H,3H~-pyl-imidinedi~ne 21~. 1,3-dimethy~ -[3-~-benzoYl-?-nitrdphenoxyj-2(~ 9 pl'ODyl ]pipel-azin-l-YI~-2.~' lH.;3H~-plrrimi-linedillne 21~. 1.3-dimethyl-6-i~-[3-13-acetyl-4-nitl-ophen-xy~-propyl]piperazin-1-vl)-2.4(1H.3H)-pyrimidinedione 216. 1,3-dimethyl-6-~4-[3-~2-benzoy]-4-nitrophenoxy!-propyl]piperazin-l-yl~-2.~(1H,3H~-pyrimidinedione 217. 1,3-dimethyl-6-~4-<3-[2-(4-bromobenzoyl~-4-nitrophenoxy]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione 218. 1,3-dimethyl-6-{4-<3-t2-(3-pyrazolylcarbonyl)-4-nitrophenoxy]propyl>piperazin-l-yl~-2,4(1H.3H)-pyrimidinedione 2~9. 1,3-dimethy]-6-~-<3-[2-(;!-pyridineCalbonyl !-1-nitrophenboxy]propyl>piperazin-l-yl~ i lH.3H)-pyrimidinedione 220. 1,3-dimethyl-fi-~-<3-t2-t3-pvridinecalbon~ -4-nitrophenoxy~propyl>piperazin-l-yl~-2.~(1H 3H)-pyrimidinedione 221. l,3-dimethyl-6-~4-<3-tJ-(4-Dyridinecal-bonYli-4-nitrophenoxy]propyl>piperazin-1-yl~- ,4-(1H,3H~-pyrimidinedione 222. 1,3-dimethyl-6-~-<3-t2-(2-pyrimidinylcarhnnyl)-4-nitrophenoxy~propyl>piperazin-1-ylt-2.~ ,3H)-pyrimidinedione 223. 1,3-dimethyl-6-~-[2-(2-acetyl-4-nitrovhenoxy!-ethyl]piperazin-1-yl~-2,411H,3H)-pyrimidinedione 22~. 1,3-dimethyl-6-~-t -(2-benzoyl-4-nitloph~noxy~-26~11389 ethyl]piDel-azine-l.-vl'~-2.~1,H.3H)-pvl-imi(linedione 22~ . 1 . 3-d i me thyl -fi- ~ ~-< 2- [2- ( 4-bl ~lm~)henzoyl ! -~-nitrophenoxy~ethyl>piperazin-l-yl~ lH.3H)-pyrimidinedione 226. 1,3-dimethyl-6-~-[2-(3-acetyl-~-nitrophenyl)-ethyl~piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione 227. 1,3-dimethyl-6-{4-~2-~2-nitro-4-acetyl)ethyl]-piperazin-]-yl3-2,4('~H,3H)-pyrimidinedi~ne 228. 1,3-dimethyl-fi-14-t2-('2-nitro-4-benzoyl)-ethyl~piperazin-1-yl~-2,i(1 Hl 3H3-pyrimidinedione 229. 1,3-dimethyl-6~ 3-~2-(2-hydroxybenzoyl)-4-nitrophenox~propyl>r3ipe3-azin-l-yl~-2.4( IH. 3H'-pyrimidinedione 230. 1.3-dimethyl-6-~'4-<3-C2-(2-chlorobenzoyl)-4-nitrophenoxy]prop~l>piperazin-l-yl~
(lH.3H~-pvrimldinedlone 231. 1,3-dimethYl-b-~ i-[~-nitro-~pyridinecarbonyl!phenylthic~propyl>plpel-azin-1-yl}-2,1~1H,3H~-pyrimidinedione 23~. 3-methyl-6-~4-t3-~-nitro-2-benz~ylphen~,xy!-propyl]piperazin-l-yl~-2.4~1H,3H)-pyrimidinedione 233. 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitr~phenoxY~-propylamino~ethylamino~-2,1(1H,3H)-pyrimidinedione 234. 1,3-dimethYI-G-(2-[N-ethYI-~-14-benzc)YI-2-nitr~phenoxy)propylamino]ethYlamino-2 1 IH.3H)-pvl~lmidinedione 2~389 23.~. 1.3-dimethyl-6-f4-~ -benzovl-4-nitll-,phenylthi~
ethyl~ipel-azin-l-yl~-2.~1H.3H!-pyrimidinedi~ne 236. 1,3-dimethyl-6-~4-('2-benzoyl-4-nitrophenyl~-piperazin-]-yl]-2,4(1H,3H)-pyrimidinedione 237. l~3-dimethyl-6-~3-~-nitro-2-(3-pyridinecarbonyl)-phenylamino]propylamino~-2,4(1H,3H)-pyrimidinedi~ne 238. 1,3-dimethyl-6-[3-(2-benzoyl-4-nitrophenylamino)-propylamino~-2,4(1H,3H)-pyrimidinedione 239. 1,3-dimethyl-6-t2-~2-benzoyl-4-nitrophenylamino'~-ethylamino]-5,4(1H,3H!-~yrimidinedione 2~0. 1.3-dimethyl-6-~'2-[1-nitro-2-~3-pyridinecarbonyl)-phenylamino]ethylamino~-2.4(1H.3H!-pyrilrlidinedione 241. 1.3-dimethyl-6-~ 2-benzoYI-4-nitro~henyl!-ethyl3piperazin-1-yl~-2.4(1H.3H!-pyrimidinedirne 242. 1,~.j-dimethyl-6-s~-[r'2-ben~oyl-4-nitrophenyl)-methyl]piperazin-l-yl~-2,4(1H.3H~-pyl~imidinedione 243. 1,3-dimethyl-6-{2-~5'2-benzoyl-4-nitrnphenyl)-methylamino]ethylamino~-2,~(lH,3H)-pyrimidinedione 24~ -dimethyl-6-{4-~3-('~-benzoyl-~-nitrophenyl;-propyl]piperazin-1-yl~-2,4(1H.3H)-pyrimidinedione 245. 1,3-dimethyl-6-{4-t2-~'4-benzoyl-2-nitrophenyl)-ethyl]piperazin-l-yl~-2,4~'1H.3H)-pvlimidinedione 246. 1,3-dimethyl-6-{4-~3-(3-methyl-4-nitro~henyloxYl-propyl]piperazin-l-yl~-2.4(lH.3H~-pyl-imidinedione 247. 1.3-dimethyl-6-s'~-~3-(~-chloro-~-nitrsJphenvloxv)-propyl ~piperazin-l-Yl ~-2.4~1H.3H!-D~;rimidlne~ione -X(~
?~8. 1,3-dimethyl-6-~4-t3-t:2-chlor~ -nitro-phenyloxy)propyl]piperazin-l-~l}-2,4~1H.3H~-pyrimidinedione 249. 1,3-dimethyl-6-~4-t3-(4-methanesulfonamido-~-nitrophenyloxy)propyl~piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione 250. 1,3-dimethyl-6-~4-t3-(4-acetamido-2-nitro-phenyloxy)propyl]piperazin-l-yl~-~.4(1H.3H)-pyrimidinedione 251. 1,3-dimethyl-6-{4-[3-(2-hYdroxY-~-nitro-phenyloxy)propyl]piperazin- 1-YI ~ -2 . ~ ( I H. 3H) -pyrimidinedione 252. 1~3-dimethyl-6-~-[3-(2-allyloxy-5-nitro- ,--phenyloxy~pl-opyl]piperazin-1-yl3 -? . ~ lH.3H!-pyrimidinedione 253. 1,3-d.imethyl-6-~4-t3-(~-methylthio- -nitrophenyloxy:3propyl]piperazin-l-yl~-2,4(1H.3H)-pyrimidinedione 2~. I,3-dimethyl-6- {~-<3- t2-(~-hYdroxYbenzyl)-4-nitrophenyloxy]propyl>pipel-azin-1-~2,4(1H,~H)-pyrimidinedione 25~. ],3-dimethyl-6-~-t3-~3-trifluoromethyl-~-nitrophenyloxy)propyl]pipera7in-l-yl~
(1H.3H~-pyrimidinedione ?56. 1,3-dimethyl-6-~-[3-/~-m*thoxyearb/ln~JI-~-nitrophenylxoy!pl-opyl]pipel-aLin-1-yl~-2~11389 -~ lH.3H)-pyrimidinedione 257. 1,3-dimethyl-6-~4-~3-(2-carboxy-~-nitrophenyloxy~propyl~piperazin-I-yl~ IH,3H)-pyrimidinedione 258. 1,3-dimethyl-6-{4-t3-(2-amino-~-nitrophenylxoy~-propyl]piperadin-1-yl3-2,~(1H.3H)-pyrimidinedione 259. 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-~-nitrophenyloxy)propyl]piperazin-1-yl~-2.~(1H,3H~-pyrimidinedione 260. 1.3-dimethyl-6-~4-[3-(2-~yano-~-nitrophenvl--,xyi-prnpyl]piperazin-l-yl}-2,4(1H,3H)-py,imidinedione 261. 1.3-dimethyl-6-i4-t3-(2-cyano-1-nitrophenyiaminol-prr1pyl~pioel-azin-l-yl~-2.4(lH.3H!-pyrlmidinedione 2fi2. 1.3-dimethyl-6-{~-[3-52-chloro-~-nitrophenYl-amino)pl-opyl~piperazin-l-yl~-2.~(1H.3Hi-pyrimidinedione 263. 1,3-dimethyl-6-~ 3-(2-methoxy-5-nitrophenyloxy)-propyl]piperazin-l-yl~ 1H,3H3-pyrimidinedione 264. 1,3-dimethyl-6-~-[3-(2-allyloxy-4-nitro-phenyloxy)propyl~piperazin-]-yl~ IH.3H~-pyrimidinedione ~265. 1,3-dimethyl-6-~4-{3-(2-hydroxy-4-nitrophenyloxY
propyl ~pipel-azin-l-yl ~ (lH. ~1H3-pyrimidinedione 266. 1,3-dimethYl-6-~4-[3-l2-benzylamino-~-nitro~henyloxy~pl-oipyl3pipel~azin-l-~ lH.3H~-D y 1- imidinedione 2~a~1389 267. I,3-dimethyl-6-~ 3-lj-melthoxy-4-nitr-,phenyldxy~-propyl~piperazin-1-yl~-~,4(1H,~H)-pyrimidinedione 268. 1,3-dimethyl-6-~.~-[3-~2,6-dichloro-~-nitrophe-nyloxy)propyl]piperazin-]-yl}-2.~(1H,3H~-pyrimidinedione 2~389 As shown in the general formula (I) above, compounds of the present invention have a basic backbone in which the phenyl and pyrimidinedione parts are linked by a structure comprising mainly an alkyl chain containing at least two nitrogen atoms. This basic back bone structure is believed to be responsible for the pha~maceutical effects.
When the compounds shown by the general formula (1) above were applied to the fol~owing arrhythmia pathological models, all the compounds demonstrated efficacy.
I0 Atrial f ibrillation model Atrial fibrillation model animals were made according to the method of A. L. Goldberger et al. (lnternational lournal of Cardiology, 13, 47-55, 1986) by anesthetizing adult mongrel dogs with pentobarbital sodium (30 mg/kg, intravenously). Using these atrial fibrillation model animals, the effects of the compound5 of the present invention on the a~rial fibrillation model were investigated by administering the compounds intravenously at a dose of 0.1 -10 mg/kg. As a result, all Of the compounds according to the present invention were confirmed to have therapeutic effects on atrial f ibrillation.
Ventricular tachYcardia model Adult mongrel dogs were anesthetized with pentobarbital sodium (30 mg/kg, intravenously). A left thoracotomy was performed in the fourth intercostal space under artificial respiration, and the left anterior descending coronary 28~)1389 artery was ligated at the border of the atrial appendage.
The blood was recirculated for 1~0 minutes after the ligation so that an cardiac infarction lesion was formed to readily induce tachycardia in each animal.
Thereafter, the ventricular tachycardia model animals were made by inducing ventricular tachycardia according to the method of Lynch (~ournal of Cardiovascular Pharmacology, ~, 1132-1141, 1984).
Using these model animals, the compounds of the present invention were confirmed to have therapeutic effects on ventricular tachycardia when administered intravenously at a dose of 0.1 - 3 mg/kg.
The compounds according to the present invention have marked therapeutic effects on the arrhythmia pathology model, i.e. atrial fibrillation model and ventricular tachycardia model; thus they are useful for the treatment and prevention of arrhythmia.
Furthermore~ the effects of the compounds of the present invention on cardiac functions were experimentally investigated and the following results were obtained.
Mongrel dogs (body weights: 8 - 15 kg~ were anesthetized with pentobarbital sodium (30 mg~kg, intravenously~. A microsensor catheter was inserted through the common carotid artery into the left ventricle of each animal so that primary differential values (dp/dt~ of the inner pressure of the left ventricle and electrocardiograms Z~389 were recorded. The compounds of the present invention were administered intravenously to the dogs ~lmg/kg) and changes in the dp/dt and electrocardiograms were investigated.
As a result, it was revealed that the compounds of the present invention significantly increased the values of dp/dt max and significantly extended QTc on the electrocardiograms.
Consequently, the compounds according to the present invention were confirmed to have an antiarrythmic action and particularly to be useful as Class 111 type antiarrythmic agents. Furthermore, the significant increase in dp~dt max demonstrated that the compounds according to the present invention have a positive inotropic action and accordingly they are useful as therapeutic agents for cardiac insufficiency.
As mentioned above, in general, most of patients with arrhythmia have deficiency in cardiac functions. In the case where, for example, antiarrythmic agents classified in Class I or 1l are given to such patients, the greatest care has to be taken for use because these agents exert more or less antiarrythmic action as well as a negative inotropic action ~action to further repress cardiac functions3 (Eivind S. Platous, Journal of Cardiovascular Pharmacology, 8~3), 459, 1986).
On the contrary, as mentioned above~ the compounds according to the present invention t-ave a positive inotropic 2Q~1389 action to significantly increase the dp/dt max, as well as an antiarrythmic action. Accordingly, they are expected to provide satisfactory results to the patients with arrhythmia, whose cardiac functions are depressed.
Representative examples of processes for the production of the compounds of the general formula (1) according to the present invention will be demonstrated hereinafter; however, these examples are not to be construed to limit the scope of the invention Among the compounds of the general formula (1) described above, a compound of the following general formula (2) can be produced according to a method containing the following step (a).
15NO 2 R ' " X; o ~0- (CH2) K-N- (CH2) n N~' N-R4 x2 R3~ ~
...(2) [rn the formula (2), ~1 and R2 each independently represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower 2al~1389 alkyloxy g-;oup; a phenyl graup; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or Rl and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure; and Xl, X2, R2, R3, R4, k and n are defined as in the formula (1) .
Step (a~:
A compound of the following general formula (9) NOz ~ -OH (~) xi ~
XZ
~in which Xl and x2 are defined as in the general formula (1) above]
and a compound of the following general formula (10 X3 o H0- (CH2) k-N- (CHz) n--N ~N-R~ (lo N~
R3! o rin which R1 is defined as in the general formula (2) above and R2, R3, R4, X3, n and k are defined as in the general formula (1) above]
are allowed to react in the presence of a dehydratecondensing agent in a solution using an appropriate solvent or in a suspension usin~ an appropriate dispersing 2(~1389 agent (Application of Mitunobu reaction; 0. Mitunabu, Synthesis, 1-~8, ]981), thereby the compound of the general formula (2) above being obtained.
The reaction is carried out at or below the reflux temperature of the solvent or dispersing agent used for the reaction. For example, the temperature in the range -10 to 80~C is selected.
Examples of the dehydratecondensing agent to be used in this reaction include various dehydratecondensing agents used ordinarily for ether bond formation. Among them, mixed condensing agents of diethylazodicarboxylate and triphenylphosphine are preferably used.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to the reaction.
For example, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane or dioxane can be used.
Next, among the compounds of the general formula (1) above, a compound of the following general formula (4) can be produced according to a method containing the following step (b).
N0z Rl RzX O
~ A''-N-(CHz) n - N ~
rln the formula (4), A" repre.sents -B"-(C~2)k- or -N ~ , in which B" represents an oxygen or sulfur atom or Z0~13~9 -N- ;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or Rl and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
k represents an integral number, 2, 3 or 4; and Xl, X2, R1, R2, R3, R4, X3 and n are defined as in the formula ~I) above3.
Step (b):
A compound of the following general formula (11 NOz ~Y ~11) - X Z
[in which y2 represents a halogen atom and X1 and x2 are defined as in the general formula (I) above]
and a compound of the following general formula (12) Rl X3 0 201 1 ~ (12) HA~-N-(CH2) n - N ~ N-R4 N~
R3~ ~
[in which A is defined as in the general formula (4) above and Rl, R2, R3, R4, X3 and n are defined as in the general formula (1) above3 are allowed to react by mixing without a solvent, dissolving Z~1389 - ~5 -using an appropriate solvent or suspending using an appropriate dispersing agent, thereby the compound of the general formula (4) above being obtained.
The reaction is carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. ~or example, a temperature in the range between 20 - 150~C is preferably selected.
The reaction can be more preferably conducted in the presence of a base in the reaction mixture.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to this reaction. For example, alcohols such as methanol and ethanol, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, dioxane, benzene and dimethylsufonoxide can be used.
~ urthermore, examples of the base effective to facilitate this reaction include triethylamine, pyridine, potassium carbonate, sodium carbonate and sodium hydroxide.
Next, among the compounds of the general formula (1) above, a compound of the following general formula (3~ can be produced according to a method containing the following - step (c).
2a~ 389 NOz A -N- (CHz) n--N ~ON-R (3, X l x2 R3' ~
[In the formula (3), A' represents -(CH2)m-, -B'-(CH2)~- or ~ , in which B' represents an oxygen or sulfur atom IR
or -N-;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group (but does not form a heterocyclic structure with Rl );
m represents an integral number, 0, 1, 2, 3 or 4;
k represents an integral number~ 2, 3 or 4;
1~ R1 is defined as in the general formula (2) above; and R2, R3, R4, X1, X2. X3 and n are defined as in the general formula (1) above.
Step (c):
A compound of the following general formula (13) ~A -Y ' (13 X ' ~
x2 [in which y1 represents a halogen atom or a substituting groue that can be an eliminating group in the reaction with a compound of the general formula (14) helow, Xl and x2 are 2~01~89 defined as in the general f~rmula (I) above, and A' is defined as in the general formula (3) above]
and a compound of the following general formula ~14) HN - ( C H 2 ~ n--N ~1~ - R ~ ( 14 N~
R3' ~
[in which Rl is defined as in the general formula ~2~ above and R2, R3, R4, X3 and n are as defined in the general formula (1) above]
are allowed to react by mixing without a solvent, dissolving using an appropriate solvent or suspending using an appropriate dispersing agent, thereby the compound of the general formula {3) above being obtained.
The reaction is carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. For example. a temperature in the range between 20 and 170~C is preferably selected.
The reaction can be more preferably conducted in the presence of a base in the reaction mixture.
Any solvent or dispersing agent can be unlimitedly used for the reaction provided it is inactive to this reaction.
For example, any of those exemplified in the step (b) above can be used.
Furthermore, examples of the base effective to facilitate this reaction include those exemplified in the - 2(~)1389 - ~8 -step (b) above.
The compounds of the general formula (1) above can also be produced according to a method containing the fallowing step (d):
5A compound of the following general formula (15) NO2 Rl R2 ~A-N- (CH2) n~N~{ (15) Xl x2 [in which A, Xl, X2, R1, R2 and n are defined as in the general formula (1) above~
and a compound of the following general formula (16) X o Y3 ~ N-R~ (163 15N~
[in which Y3 is a halogen atom or a substituting group that t can be an eliminating group in the reaction with the compound of the general formula (15) above and R3, R4 and X3 are defined as in the general formula (1) above]
are allowed to react by mixing without a solvent, dissolving using an appropriate solvent or suspending using an appropriate dispersing agent, thereby the compound of the general formula (1) above being obtained The reaction can be earried out at a temperature in the range from room temperature to the reflux temperature of the z~al~ss reaction mixture. For example, a temperature in the range between 20 and 150~C is preferably selected.
The reaction can be more preferably conducted in the presence of a base in the reaction mixture.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to this reaction. For example, any of those exemplified in the step (b) above can be used.
Furthermore, examples of the base useful to facilitate this reaction include those exemplified in the step (b~
above.
Next, among the compounds of the general formula (1) above, a compound of the following general formula (5) can be produced according to a method containing the following step (e~.
~ A-N- (C ~ 2 ) Z- g ~ - Y ~
~In the formula (S), A represents -(CH2)m-, -B-(CH2)k-, -D-~CH2)1 ~ -N ~ or -NHCH2CH-CH2 , OH
F~S
wherein B represents an oxygen or sulfur atom, -N-, - Z~ 89 - so -o o o OH ~
Il 11 11 l 11 -CNH- or -CO- and ~ represents -NHC-, -CH- or -C-;
R represents a hydrogen atom, a lower alkyloxycarbonyl.
unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino. lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or may be so linked with R5 as to make an alkylene chain and thus . form a heterocyclic structure but not linked with any of other sites to form heterocyclic structure;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl grou~; and X1, X2, X3, R3 and R4 are defined as in the formula (1) above Step ~e):
A compound of the following general formula (17) N0z Rl' ~ A-NH
X' Xz [in which Xl and x2 are defined as in the general formula Z0~31389 (1~ above and A and Rl are defined as in the general formula (5) above]
and a compound of the folIowing general formula (18) ~N ~ N-R~ (18) N~
R3/ ~
~in which R3, ~4 and X3 are defined as in the general formula (1~ above]
are allowed to react hy mixing without a solvent, dissolving using an appropriate solvent or suseending using an appropriate dispersing agent, thereby the compound of the general formula (5) above being obtained.
The reaction is carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. For example, a temperature in the range between 20~C and 180~C is preferably selected.
Furthermore, the reaction can be more preferably conducted in the presence of an acid catalyst in the reaction mixture.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to this reaction. For example, any of those exemplified in the step (b) above can he used.
Furthermore, examples of the above-mentioned acid catalyst include p-toluenesulfonic acid and an acidic ion ~Cl 01389 exchange resin (for example, AmberlistR (Rhome and Haas, USA.
e.g., Amberlist 15R)).
Among the compounds of the general formula (I) above, a compound of the following general formula (7) can also be produced according to a method containing the following step ~f). I
N0z R'- R2,X 0 X~A-N- (CH2) n--N ~N-R4 X2 R3 ~
tln the formula (7), A represents -(CH2)m-, -B-(CH2)k-, -1~- (CH2 ) I -, - N~, or -NHCH2C~l-G~2-, OH
wherein B represents an oxygen or sulfur atom, -N-, O O O OH O
Il 11 1~ 1 ~I
-CNH- or -CO- and D represents -NHC-, -CH- or -C-;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated. Iower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl gro~lps may be substituted by a substituti-ng group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by ~ halogen atom or a lower alkyloxy group; a 2~1)1389 phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group; or Rl and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure; and Xl, X2, X3, R~, R4, m, k, I and n are defined as in the general formula ~1) above].
Step (f):
A compound of the general formula (17) above and a compound of the following general formula (19) RZ' ~~
Y~- (CHz) n--N ~ N-R~ (lg lS N~
R3' ~
[in the formula (19), R2 represents a hydrogen atom, a lower alkyloxycarbonyl, unsatnrated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkrloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl 2 ~ Q 1 ~ 8 9 . _ group~ and is not so linked with Rl' to form any heterocyclic ring;
R3, R4, X3 and n are defined as in the general formula ~1) above; and Y4 represents a halogen atom or a substituting group that can be an eliminating group in the reaction with a compound of the general formula (17) above]
are treated in the same manner as in the step (c) above, thereby the compound of the general formula ~7~ above being obtained.
Among the compounds of the general formula (1) above~ a compound of the following general formula (8) can also be produced according to a method containing the follo~ing step (g).
NO2 R"-- R2.X o ~A----N- ~CH2) n - N ~ -R4 (8) ( tin the formula (8), A"' represents -(CH2~m-, -B'-'-(CH2)k-, -D-(CH2)1-. - ~ or -NHCH2CH-CH2 ;
OH
5 ' O
B"' represents an oxygen or sulfur atom, -N-, -CNH- or -CO-;
~ Il 1 11 D represents -NHC-, -CH- or -C-;
~ .... .
2~)1389 R~ and R2 each independently reprosent a hydrogen atom. a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be replaced by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower 1"' alkyloxy group and a lower alkyloxycarbonyl group~, R
does not link to other sites including R2 or R5 ;
R is defined as in the general formula (3) above; and X1, X2, X3, A, R3, R4 and n are defined as in the formula (1) above].
Step (g):
A compound of the following general formula (20 20~A;" N- (CH z ) n--N ~ R- ~20 ) ~in w~ich A"' and R2 are defined as in the general formula (8) above; and X1, X2, X3, R3, R4 and n are defined as in the general formula (I) above]
and a compound of the following general formula (21) 251''' 4 (21) [in which Y4 represents a halogen atom or a substituting 2~1389 grollp that can be elîminated in the rea tion with a compound of the general formula (20) above and R is defined as in the general formula (8) above]
are treated in the same manner as in the step (c~ above;
thereby the compound of the general formula (8) above being obtained.
Further, for yl~ y3 and Y4 in the compounds to be used in the production steps above, examples of the substituting group that can be an eliminating group include arylsulfonyloxy group such as p-toluenesulfonyloxy group and alkylsulfonyloxy group such as methanesulfonyloxy group.
The relationships among Rl, Rl , Rl , Rl , R2, R- , R5 and R5 can be summarized as foLlows:
R may link to R2 or R5 as to form a heterocyclic structure. R
may link only to R5. Rl may link only to R2. R1 , R2 and R5 form no linkage, i.e., no heterocyclic structure with other sites.
R , R1 , R1 & R1 R2 & R2 and R5 & R5 are synonymously defined except their above relationshipS.
A compound of the general for~ula (18) above can be produced according to a method containing the following step (h).
Step (h):
A compound of the general formula (16) above and 2-aminoethanol are treated in the same manner as in the step (d) above so that a comPound of the following general formula (22) can be prePared.
Z(~ 389 .
Xj~J~N R~
HocH2-cH2-NH~N~o (2-~ ) [In the formula (21), X3, ~3 and R~ are defined as in the general formula (I) above].
The resultant compound is either sulfonated using methanesulfonyl chloride, p-toluenesulfonyl chloride or the like, or halogenized using thionyl chloride or phosphorus tribromide. The compound thus obtained is mixed in the presence of a base such as sodium hydroxide or sodium hydride and in a solvent such as acetonitrile, chloroform, benzene dimethylsulfonoxide and methanol at room temperature 15 or under heating, thereby a compound of the general formula ~18) above being obtained.
A pharmaceutically acceptable acid addition salt of a compound of the general formula (1) above can be produced by allowing the compound of the general formula (1) above to react in w~ter or an organic solvent or the mixture thereof, for example, with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid, oxalic acid or methanesulfonic acid.
~hen the compounds of the general formula (1) above according to the present invention and the acid addition Z~1389 salts thereof are used as a theraPeUtiC agent to treat patients with cardiac malfunctions such as arrhythmia and cardiac insufficiency, the amount and form of doses are different depending on the properties of the compound of the present invention to be used as an active ingredient and on the symptoms of the patients to be treated. ~or example, the amount in the range from 10 to 1,000 mg/day, preferably lO -500 mg/day for an adult can be orally administered in forms such as tablets, granules, powders, suspensions and capsules, or parenterally in forms of depositories, injections, fluids for infusion, inhalations or plasters. Daily doses by injection for adults, in particular phleboclysis, may range from 1 - 1,000 mg, preferably 1 - 300 mg.
General processes for producing pharmaceutical compositions of the present invention include a method in which the compound o~ the present invention is dissolved in an appropriate amount in an oil selected from the group consisting of cotton seed oil, corn oil, peanut oil, olive oil and the like so as to prepare non-aqueous injections; a method in which the compound of the present invention is either suspended or emulsified in water in the presence of an appropriate surfactant so as to prepare aqueous injections; or a method in which the compound of the present invention is prepared in a tablet form ~y adding lactose, crystallized cellulose~ corn starch or the like and finally adding magnesium stearate. However, the pharmaceutical preparations of the present invention can be prepared by any ordinary method in ~ddition to the methods exemplified above.
2C~1389 Useful antiarrythmic agents, therapeutic agents for cardiac insufficiency can be provided by the compounds of the present invention.
The following Examples demanstrate the present invention more in detail; however, it should be understood that they are not intended to limit the invention.
X~1389 Example 1 Preparation of 1,3-dimethyl-6-[4-(4-nitrophenyl)pipera-zin-1-yl3-2,4(1H,3H)-pyrimidinedione (compound 1):
O
02N~F + HNJI~N-CH3 ~ 0 (compound 2)-CH~
> o2N-~-~I4~N-CH3 (compound 1) CH3 In the first place, 0.36 ml of 4-fluoronitrobenzene, 1 g of sodium bicarbonate and 0.5 g of 1,3-dimethyl-6-(piperazin-1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) were added to 5 ml of dimethyl sulfoxide, and reaction was then performed at 100~C for 3 hours. Afterward, the reaction mixture was poured into 50 ml of water and was then extracted with chloroform.
Next, the chloroform extract was washed with water and was then dried over anhydrous magnesium sulfate, and the used solvent was distilled off under reduced pressure. The resulting residue was then purified with a silica gel column chromatograph (chloroform/methanol = 40:1 in terms of volume ~1389 - 61 _ ratio) in order to obtain 0.44 g of 1,3-dimethyl-6-[4-(4-nitrophenyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 1).
Analytical results of the resulting crystalline compound 1:
Melting point: 249-250~C
IR V KBrmax (cm~1): 1700, 1660, 1610, 1530 1340, 840 NMR (d6-DMSO), ~ppm: 8.13, 6.98 (dx2, 2Hx2), 5.23 (s, 1H), 3.23, 3.36 (Sx2, 3Hx2), 3.0 (m, 8H) Values of elemental analysis (as C16H19NsO4) Calcd. (%): C 55.65; H 5.55; N 20.28 Found (%): C 55.34; H 5.76; N 20.46 Example 2 Preparation of 1,3-dimethyl-6-[4-(4-nitrobenzyl)pipera-zine-1-yl]-2,4(1H,3H)-pyrimidinedione oxalate (compound 3):
H ~-~~ C H 3 ( compound 2) ,N O
02 N~CH 2 Br (COOH) 2 /CH 3 OH
02 N~CH 2 N, N4~N-CH 3 (COOH) 2 (compound 3) C H 3 First, 0.48 g of 4-nitrobenzyl bromide, 0.5 g of 1,3-dimethyl-6-(piperazin -1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) and 0.5 ml of triethylamine were suspended in 5 ml of isopropanol, and the resulting suspension was then heated under reflux for 8 hours. Afterward, the used solvent was removed from the resulting reaction mixture by distillation under reduced pressure, and the residue was dissolved in chloroform and was then washed with water. The washed organic layer was dried over anhydrous sodium sulfate. Furthermore, the dried organic layer was subjected to distillation under reduced pressure so as to remove the solvent therefrom, and the residue was then purified through a silica gel column chromatograph (chloroformtmethanol =
50/1 to 20/1 in terms of volume ratio) in order to obtain 0.88 g of 1,3-dimethyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.6 (m, 2H), 3,0 (m, 2H), 3.22, 3.34 (Sx2, 3Hx2), 3.36 (S, 2H), 5.14 (S, 1H) ;~01389 7.55, 8.17 (dx2, 2Hx2) Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in an ordinary manner, thereby preparing 1,3-dimethyl-6-[4-(4-nitrobenzyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione oxalate (compound 3).
Analytical results of the crystalline compound 3 thus obtained:
Melting point: 211-212~C (decomposed) IR y KBrmax (cm~1): 2950, 1720, 1670, 1650 1620, 1520, 1360, 760 Values of elemental analysis [as C17H21N5~4-(C~~H)2]
Calcd. (%): C 50.78; H 5.16; N 15.58 Found (%): C 50.70; H 5.44; N 15.77 Example 3 Preparation of 1,3-dimethyl-6-{2-<N-ethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino~-2,4(1H,3H)-pyrimidine-dione hydrochloride (compound 4):
~ N-CH3 Cl ~ ~0 Cl-13 HOCH2CH2NH2 CH3~SO2Cl > >
- 64 _ -~ CHa ~ SOa~CH2CH2NH ~ ~ N-CH3 >
(compound 5) CH 3 NaH/DMSO N ~ ~~CHa > / N~o >
(Compound 6) CH3 02N ~ CH2CH2CH2NH HCl/CH30H
(compound 7) CH2CH3 ~
02N ~ CH2CH2CH2-N-CH2CH2NH y ~ -CH3 (compound 4) CH~
(1) Preparation of 1,3-dimethyl-6-[2-(p-toluenesulfo-nyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 5):
First, 35.0 g of 2-aminoethanol was heated up to 90~C
and then taken out from the oil bath, and 50.0 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione was added thereto, so that reaction was performed therebetween. In ~0~1389 this case, the addition was carried out at such a velocity that the reaction temperature was maintained in the range of 90 to 110~C. After completion of the addition, the reaction mixture was stirred for 10 minutes, and 300 ml of dioxane/-methanol (which was 10/1 in terms of volume ratio) was thenadded thereto. Afterward, the mixture was allowed to stand overnight. The resulting crystals were then washed with a small amount of dioxane, followed by drying to obtain 49.0 g of white crystals of 1,3-dimethyl-6-(2-hydroxyethylamino)-2,4(1H,3H)-pyrimidinedione.
Next, 200 ml of a pyridine suspension containing 49.0 g of the above-mentioned white crystals was cooled to -5~C, and 40.0 g of p-toluenesulfonyl chloride ~as then added thereto at such a velocity that the reaction temperature does not rise up to 5~C or more. In order for the suspen-sion of the reaction mixture to disappear completely, 51.0 g of p-toluenesulfonyl chloride was further used.
Moreover, the reaction mixture was then poured into 1.5 liters of ice water containing 70 g of potassium carbonate and was then allowed to stand overnight. The resulting crystals were collected by filtration, then washed with water, and dried under reduced pressure, thereby preparing 50.5 g of light yellow crystals of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 5).
Analytical results of the crystalline compound 5 thus obtained:
Melting point: 146.0-149.0~C
IR ~ KBrmax (cm~1): 3270, 1682, 1615, 1550, 1480, 1435, 1360, 1190, 1178, 1010, 903, 780 (2) Preparation of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6):
To 150 ml of an anhydrous dimethyl sulfoxide solution containing 47.2 g of the above prepared compound 5 was slowly added 6.24 g of sodium hydride (60% dispersion in mineral oil) at room temperature. The resulting liquid mixture was then stirred vigorously at ~oom temperature for 5 hours and was cooled, and a small amount of water was then added thereto in order to bring the reaction to an end.
Afterward, this mixture was poured into 1 liter of water containing 70 g of potassium carbonate and was then extracted with 200 ml of chloroform three times. The combined organic layers were then dried over anhydrous sodium sulfate and was concentrated, and 300 ml of ether was added to the resulting concentrate. Afterward, the mixture was allowed to stand overnight.
Light yellow crystals which had been deposited by the overnight standing were collected by filtration and were then washed with ether, followed by drying under reduced _ 67 -pressure to obtain 15.2 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6).
Analytical results of the crystalline compound 6 thus obtained:
Melting point: 126.0-126.5~C
IR ~ KBrmax (cm~1): 1705, 1650, 1612, 1470, 1440, 1305, 1160, 783, 490 H-NMR (CDCl3), ~ppm: 2.34 (s, 4H), 3.35 (s, 3H), 3.56 (s, 3H), 5.25 (s, 1H) (3) Preparation of 1,3-dimethyl-6-~2-<N-ethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)pyrimidine-dione hydrochloride (compound 4):
In 5 ml of chloroform were dissolved 1.28 g of N-ethyl-N-[3-(4-nitrophenyl)propyl]amine (compound 7) and 1.11 g of the above prepared 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6), and the resulting mixture was then concentrated under reduced pressure.
Afterward, 10 mg of Amberlist 15 (made by Rohm & Haas Co.) was added to the residue (concentrate), and the mixture was then heated at 80~C for 1 hour.
Next, the resulting reaction mixture was dissolved in 20 ml of ethyl acetate, and the Amberlist was removed therefrom by filtration. Afterward, 30 ml of n-hexane was added to the filtrate.
The solution was allowed to stand overnight, and the 20~1389 - 68 _ deposited light yellow crystals were then collected by filtration. After washing with ether, the crystals were dried under reduced pressure to obtain 2.20 g of 1,3-dimethyl-6- 2- N-ethyl-N-[3-(4-nitrophenyl)propyl]amino -ethylamino -2,4(1H,3H)-pyrimidinedione.
This product was further recrystallized from ethyl acetate and n-hexane, followed by filtering, washing and drying in order to obtain 1.85 g of light yellow crystals.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
IR ~ KBrmax (cm-1): 3310, 2940, 1692, 1620, 1600, 1545, 1515, 1345, 1205, 770, 755 1H-NMR (CDCl3), ~ppm: 1.07 (t, 3H, J=7.5 Hz), 1.90 (m, 2H), 2.17-3.27 (m, 10H), 3.37 (s, 3H), 3.44 (s, 3H), 4.90 (s, 1H), 5.64 (brs, 1H), 7.47 (m, 2H), 8.30 (m, 2H) Values of elemental analysis (as C1gH27NsO4) Calcd. (%): C 58.60; H 6.99; N 17.98 Found (%): C 58.61; H 7.41; N 17.57 Moreover, the light yellow crystals which had been recrystallized from ethyl acetate and n-hexane were treated with hydrochloric acid/methanol in a usual manner in order to obtain an amorphous powder of 1,3-dimethyl-6-{2-~N-ethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 4).
Analytical results of the amorphous powder of the compound 4:
IR V KBrmax (cm~1): 3450, 1705, 1608, 1513, 1345 Values of elemental analysis (as C1gH27NsO4 HCl) Calcd. (%): C 53.58; H 6.63; N 16.44; Cl 8.33 Found (%): C 53.11; H 6.81; N 16.12; Cl 7.95 Example 4 Preparation of 1,3-dimethyl-6-~2-~N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione fumarate (compound 8):
02N ~ CH2CH2CH20SO2 ~ CH3 ' CH2CH20H
> NO2 ~ CH2CH2CH2NH
(compound 9) ~
CH3 ~ S03CH2CH2NH ~ ~ N-CH3 (compound 5) C H3 >
~n ~ ~ ~ 8 9 _ 70 -(=CHCOOH)2 CH2CH20H ~
02N ~ CH2CH2CH2NCH2CH2NH ~ N-CH~
N~o (=CHCOOH)2 (compound 8) C H~ -(1) Preparation of N-(2-hydroxyethyl)-N-l3-(4-nitro-phenyl)propyl]amine (compound 9):
A mixture of 37.5 g of 3-(4-nitrophenyl)propyl p-toluene sulfonate, 125 g of aminoethanol and 65 ml of dioxane was heated with stirring at a temperature of 90 to 100~C for 3 hours. Thereafter, the used solvent was distilled off from the mixture under reduced pressure, and the residue was dissolved in 800 ml of chloroform and the solution was then washed with 1 liter of water. The washed ( organic layer was further washed with a 0.5 N sodium hydroxide solution and then with water, followed by drying over anhydrous sodium sulfate. The dried organic layer was then treated under reduced pressure to distill off the solvent therefrom, and the residue was recrystallized from benzene/hexane (which was 2/1 in terms of volume ratio).
The obtained crystals were collected by filtration, washed and dried, thereby preparing 21 g of N-(2-hydroxyethyl)-N-.~
~, ~,. -~ ~ Q 11 ~ 8 ~
[3-(4-nitrophenyl)propyl]amine (compound 9).
Analytical results of the crystalline compound 9 thus obtained:
Melting point: 80.5-81~C
(2) Preparation of 1,3-dimethyl-6-~2-<N-(2-hydroxy-ethyl)-N-[3-(4-nitrophenyl)propyl]amino)ethylamino}-2,4-(1H,3H)-pyrimidinedione fumarate (compound 8):
In 350 ml of methanol was dissolved 23.2 g of 1,3-dimethyl-6-[2-(p-tolllen~r~11fonyloxy)ethylamino]-2,4(lH,3H)-pyrimidinedione (compound 5) synthesized in Example 3-(1), and 2.76 g of sodium hydroxide was further added thereto slowly. The resulting mixture was stirred at a temperature of S0 to 60~C for 1 hour, and the solvent was then distilled off from the reaction mixture. Afterward, 120 ml of chloroform was added to the residue, and insoluble materials were removed by filtration therefrom. To the filtrate were added 17 g of N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]-( amine (compound 9) and 0.66 g of p-toluene-sulfonic acid, and the reaction mixture was then treated under reduced pressure to distill off the solvent therefrom. The solvent-free residue was heated and stirred at 80~C for 1 hour and was then dissolved in 480 ml of chloroform, and the reaction mixture was extracted twice with 300 ml of O.S N
hydrochloric acid. Afterward, potassium carbonate was added to the extract (hydrochloric acid solution) with the ,,~ .
ZO~)1389 - 72 _ intention of making the latter alkaline, and the liquid mixture was then stirred at room temperature for 1 hour.
The resulting crystals were then collected by filtration.
The crystals were dried, recrystallized from ethanol, collected by filtration, washed and dried in order to obtain 22.1 g of 1,3-dimethyl-6-~2-<N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amino>ethylamino~-2,4(1H,3H)-pyrimidine-dione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 117.5-118.5~C
H-NMR (CDCl3), ~ppm: 1.86 (m, 2H), 2.48-3.00 (m, 11H), 3.00-3.26 (m, 2H), 3.27 (s, 3H), 3.39 (s, 3H), 3.71 (m, 2H), 4.78 (s, 1H), 6.06 (m, 1H), 7.38 (d, 2H), 8.18 (d, 2H) This pyrimidinedione derivative was treated with a fumaric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)-propyl]amino)ethylamino}-2,4(1H,3H)-pyrimidinedione fumarate (compound 8).
Analytical results of the prepared crystalline compound 8:
Melting point: 152.5-153.5~C
IR ~ KBrmax (cm-1): 3400, 2960, 1700, 1630, 2001:~39 1600, 1555, 1520, 1450, 1355, 1250, 1070, 990, 780 3) Preparation of 1,3-dimethyl-6-~2-(N-(2-hydroxy-ethyl)-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4-(1H,3H)-pyrimidinedione hydrochloride (compund 8'):
1,3-Dimethyl-6-{2-<N-(2-hydroxyethyl)-N-[3-(4-nitro-phenyl)propyl]amino~ethylamino32,4(1H,3H)-pyrimidinedione (free from of compound 8) (2.6 g ) was dissolved in 26 ml methanol under heating and to the resulting solution was added 2.7 ml 13% (w/w) of HCl/methanol solution drop by drop, while the temperature of the mixture was maintained at 40~C.
The resulting mixture was cooled on ice and was left overnight. Crystals thus formed were collected by filtra-tion and dried in vacuum; thus, 1,3-dimethyl-6-{2-<N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amino~ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 8') was obtained.
Analytical results of the crystalline 8' thus obtained:
Melting point: 172-174~C
IR V KBrmax (cm-1): 3230, 1640, 1605, 1540, 1340, 1240 Example 5 Preparation of 1,3-dimethyl-6-{4-[2-(2-nitrophenyl)-2 ~ Q ~ 3 8 9 - 74 _ ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 10):
~ CH2CH20H ~ ~ cH2cH2Br ~2 . 02 (compound 11) ( HN ~ ~ ~ N-CH~
(compound 2) C H~ (COOH) 2 /CH~ON
O
~ CH2CH2 ~ ~ N-CH~
? '-~NO2 N ~ (COOH)2 (compound 10) CH~
(1) Preparation of 2-(2-nitrophenyl)ethyl bromide (compound 11):
( First, 2.5 ml of 2-(2-nitrophenyl)ethanol and 5.4 ml of PBr3 were mixed and stirred at 0~C for 30 minutes to perform reaction therebetween, and the resulting reaction mixture was diluted with 30 ml of benzene and was then poured into 30 ml of water. Afterward, the separated organic layer~was collected, dried over anhydrous sodium sulfate, and then treated under reduced pressure to distill off the solvent therefrom, thereby preparing 3 g of a crude product, ~ ' ;~
Z~1~1389 _ 75 -2-(2-nitrophenyl)ethyl bromide (compound 11).
(2) Preparation of 1,3-dimethyl-6-{4-[2-(2-nitro-phenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 10):
To 15 ml of isopropanol were added 3.0 g of the above prepared compound 11, 3.2 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) and 4.2 ml of triethylamine, and the resulting mixture was then treated by the same procedure as in Example 2 in order to obtain 2.2 g of 1,3-dimethyl-6-{4-[2-(2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.7-3.0 (m, 12H), 3.39 (s, 3H), 3.41 (s, 3H), 5.11 (s, 1H), 7.53 (m, 3H), 7.96 (m, 1H) Furthermore, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner, thereby preparing 1,3-dimethyl-6-{4-[2-(2-nitro-phenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 10).
Analytical results of the prepared crystalline compound 10:
Melting point: 212-214~C
Z~1389 Values of elemental analysis (as C18H23N5o4-(cOOH)2-2H2o) Calcd. (%): C 50.85; H 5.55; N 14.82 Found (~): C 50.57; H 5.54; N 14.44 IR ~ KBrmax (cm-1): 3050, 2940, 1720, 1680, 1630, 1550, 1380, 770 Example 6 Preparation of 1,3-dimethyl-6-[2-(4-nitroanilino)ethyl-amino]-2,4(1H,3H)-pyrimidinedione (compound 12):
02N ~ F + H2NCH2CH2NH ~ oN-CH3 (Compound 13) C H3 > 02N ~ -NHCH2CH2NH ~ ~ -CH3 (compound 12) C H3N
The same procedure as in Example 1 was repeated with the exception that 1,3-dimethyl-6-(piperazin-1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) was replaced with 0.45 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), in order to obtain 0.5 g of 1,3-dimethyl-6-[2-(4-nitroanilino)ethylamino]-2,4(1H,3H)-2~389 pyrimidinedione (compound 12).
Analytical results of the crystalline compound 12 thus obtained:
Melting point: 308~C (decomposed) IR ~ KBrmax (cm-1): 1690, 1660, 1600, 1550, 1320, 850 NMR (DMSO-d6), ~ppm: 2.9 (m, 2H), 3.1 (m, 2H), 3.29 (s, 3H), 3.38 (s, 3H), 5.09 (s, 1H), 7.04 (d, 2H), 8.09 (d, 2H) Values of elemental analysis (as C14H17NsO4) Calcd. (%): C 52.66; H 5.37; N 21.93 Found (%): C 52.55; H 5.34; N 21.82 Example 7 Preparation of 1,3-dimethyl-6-~4-[2-(4-nitrophenyl)-ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 14):
, ~ ~ 021~CH2CH2Br H ~ N ~ N-CH3 >
/~ 0 (compound 2) HCl/CH30H
>
- 78 _ -CH2CH2N ~ ~ -CH3 (compound 14) CH3 The same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide was replaced with 0.51 g of 4-nitrophenethyl bromide, in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrophenyl)ethyl]piperazin -1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.8 (m, 12H), 3.22 (s, 3H), 3.36 (s, 3H), 5.19 (s, 1H), 7.36 (d, 2H), 8.12 (d, 2H) Moreover, this pyrimidinedione derivative was treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[2-(4-nitrophenyl)ethyl]pipera-zin-1-yl~-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 14).
Analytical results of the crystalline compound 14 thus obtained:
Melting point: 263-266~C (decomposed) Values of elemental analysis tas C1gH23NsO4-HCl-0.5H2O) Calcd. (%): C 51.61; H 6.02; N 16.72; Cl 8.46 Found (%): C 51.78; H 6.28; N 16.93; Cl 8.60 IR V KBrmax (cm~1): 2950, 2500, 1700, 1690, 1630, 1520, 1350, 805 Example 8 Preparation of 1,3-dimethyl-6-[2-(4-nitrobenzylamino)-ethylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 15):
02N ~ -CH2Br + H2N-CH2CH2NH ~ N-CH3 (compound 13) CH3 (COOH)2/CH30H
> >
02N ~ CH2NHCH2CH2NH ~ N-CH3 N ~ n .(COOH)2 (compound 15) C H3 u The same procedure as in Example 2 was repeated with the exception that 1,3-dimethyl-6-(piperazin-1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) was replaced with - X~ 389 - 80 _ 0.45 g of 6-t2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), in order to obtain 1,3-dimethyl-6-[2-(4-nitrobenzylamino)ethylamino]-2,4(1H,3H)-pyrimidinedione.
Analytical results of the prepared pyrimidinedione derivative:
NMR (CDCl3:DMSO-d6=1:1), ~ppm: 2.9 (m, 2H), 3.2 (m, 2H), 3.30 (s, 3H), 3.38 (s, 3H), 3.60 (m, 2H), 5.07 (s, 1H), 7.42 (d, 2H), 8.06 (d, 2H) Moreover, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain crystals of 1,3-dimethyl-6-[2-(4-nitrobenzylamino)-ethylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 15).
Analytical results of the crystalline compound 15 thus obtained:
Melting point: 203-205~C (decomposed) IR V KBrmax (cm-1): 3150, 2900, 1710, 1650, 1640, 1630, 870 Values of elemental analysis [as C1sH19NsO4 (COoH)2~o 5H2o]
Calcd. (%): C 47.22; H 5.13; N 16.20 Found (%): C 47.04; H 4.40; N 16.61 Example 9 Preparation of 1,3-dimethyl-6-{2-[2-(4-nitrophenyl)-ethylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 16):
02N ~ CH2CH2Br_t H2NCH2CH2NH ~ N-CH~
(compound 13)C H~
(COOH)2/CH 3 OH
> >
02N ~ CH2CH2NHCH2CH2NH ~ \N-CH~ -(COmpound 16) ~N ~ ~ ~(COOH~2 The same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide and 1,3-dimethyl-6-piperazin -1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) were replaced with 0.51 g of 2-(4-nitrophenyl)ethyl bromide and 0.45 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), respectively, in order to obtain 1,3-dimethyl-6-{2-[2-(4-nitrophenyl)ethylamino]-ethylamino3-2,4(1H,3H)-pyrimidinedione.
-- 2~)13~9 Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.7-3.2 (m, 6H), 3.29 (s, 3H), 3.37 (s, 3H), 3.51 (t, 2H), 5.01 (s, 1H), 8.13 (d, 2H), 8.43 (d, 2H) Furthermore, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner, thereby preparing crystals of 1,3-dimethyl-6- 2-[2-(4-nitrophenyl)ethylamino]ethylamino -2,4(1H,3H)-pyrimidine-dione oxalate (compound 16).
Analytical results of the crystalline compound 16 thus obtained:
Melting point: 200-202~C (decomposed) Values of elemental analysis (as C16H21NsO4-(cOoH)2o2H2o) Calcd. (%): C 48.43; H 5.42; N 15.69 Found (%): C 48.52; H 5.16; N 16.25 IR KBrmax (cm-1): 3100, 2900, 1710, 1640, 1620, 1560, 1360, 850 Example 10 Preparation of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 17):
_ 83 -O CHaNHCH2CH2NHCH~
C1 ~ _~N-CH~
3 o CH~
CH~ ~
CH~NHCH2CH2N ~ N-CH~
( N ~ o (compound 18)C H~
O2N ~ CH2CH2CH2B r (COOH)2/CH~OH
CH3 CH3 ~
02N ~ CH2CH2CH2NCH2CH2N ~ N-CH3 ~ N ~ o (COOH)2 (compound 17) C H3 (1) Preparation of 1,3-dimethyl-6-{N-methyl-N-~2-(methylamino)ethyl]amino}-2,4(1H,3H)-pyrimidinedione (compound 18):
In 200 ml of chloroform were dissolved 50 g of N,N'-dimethylethylenediamine and 19.8 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione, and the reaction mixture was then heated with stirring under reflux for B
~ . . ..
--- 2~1389 - 84 _ 5 hours.
The reaction mixture was washed with water, and a separated organic layer was then dried over anhydrous sodium sulfate. Furthermore, the dried organic layer was treated under reduced pressure to distill off the solvent, and ether was then added to the resulting residue so as to deposit crystals. The latter were then collected by filtration, washed and dried in order to obtain 10 g of 1,3-dimethyl-6-{N-methyl-N-[2-(methylamino)ethyl]amino}-2,4(1H,3H)-pyridine-dione (compound 18).
Analytical results of the crystalline compound 18 thus obtained:
'! NMR (CDCl3), ~ppm: 2.7 (s, 3H), 2.5-3.3 (m, 4H), 3.25 (s, 3H), 3.3 (s, 3H), 3.33 (s, 3H), 5.25 (s, 1H) (2) Preparation of 1,3-dimethyl-6-~N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 17):
To 60 ml of isopropanol were added 5.0 g of the above compound 18, 5.5 g of 3-(4-nitrophenyl)propyl bromide and 6 ml of triethylamine, and the resuting mixture was then treated by the same procedure as in Example 2 in order to obtain 8.1 g of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione.
~1389 Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ,~ppm: 1.5-2.2 (m, 2H), 2.25 (s, 3H), 2.25-3.2 (m, 8H), 3.3 (s, 3H), 3.35 (s, 3H), 5.25 (s, 1H), 7.3 (d, 2H), 8.15 (d, 2H) Moreover, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain crystals of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1 H,3H)-pyrimidine-10 dione oxalate (compound 17).
Analytical results of the prepared crystalline compound 17:
Values of elemental analysis [as C1gH27NsO4-(cOoH)2]
Calcd. (%): C 52.60; H 6.10; N 14.61 Found (%): C 52.41; H 6.33; N 14.21 Example 11 The same procedure as in Example 3-(3) was repeated with the exception that N-ethyl-N-[3-(4-nitrophenyl)propyl]-20 amine (compound 7) was replaced with each amino compound in which the ethyl group portion (R1 ) and the number (m) of carbon atoms in an alkyl chain of the compound 7 were as shown in Table 1, in order to obtain compounds 19 to 24.
Physical properties of these compounds are set forth in ~5 Table 1.
-2~0~89 ~ _ _ ~
C~ ~D U~ O
~ ~ ~ O O ~
_z .. .. .. ..
~ _ _ _ _ ~ o <s~ U~ ~ ~ ~ ~
:~ ~C .. .. .. ..
_ _ o .. .. .. ..
O O ~ ~~ CJ', o , o o ~C
~ ~ In 0 0-1~ 0-1~ 00 ~ O
o~ ~ ~ ~ ~Z ~Z ~ Z ~ Z ~Z ~ Z
,Z =~ ~ ~ ~ ~~ ~ ~ I
1~ 0 ~ 0 0 00 0~ 0 C O~ C~
Z ~ ~,C~ _ C,,~ _C~ _C,) _ C~ _ O _ ---- ~~ t-- ~ o oIn ou~ 0 ~ a~
U
-- X' ' '~ ~o oIn o ~ ~ o ~ ~ o O ~ ~ ~ ~ ~ ~ 0 --.- --~
~ ~~ ~ ~ ~ ~ Q ~ Q
11 ~ _ _ o oo o ~ o ~ o o oo U~
O H~ ~ f'~
~n o o o U
~ ~n o o o C ~O ~
I
o In u~If) . . .
~ l ~
o z -N
U
S~ -~ O ~ O
C~ Z
g Example 12 Preparation of 1,3-dimethyl-6-{2-<N-ethyl-N-[3-(3-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidine-dione hydrochloride (compound 25):
C2HsNH2 ~ CH2CH2CH20SO2 ~ CH3 >
NOz CH3 ~ 03CHzCH2NH ~ N-CHs ~N ~ o (compound 5) C H3 HCl/CH 3 OH
>
~ CH2CH2CH2NCH2CH2NH ~ N-CH3 NO2 /N ~ o HCl (compound 25) C H3 The same procedure as in Example 4 was repeated with the exception that 37.5 g of 3-(3-nitrophenyl)propyl p-toluene sulfonate, 120 g of ethylamine and 188 g of 1,3-dimethyl-6-l2-(p-toluenesulfonyloxy)ethylamino-2,4-(1H,3H)-pyrimidinedione (compound 5) were used as starting ~0~1389 .
- 88 _ materials, in order to obtain crystals of 1,3-dimethyl-6-{2-<N-ethyl-N-[3-(3-nitrophenyl)propyl]amino> ethylamino3-2,4(1 H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
NMR (CDC13), ,~ppm: 1.00 (t, 3H), 1.6-2.0 (m, 2H),-2.4-2.8 (m, 8H), 2.9-3.1 (m, 2H), 3.2 (s, 3H), 3.3 (s, 3H), 4.75 (s, 1H), 5.5 (br, 1H), 7.3-7.4 (m, 2H), 7.8-8.0 (m, 2H) The thus obtained crystals were treated with a hydrochloric acid/methanol solution in an ordinary manner to obtain crystals of 1,3-dimethyl-6-{2-(N-ethyl-N-[3-(3-nitrophenyl)propyl]amino>ethylamino} -2,4(1 H,3H)-pyrimidine-dione hydrochloride (compound 25).
Analytical results of the crystalline compound 25 thus obtained:
Values of elemental analysis (as C1gH27NsO4-HCl) Calcd. (%): C 53.58; H 6.63; N 16.44; Cl 8.33 Found (%): C 53.02; H 6.79; N 16.01; Cl 7.98 Example 13 Preparation of 1,3-dimethyl-6-~N-ethyl-N-~2-[4-(4-nitro-phenyl)butylamino]ethyl>amino~ -2,4(1 H,3H)-pyrimidinedione oxalate (compound 26):
20~ 89 _ 89 -~ HOCH2CH2NHC2Hs Cl ~ N-CH3 >
/N
C,2 H s ~' HOCH 2 CH 2 N ~ N-CH 3 /N~o (compound 27)CH3 ~ H
>
1 s ~ N C H 2 G H ~ N ~ON- G H a ~ ~ o (compound 29) ~ CH3 >
C~2Hs ~
NH2CH2CH2N ~ /N-CH 3 /N~o (compound 28) CH 3 - Z6)~ 89 02N ~ -(CH2)3CH0 NaBH4 (COOH)2/CH3OH
> > . >
C2H5 ~
02N ~ (CH2)4-NHCH2CH2~ ~ N-CH3 (compound 26) C~ ~ ~ ~(CO2H)2 (1) Preparation of 1,3-dimethyl -6-[ N-ethyl-N-( 2-hydroxyethyl)amino]-2,4(1H,3H)-pyrimidinedione (compound 27):
Up to 100~C, 11 g of N-ethylaminoethanol was heated, and while the above temperature was maintained, 10 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione was added thereto little by little.
The reaction mixture was heated at the same temperature for 1 hour, and 100 ml of dioxane was then added thereto, ~ollowed by stirring under ice cooling for 1 hour.
The crystals deposited by the above stirring were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Afterward, the residue (concentrate) was purified through a silica gel column chromatograph (ethyl acetate/methanol = 20/1 in terms of volume ratio) to obtain 7.2 g of 1,3-dimethyl-6-[N-ethyl-N-( 2 -hydroxyethyl)amino]-2,4(1H,3H)-pyrimidinedione -2~)1389 (compound 27).
Analytical results of the compound 27 thus obtained:
NMR (CDCl3), ,~ppm: 1.15 (t, 3H), 3.0-3.3 (m, 4H), 3.3 (s, 3H), 3.4 (s, 3H), 3.6-3.9 (m, 2H), 5.35 (s, 1H) (2) Preparation of 1,3-dimethyl-6-[N-ethyl-N-(2-amino-ethyl)amino]-2,4(1 H,3H)-pyrimidinedione (compound 28):
In 200 ml of tetrahydrofurane were suspended 16.8 g of the above compound 27, 8.6 g of triphenylphosphine and 11.96 g of phthalimide, and 14.81 g of diethyl azodicarboxy-late was further added dropwise to the resulting suspension under ice cooling.
Next, after completion of the addition, the used solvent was distilled off from the reaction mixture under reduced pressure, and the residue was then purified through a silica gel column chromatograph (ethyl acetate) in order to obtain 22.5 g of 6-[N-ethyl-N-(2-phthaloylaminoethyl)-amino]-1,3-dimethyl-2,4(1 H,3H)-pyrimidinedione (compound 29). The latter compound was then treated with hydrazine monohydrate in ethanol in a usual method to remove the phthaloyl group therefrom, thereby preparing crystals of 1,3-dimethyl-6-[N-ethyl-N-(2-aminoethyl)amino]_2,4(1 H,3H)-pyrimidinedione (compound 28).
Analytical results of the crystalline compound 28 thus obtained:
25~0~389 NMR (CDCl3:DMSO-d6 = 1:1, v/v), 5ppm: 1.15 (t, 3H), 2.65 (q, 2H), 2.6-3.3 (m, 4H), 3.3 (s, 3H), 3.4 (s, 3H), 4.8 (s, 1H) (3) Preparation of 1,3-dimethyl-6-{N-ethyl-N-~2-[4-(4-nitrophenyl)butylamino]ethyl>amino3-2,4(1H,3H)-pyrimidine-dione oxalate (compound 26):
In 25 ml of ethanol were dissolved 1.58 g of 1,3-dimethyl-6-[N-ethyl-N-(2-aminoethyl)amino]-2,4(1H,3H)-pyrimidinedione (compound 28) and 1.35 g of 4-(4-nitro-phenyl)butanal, and 0.5 g of molecular shieves (3A) (made byJunsei Kagaku Co., Ltd.) was then added to the solution, followed by stirring at room temperature for 3 hours.
To the resulting reaction mixture was added 0.8 g of sodium borohydride, and the mixture was then stirred for 2 hours. A small amount of water was added to the mixture, and the solvent was then distilled off from the mixture under reduced pressure. Afterward, the resulting residue was dissolved in chloroform. The chloroform solution was washed with water, and a separated organic layer was then dried over anhydous sodium sulfate. The solution was treated under reduced pressure so as to distill off the solvent. The resulting residue was purified through a silica gel column chromatograph (chloroform/methanol = 30/1 in terms of volume), then recrystallized from ethyl acetate, collected by filtration, washed, and dried in order to - 236~389 obtain 0.78 g of 1,3-dimethyl-6-{N-ethyl-N- (2-[4-(4-nitro-phenyl)butylamino]ethyl) amino~ -2,4(1H,3H)-pyrimidinedione.
Analytical results of the obtained crystalline pyrimidinedione derivative:
NMR (CDCl3), ~ppm: 1.05 (t, 3H), 1.4-1.8 (m, 4H), 2.2-2.8 (m, 8H), 2.9-3.1 (m, 2H), 3.3 (s, 6H), 4.8 (s, 1H), 5.6 (m, 1H), 7.35 (d, 2H), 8.15 (d, 2H) The thus obtained crystals were treated with an oxalic 10 acid/methanol solution in a usual manner in order to prepare 1,3-dimethyl-6-~N-ethyl-N- (2-[4-(4-nitrophenyl)butylamino]-ethyl) amino}-2,4(1 H,3H)-pyrimidinedione oxalate (compound 26).
Analytical results of the crystalline compound 26 thus obtained:
Melting point: 164-166~C
Values of elemental analysis [as C20H2gNsO4~(COOH)2]
Calcd. (%): C 53.54; H 6.33; N 14.19 Found (%): C 53.21; H 6.32; N 13.98 Example 14 Preparation of 1,3-dimethyl-6-[3-(4-nitroanilino)-propylamino]-2,4(1 H,3H)-pyrimidinedione oxalate (compound 30):
-Z~1389 - 94 _ p NH 2 -(CH 2 ) 3 -NH 2 Cl ~ ~N-CH3 >
~ N o ~ NO2 ~ F
NH2-(CH2~3-NH ~ ~N-CH3 (compound 31) CH3 (COOH)2/CH30H-NO2 ~ NH-(CH2~3-NH ~ N-CH 3 (compound 30) C ~ ~ ~(COOH)2 (1) Preparation of 1,3-dimethyl-6-(3-aminopropyl-amino)-2, 4(1 H,3H)-pyrimidinedione (compound 31):
The same procedure as in Example 10-(1) was repeated with the exception that N,N'-dimethylethylenediamine was replaced with 50 g of 1,3-diaminopropane, in order to obtain 9.5 g of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione (compound 31).
Analytical results of the compound 31 thus obtained:
2~389 NMR (CDCl3), ,~ppm: 1.75-2.10 (m, 2H), 2.75-3.48 (m, 4H), 3.12 (s, 3H), 3.35 (s, 3H), 4.75 (s, 1H) (2) Preparation of 1,3-dimethyl-6-[3-(4-nitroanilino)-5 propylamino]-2,4(1 H,3H)-pyrimidinedione oxalate (compound 30):
The same procedure as in Example 1 was repeated with the exception that the compound 2 was replaced with 0.5 g of the above compound 31, in order to obtain 1,3-dimethyl-6-[3-(4-nitroanilino)propylamino]-2,4(1H,3H)-pyrimidinedione.
The latter compound was further treated with an oxalic acid/methanol solution in a usual manner, thereby preparing 0.45 g of crystalline 1,3-dimethyl-6-[3-(4-nitroanilino)-propylamino]-2,4(1 H,3H)-pyrimidinedione oxalate 15 (compound 30).
Analytical results of the crystalline compound 30 thus obtained:
Melting point: 213-21 4~C (decomposed) IR 1~ KBrmax (cm-1): 2600, 1700, 1640, 1600 1560, 1320, 840 Values of elemental analysis [as C1sH1gNsO4-2(COOH)2]
Calcd. (%): C 50.79; H 5.33; N 18.51 Found (%): C 50.95; H 5.38; N 18.82 Example 15 Preparation of 1,3-dimethyl-6-[3-(4-nitrobenzylamino)-2(~)1389 _ 96 -propylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 32):
NH2-(CH2) 3 -NH ~ N-CH 3 (compound 31) /N 0 NO2 ~ -CH2Br (COOH) 2 /CH 3 OH
> >
NO2 ~ CH2NH-(CH2)3-NH ~ N-CH3 (compound 32) CH (COOH)2 To 20 ml of isopropanol were added 1.45 g of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione (compound 31) obtained in Example 14-(1), 1.44 g of p-nitrobenzyl bromide and 1.5 ml of triethylamine, and the resulting mixture was then treated in the same manner as in Example 2 in order to obtain crystals of 1,3-dimethyl-6-[3-(4-nitrobenzylamino)propylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 32).
Analytical results of the crystalline compound 32 thus obtained:
Melting point: 175-178~C
IR y KBrmax (cm-1): 2600, 1690, 1620, 1610 1550, 1350, 850 Values of elemental analysis [as C16H21N5o4-(cooH)2~3H2o]
Calcd. (%): C 43.99; H 5.95; N 14.25 Found (%): C 43.52; H 6.05; N 14.33 Example 16 The same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide was replaced with 0.51 g of 3-(4-nitrophenyl)propyl bromide, in order to obtain 1,3-dimethyl-6-{4-[3-(4-nitrophenyl)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 33).
Furthermore, the same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide was replaced with 0.55 g of 4-(4-nitrophenyl)butyl bromide and that the oxalic acid/methanol solution was replaced with hydrochloric acid/methanol, in order to obtain 1,3-dimethyl-6-{4-[4-(4-nitrophenyl)butyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 34).
Physical properties of these compounds were as follows:
(1) 1,3-dimethyl-6-~4-[3-(4-nitrophenyl)propyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 33) 20~1389 NO2- ~ -CH2CH2CH2Br + HN N ~ N-CH3 (compound 2) (CO2H)2/CH3OH A n ~
> NO2- ~ Nl~o (compound 33) Melting point: 153-156~C (decomposed) IR V KBrmax (cm~1): 2550, 1680, 1630, 1600 1590, 1510, 1340, 850 Values of elemental analysis [as C1 gH25N5O4-(cOOH)2-1~5H2O]
Calcd. (%): C 50.00; H 5.99; N 13.88 Found (%): C 50.24; H 5.64; N 13.23 (2) 1,3 -dimethyl -6-{4-[4-(4 -nitrophenyl)butyl]pipera-zine-1-yl} -2,4(1H,3H)-pyrimidinedione hydrochloride (compound 3 4) NO2- ~ CH2cH2cH2cH2Br + HN N- ~ -CH3 >
(compound 2) 2~1389 HCl/CH30H n ~4 > N02-~-CH2CH2CH2CH2NL~Ny N-CH3 HCl (compound 34) Melting point: 202-205.5~C
IR V KBrmax (cm-1): 2920, 2450, 1700, 1650 1615, 1440, 1345, 791, 762, 740' Values of elemental analysis tas C20H27NsO4 HCl]
Calcd. (%): C 54.85; H 6.44; N 15.99; Cl 8.10 Found (~): C 54.20; H 6.67; N 15.56; Cl 8.95 Example 17 Preparation of tablets containing, as an effective component, 1,3-dimethyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione oxalate (compound 3) which can be obtained by the process of Example 2:
With 20 g of corn starch were mixed 1 g of the above pyrimidinedione derivative oxalate (compound 3) and 123 g of lactose, and the mixture was further mixed with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in 100 ml of water, so as to form grains, followed by drying the grains at 50~C for 4 hours. Afterward, 1 g of magnesium stearate was added to the dried grains and was then mixed sufficiently. The mixture was then formed into tablets by the use of a tableting machine, the weight of each tablet -being 150 mg.
Example 18 Preparation of capsules containing, as an effective component, 1,3-dimethyl-6-~2-<N-ethyl-N-[3-(4-nitrophenyl)-propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 4) which can be obtained by the process of Example 3:
With 25 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (com-pound 4) and 120 g of lactose, and hard capsules were filled with the resulting mixture by the use of a capsule filling machine to prepare capsules, the content of the mixture in each capsule being 150 mg.
Example 19 1) Preparation of an injection containing, as an effective component, 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione fumarate (compound 8) which can be obtained by the process of Example 4:
In distilled water for injection were dissolved 20 mg of the above pyrimidinedione derivative fumarate (compound 8) and 0.85 g of sodium chloride, and the total volume of the liquid was regulated to be 100 ml, thereby preparing an injection.
2) Preparation of capsules containing, as an effective Z(~13~9 component, 1,3-dimethyl-6-{2-(N-(2-hydroxyethyl-N-[3-(4-nitrophenyl)propyl]amino~ethylamino}-2,4(1H,3H)-pyrimidine-dione hydrochloride (compound 8') which can be otained by process of Example 4:
With 24 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (compound 8') and 120 g of lactose and the resulting mixture and 1 g of magnesium stearate were mixed to prepare the final mixture.
Hard capsules were filled with the resulting final mixture by the use of a capsule filling machine to prepare capsules, the content of the mixture in each capsule being 150 mg.
Pharmacological Test 1 (1) Influence on myocardial action potential duration time (APD7s) To a hybrid adult dog, 30 mg/kg of pentobarbital was administered through a vein, and after being anesthetized, the heart was removed. Afterward, the right ventricular free- wall of the heart was cut out in a Tyrode solution.
The right ventricular free wall was fixed in an incubator at 37~C, and a nutritional solution (20 ml of the Tyrode solution) was refluxed.
In this isolated condition, myocardial action potential duration times (APD7s) were measured before and after the 26~ 389 administration of the respective compounds prepared in the above examples in Table 2 and d-sotalol as a control medicine, and APD75(%) was calculated from the measured results in accordance with the formula:
APD7s(%) = (B - A)/A x 100 A: APD7s before administration B: APD7s after administration Here, APD7s was measured as follows: A field stimula-- tion of 1 Hz was given to the right ventricular free wall, and any variation ~fan action potential was depicted on an oscilloscope via a glass microelectrode (10 to 20 MQ) thrust into a Purkinje fiber of the free wall and via an amplifier.
Afterward, a waveform on the oscilloscope was analyzed by the use of a computer, and the ti~c of from a point of the action potential generation to a point of 75% repolarization was measured. This measured time was regarded as the myocardial action potential duration time (APD7s).
Each of the compounds and d-sotalol shown in Table 2 was separately added to the refluxing nutritional solution (20 ml), and after 20 minutes' incubation, APD7s after the administration was calculated from the variation of the myocardial action potential duration time.
Incidentally, this test was carried out in accordance with a Sato et al's method [H. Sato, K. Hashimoto, Arzneimit-tel Forschung, 34 (1), 3a, 376-380 (1984)].
2~389 - 103 _ The results are set forth in Table 2.
(2) Influence on ventricular muscle refractory period Refractory periods were measured in the following manner before and after each of the compounds and d-sotalol shown in Table 2 was separately administered to a vein or a duodenum, and ERP (%; extensibility of refractory period) was calculated from the measured values:
ERP (~) = (W - Y)/Y x 100 W: Refractory period after administration Y: Refractory period before administration To a mongrel adult dog, 30 mgtkg of pentobarbital was administered intravenously, and afterbeinganesthetized, apair of silver-silver chloride electrodes separated by 3 mm was sewn on an opened right ventricule, and electrical stimula-tion was given at an interval of 400 msec at a duration timeof 4 msec under a current twice as much as the threshold.
Afterward, a small amount of alcohol was injected into a sinus artery in order toextinguishapacemaker activity, and the ventricular refractory period (ERP) was measured under 20 ventricule pacing.
That is,each ltraincomprisedlOstimulationshaving intervals of 400 msec, and an interval between the trains was usually 400 msec. However, this interval was shortened 10 msec by 10 msec at the time of the refractory period measurement, and an interval between the trains at the time 2~1389 when reaction to the first stimulation of the traindisappeared was regarded as the refractory period.
In this case, the electrical stimulation was fed in accordance with a program by a heart stimulation device (Diamedical Co., Ltd.; DHM-226-3).
The results are set forth in Table 2.
Table 2 (results of pharmacological test) Com- APD75 (%) ER;' (%) pound Dose (~g~ml) Dose mg/kg,i.v.) No. 0.3 1.0 3.0 10.0 0.10.: 1.0 3.0 1 - - - - 3.63.6 10.3 4 - 11 16 - 5.611.1 16.7 16.7 8 16 22 38 - 010.7 21.4 14.2 - - 2 11 6.76.7 13.3 20 14 18 43 - - 1433.5 - - 6 16 6.312.5 12.5 18.8 16 - - 22 - 6.713.3 13.3 26 - 20 30 35 6.56.5 6.5 6.5 33 - 17 22 31 14.314.3 17.9 21.4 d-sota- 0 3 7.4 15.8 1.76.7 8.7 15.5 lol - 2~ 389 Toxicity Test 1 Each of the compounds prepared in the above-mentioned examples was administered into a mouse (ddY strain, male).
In each case, oral administration (p.o.) and intra perito-neal administration (i.p.) were separately carried out in adose of 300 mg/kg and 250 mg/kg, respectively.
A mortality rate (number of specimens: one group = 2 to 4 mice) of the mice 24 hours after the administration was calculated, and the results are set forth in Table 3.
Table 3 (results of toxicity test) CompoundMortality Rate (%) Number300 mg/kg (p.o.)250 mg/kg (i.p.) Example 20 Preparation of 1,3-dimethyl-6-~4-[3-(4-nitrophenoxy)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 35):
HocH2cH2cH2Br + HN N ~ N-CH3 N
(compound 37) HOCH2CH2CH2N~__,N ~ N-CH3 ,N
(compound 36) 02N ~ OH j HCl/CH30H
2002N ~ OCH2CH2CH2N N ~ N-CH3 (compound 35) CH3 (1) Preparation of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-1-yl]-2, 4(1H,3H)-pyrimidinedione (compound 36):
25To 250 ml of ethanol were added 14.1 g of 1,3-dimethyl-28~389 -- 107 _ 6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37), 11.7 g of 3-bromo-1-propanol and 13 g of triethylamine, and the mixture was then heated under reflux for 20 hours to perform reaction. After completion of the reaction, the reaction mixture was concentrated to dryness, and the residue was then dissolved in 300 ml of chloroform. The resulting solution was washed with 100 ml of water twice, and the washed orgnaic layer was then dried over anhydrous magnesium sulfate. This organic layer was treated under reduced pressure to distill off the solvent, thereby obtaining 20.5 g of a composition. Afterward, ether was added to this composition, followed by crystallizing, recovering, washing and drying in order to obtain 12.4 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4-(lH,3H)-pyrimidinedione (compound 36) (yield 69.8%).
Analytical results of the crystalline compound 36 thus obtained:
Melting point: 119-121~C
NMR (CDCl3), ~ppm: 1.8 (dt, 2H), 2.7 (m, 6H), 3.02 (m, 4H), 3.36 (s, 3H), 3.43 (s, 3H), 3.82 (t, 2H), 4.34 (br, 1H), 5.26 (s, 1H) IR v KBrmax (cm~1): 3380, 3180, 2830, 1695, 1650, 1605, 1440, 1213, 1068, 1000, 921, 760 (2) Preparation of 1,3-dimethyl-6-~4-[3-(4-nitro-phenoxy)propyl]piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione _ 108 --hydrochloride (compound 35):
In 15 ml of anhydrous tetrahydrofuran were suspended 1.0 g of the above compound 36, 1.1 g of triphenylphosphine and 0.57 g of 4-nitrophenol, and 15 ml of an anhydrous tetrahydrofuran solution containing 0.71 g of diethyl azodicarboxylate was further added to the resulting suspension at room temperature.
Next, the resulting reaction mixture was stirred for 10 minutes and then concentrated to dryness, and the residue was purified through a silica gel column chromatograph (methanol/ethyl acetate = 1/15 to 1/7 in the terms of volume ratio) to obtain 1.3 g of 1,3-dimethyl-6-{4-[3-(4-nitro-phenoxy)propyl]piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione (yield 80%).
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 167-170~C
Values of elemental analysis (as C1gH2sN3Os) Calcd. (%): C 56.57; H 6.25; N 17.36 Found (96): C 56.29; H 6.17; N 17.17 Furthermore, the thus obtained 1,3-dimethyl-6-{4-[3-(4-nitrophenoxy)propyl]piperazin-1-yl} -2,4(1H,3H)-pyrimidine-dione was treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-~4-[3-(4-nitro-phenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione 2~ 89 hydrochloride (compound 35).
Analytical results of the crystalline compound 35 thus obtained:
Melting point: 244-246~C (decomposed) Example 21 Preparation of 1,3-dimethyl-6-{4-[3-(3-nitrophenoxy)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 38):
~OH + BrcH2cH2cH2Br ' > ~OCH2CH2CH2Br 0 2 N - (compound 39) HNN~N-CH3 HCl/CH30H
~Nff (compound 37) - 2~0~389 ~OCH2CH2CH2N N~;~N-CH~
(compound 38) CH 3 (1) Preparation of 3-(3-nitrophenoxy)propyl bromide (compound 39):
To 100 ml of methyl ethyl ketone were added 13.9 g of 3-nitrophenol, 101 g of 1,3-dibromopropane and 15.2 g of anhydrous potassium carbonate, and the mixture was then heated under reflux for 2 hours to perform reaction. After completion of the reaction, insoluble matters were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Next, the resulting concentrate was dissolved in 300 ml of chloroform, and this chloroform solution was washed with water. Afterward, the washed organic layer was then dried over anhydrous magnesium sulfate. This organic layer was then treated under reduced pressure to distill off the solvent, thereby obtaining 24.6 g of 3-(3-nitrophenoxy)propyl bromide (compound 39) as an oily product. This product could be used in the subsequent reaction without purifying particularly.
(2) Preparation of 1,3-dimethyl-6-~4-[3-(3-nitro-phenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 38):
- 2~01389 In 20 ml of dioxane were dissolved 1.69 g of the above oily compound 39, 1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37) and 1 ml of triethylamine, and the solution was then heated under reflux for 4 hours to perform reaction. After completion of the reaction, insoluble matters were removed from the reaction mixture by filtration, the resulting filtrate was then concentrated. The residue (concentrate) was dissolved in chloroform, and the resulting chloroform solution was then washed with water. Afterward, the water-washed organic layer was dried over anhydrous magnesium sulfate and then treated under reduced pressure to distill off the solvent.
Furthermore, the residue was purified through a silica gel column chromatograph (chloroform/methanol = 100/1 to 25/1 in terms of volume ratio), and the purified material was then recrystallized from methanol. Afterward, the crystals were collected by filtration, washed and dried in order to obtain 1.35 g of 1,3-dimethyl-6-~4-[3-(3-nitrophenoxy)propyl]-piperazin -1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 164-165~C
NMR(CDC13), ~ppm: 1.8-2.2 (m, 2H), 2.4-2.8 (m, 6H), 2.8-3.8 (m, 4H), 3.34 (s, 3H), 3.42 (s, 3H), 4.15 (t, 2H), 5.25 (s, 1H), 7.1-8.0 (m, 4H) -- ZC~389 Values of elemental analysis (as C1gH2sNsOs) Calcd. (~): C 56.57; H 6.25; N 17.36 Found (%): C 56.27; H 6.69; N 17.21 Next, the thus obtained 1,3-dimethyl-6- 4-[3-(3-nitro-phenoxy)propyl]piperazin-1-yl -2,4(1H,3H)-pyrimidinedione was treated with a hydrochloric acid/methanol solution to obtain 1,3-dimethyl-6-~4-[3-(3-nitrophenoxy)propyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 38).
10Analytical results of the crystalline compound 38 thus obtained:
IR V KBrmax (cm~1): 1690, 1650, 1525, 1345, 1240, 1200, 1025, 980, 790, 760, 740, 670 Values of elemental analysis (as C1gH2sNsOs HCl MeOH) 15Calcd. (%): C 51.00; H 6.21; N 14.87; Cl 7.53 Found (%): C 50.60; H 6.71; N 14.81; Cl 7.74 Example 22 Preparation of 1,3-dimethyl-6-~4-[2-(4-nitrobenzoyl-oxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40):
HOCH2CH2N~ N~N-CH3 O
(compound 41) CH~
2(~)1389 - 113 _ 02N ~ COCl (COOH)2/CH~OH
02N ~ COOCH2CH2N N ~ N-CH3 N ~ . ( COOH)2 (compound 40) / u To 5 ml of tetrahydrofuran were added 0. 5 g of 4-nitrobenzoyl chloride, 0.47 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) and 1.5 ml of triethylamine, and the resulting mixture was stirred at room temperature overnight.
Afterward, the used solvent was distilled off under reduced pressure, and the residue was then dissolved in chloroform.
The resulting chloroform solution was washed with water, then dried over anhydrous sodium sulfate, and concentrated to dryness, thereby obtaining a crude product. The latter was then purified through a silica gel column chromatograph (chloroform/methanol = 4û/1 in terms of volume ratio) in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)-ethyl]piperazin-1 -yl3 -2,4(1H,3H)-pyrimidinedione. Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.84 g 2 5 of 1,3-dimethyl-6-~4-[2-(4-nitrobenzoyloxy)ethyl]piperazine-_ 114 -1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40).
Analytical results of the crystalline compound 40 thus obtained:
Melting point: 171-173~C (decomposed) S IR ~ KBrmax (cm 1): 3100, 2550, 1740, 1700, 1660, 1640, 1540, 1360, 850 Values of elemental analysis ~as C1gH25NsO6-(cOoH)2-2H2o]
Calcd. (%): C 46.24; H 5.73; N 12.84 Found (%): C 46.64; H 5.38; N 12.83 Example 23 Preparation of 1,3-dimethyl-6-[4-(4-nitrophenacyl)-piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 42):
HN N~N~CHa N~
CHa ~_~ Br (compound 37) 02N~COCH~ 2 ~ -r~
2~1389 - 115 _ 02N ~ COCH2N N ~ ~ N-CH3 (compound 43) C H3 HCI/CH30H A ~
- 02N ~ COCH2N N ~ N-CH3 N ~ HCl (compound 42) C H 3 In 200 ml of chloroform was dissolved 8.25 g of 4-nitroacetophenone, and 20 ml of a chloroform solution containing 8 g of bromine was added dropwise thereto under cooling. The resulting reaction mixture was concentrated, and the residue (concentrate) was recrystallized from chloroform/ether, collected by filtration, washed, and dried to obtain 8.03 g of p-nitrophenacyl bromide.
Next, to 150 ml of dioxane were added 4.88 g of the above prepared p-nitrophenacyl bromide, 4.48 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37) and 4.2 ml of triethylamine, and the solution was heated under reflux for 1 hour. Afterward, the reaction mixture was cooled to deposit crystals, and the latter were 26:~C)1389 collected by filtration, dissolved in chloroform, washed with water, and dried (over anhydrous sodium sulfate).
Afterward, the used solvent was distilled off, and methanol was then added to the residue so as to crystallize it. The resulting crystals were then collected by filtration, washed, and dried to obtain 4.02 g of 1,3-dimethyl-6-[4-(4-nitrophenacyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 43).
Analytical results of the crystalline compound 43 thus obtained:
Melting point: 189-192~C
Values of elemental analysis (as C18H21N5~5 2CH30H) Calcd. (%): C 55.08; H 5.75; N 17.36 Found (%): C 54.86; H 5.44; N 17.62 NMR (CF3COOH), ~ppm: 3.63 (s, 3H), 3.73 (s, 3H), 3.7-4.3 (m, 8H), 5.21 (s, 2H), 6.12 (s, 1H), 8.28 (s, 2H), 8.52 (d, 2H) Furthermore, 0.9 g of the compound 43 was treated with a hydrochloric acid/methanol solution in a usual manner to obtain 0.91 g of 1,3-dimethyl-6-[4-(4-nitrophenacyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 42).
Analytical results of the crystalline compound 42 thus obtained:
Melting point: 257-262~C
-_ 117 -IR V KBrmax (cm~1): 1685, 1630, 1520, 1340, 1190, 960, 845, 790, 740 Values of elemental analysis (as C1gH21NsOs-HCl-~CH30H) Calcd. (%): C 50.52; H 5.50; N 15.92; Cl 8.06 Found (%): C 50.77; H 5.29; N 15.82; Cl 7.61 Example 24 Preparation of 1,3-dimethyl-6-{4-l2-hydroxy-2-(4-nitrophenyl)ethyl]piperazin-1-yl~-2,4-(1H,3H)-pyrimidine-dione hydrochloride (compound 44):
O 2 N ~ C O C H 2 N~_JN ~ N-CH 3 >
(compound 43) C/H
LiAlH4 HCl/CH30H
> >
OH O
02N~CHCH2-N, N~N-CH~ ~HCl (compound 44) CH 3 Under ice cooling, 3.46 g of lithium aluminum hydride ; .. , 2~ 89 -was added to 700 ml of a dried tetrahydrofuran suspension containing 8.12 g of 1,3-dimethyl-6-[4-(4-nitrophenacyl)-piperazin-1-yl~-2,4-(1H,3H)-pyrimidinedione (compound 43), and the mixture was then stirred at the same temperature for 30 minutes, followed by stirring at room temperature for 2 hours.
After completion of the stirring operation, 50 ml of water was added to the reaction mixture under cooling in order to bring the reaction to an end, and insoluble matters were removed therefrom by filtration and the filtrate was then concentrated.
The residue (concentrate) was dissolved in chloroform, washed with water and dried (over anhydrous sodium sulfate), and the resulting organic layer was concentrated to a small amount. Afterward, the concentrate was purified through a silica gel column chromatograph (chloroform/methanol = 100:1 to 100:2 in terms of volume ratio), thereby preparing 3.7 g of 1,3-dimethyl-6-{4-[2-hydroxy-2-(4-nitrophenyl)ethyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 205-207~C
NMR (DMSO-d6), ~ppm: 2.5-2.7 (m, 6H), 2.7-2.95 (m, 4H), 3.06 (s, 3H), 3.20 (s, 3H), 4.79 (t, lH), 7.47 (d, 2H), 8.04 (d, 2H) ~31389 Next, 0.55 g of this pyrimidinedione derivative was treated with a hydrochloric acid/methanol solution in a usual manner in order to obtain 0.53 g of 1,3-dimethyl-6-~4-[2-hydroxy-2-(4-nitrophenyl)ethyl]piperazin-1 -yl3 -2,4-(1H,3H)-pyrimidinedione hydrochloride (compound 44).
Analytical results of the crystalline compound 44 thus obtained:
Melting point: 250-265~C (gradually colored and decomposed) Values of elemental analysis (as C18H22NsOs-Hcl-4H2O):
Calcd. (%): C 50.23; H 5.74; N 16.27; Cl 8.24 Found (%): C 50.22; H 6.07; N 16.04; Cl 8.20 IR V KBrmax (cm~1): 1700, 1620, 1430, 1340, 1190, 1165, 850, 785 Example 25 Preparation of 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyl-amino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45):
NH2CH2CH2Br HBr NO2 ~COC 1 X~1389 H-N N ~ N-CH3 N
(compound 37) ~ 02N ~ CONHCHzCH2Br (compound 46) HCl/CH30H
>
o2N~CoNHCH2CH2-N~J~4~,N-CH3 (compund 45) / 0 CH~ 2HCl (1) Preparation of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46):
In 30 ml of chloroform were added 3 g of 4-nitrobenzoyl chloride, 3.3 g of 2-aminoethyl bromide hydrobromide and 3.9 ml of pyridine under ice cooling, and they were stirred at the same temperature for 1 hour. The reaction mixture was then washed with water, and the resulting organic layer was concentrated to obtain a crude product of 2-(4-nitro-benzoylamino)ethyl bromide. Afterward, the latter was 2~389 recrystallized from hexane/ethanol, the resulting crystals were collected by filtration, washed and dried to prepare 2.9 g of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46).
Analytical results of the crystalline compound 46 thus obtained:
Melting point: 104-108~C
(2) Preparation of 1,3-dimethyl-6-{4-[2-(4-nitroben-zoylamino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45):
A mixture of 1.3 g of the compound 46 obtained in the paragraph (1), 1.8 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione (compound 37), 1.3 ml of triethyl-amine and 10 ml of isopropanol was heated under reflux for 3 hours.
Next, the used solvent was distilled off from the resulting reaction mixture, and water was added to the reaction mixture, followed by extracting with chloroform.
Furthermore, a chloroform extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in order to obtain a crude product. Afterward, the latter was recrystallized from hexane/ethanol, and the resulting crystals were collected by filtration, washed and dried in order to obtain 1.77 g of 1,3-dimethyl-6-{4-[2-(4-nitro-benzoylamino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 169-171~C
IR V KBrmax (cm~1): 3000, 2900, 1700, 1640, 1530, 1340, 850, 700 Next, the thus obtained pyrimidinedione derivative crystals were treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-~4-[2-(4-nitrobenzoylamino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45).
Analytical results of the crystalline compound 45 thus obtained:
Melting point: 283-285~C (decomposed) Values of elemental analysis (as C1gH24N6O5 2HCl):
Calcd. (~): C 46.62; H 5.66; N 17.20; Cl 14.49 Found (~): C 46.45; H 5.79; N 17.01; Cl 14.67 Example 26 Preparation of 1,3-dimethyl-6-{4-[N-(4-nitrophenyl)-carbamoylmethyl]piperazin-1-yl}-2,4(1H,3H)pyrimidinedione oxalate (compound 47):
BrCH2COBr 02N~NH2 Z~389 HN N ~ N-CH3 N
(compound 37) 02N { ~ NHCOCH2Br (compound 48) (COOH) 2/CH 3 OH
~
0 2N~NHCOCH 2N~JN~ ~ (COOH)- 2 (compound 47) C H 3 A mixture of 0.8 g of 4-nitroaniline, 0.6 ml of bromoacetyl bromide, 1.5 g of anhydrous potassium carbonate and 10 ml of dimethyl sulfoxide was stirred at 100~C for 4 hours, and insoluble matters were removed from the mixture by filtration while the latter was hot. The filtrate was cooled to deposit 4-(bromoacetamide)nitrobenzene (compound 48) crystals, and the latter were collected by filtration and then heated under reflux for 16 hours together with 1.3 g of 1,3-dimethyl-6~ piperazinyl)-2,4(1H,3H)-pyrimi-dinedione (compound 37), 1.6 g of triethylamine and 15 ml 2~)1389 of isopropanol.
After cooling, the used solvent was distilled off, and the residue was then dissolved in chloroform. Afterward, the resulting solution was washed with water and dried over 5 anhydrous sodium sulfate.
Afterward, the solvent was distilled off from the dried chloroform solution under reduced pressure, and the residue was purified through a silica gel chromatograph (chloro-form/methanol = 100/1 to 25/1 in terms of volume ratio) to obtain 0.85 g of 1,3-dimethyl-6-~4-[N-(4-nitrophenyl)car-bamoylmethyl]piperazin-1-yl} -2,4(1H,3H)pyrimidinedione.
Analytical results of the crystalline pyrimidine derivative thus obtained:
NMR (DMSO-d6), ,~ppm: 2.5-2.9 (m, 10H), 3.28 (s, 3H), 3.37 (s, 3H), 5.00 (s, 1H), 7.29 (d, 2H), 8.01 (d, 2H) Next, this pyrimidine derivative was treated with an oxalic acid/methanol solution in a usual manner, thereby preparing 0.81 g of 1,3-dimethyl-6-~4-[N-(4-nitrophenyl)-carbamoylmethyl]piperazin-1-yl~-2,4(1H,3H)pyrimidinedione 20 oxalate (compound 47).
Analytical results of the crystalline compound 47 thus obtained:
Melting point: 281-283~C (decomposed) Values of elemental analysis (as C18H22N6Os (cOoH)2-H2o) Calcd. (%): C 47.06; H 5.13; N 16.46 Found (%): C 46.90; H 5.34; N 16.37 Example 27 Preparation of 1,3-dimethyl-6-~4-[3-(4-nitroanilino)-2-hydroxypropyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 49):
o ClCH2CH-CH2N N ~ -CH~
b H ~N~o (Compound 50) CH~
NH3/CH~OH 02N ~ F (COOH)2/CH30H
1s ~ >
02N ~ NHCH2CH-CH2N N ~ N-CH3 OH jN-~o (COOH)2 (compound 49) CH3 In the first place, 20 ml (0.1 g/ml) of an ammonic methanol solution containing 2.0 g of 1,3-dimethyl-6-~4-(3-chloro-2-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidine-dione (compound 50) was heated at 90~C for 8 hours. The B
~ . .
Z~1389 reaction mixture was concentrated under reduced pressure, and the residue (concentrate) was mixed with 0.9 g of 4-nitrofluorobenzene and 1 ml of triethylamine and then heated at 90~C for 2 hours. The resulting reaction mixture was poured into 100 ml of water, and the deposited crystals were then collected by filtration, washed with methanol/-ether, and dried in order to obtain 2.15 g of yellow crystalline 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-2-hydroxy-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Furthermore, the yellow crystals were treated with an oxalic acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-2-hydroxypropyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 49).
Analytical results of the crystalline compound 49 thus obtained:
IR ~ KBrmax tcm~1): 3375 (br), 1693, 1640, 1600, 1470 (br), 1308, 1113 Values of elemental analysis [as C19H26N6~5-(C~2H)2]:
Calcd. (~): C 49.60; H 5.55; N 16.53 Found (%): C 50.10; H 5.98; N 16.79 Example 28 Preparation of 1,3-dimethyl-6-{4-[3-(4-nitrophenylthio)-propyl]piperazin-1-yl 3 -2,4(1H,3H)-pyrimidinedione oxalate (compound 51):
!20n~389 ' ~ BrCH2CH2CH2Br 02N ~ SH
s o2N~scH2cH2cH2Br ?
(compound 52) 0 HN N ~ N-CH~
N ~ . .
CHa (compound 37) ~ (COOH~2/CH30H~
02N ~ SCH2CH2CH2N N ~ N-CHs N ~ -1.5(COOH)2 (compound 51) ~ u CHa (1) Preparation of 3-(4-nitrophenylthio)propyl bromide (compound 52):
To 50 ml of a 2-butanone solution containing 5.5 g of 4-nitrothiophenol and 28.3 g of 1,3-dibromopropane was added 9.0 g of anhydrous potassium carbonate, and the solution was then stirred for 30 minutes at room temperature.
Afterward, insoluble matters were removed from the ~' ~ .
26~1389 resulting reaction mixture by filtration, and the filtrate was then concentrated. The concentrate was dissolved in chloroform, and the resulting chloroform solution was then washed with water. Furthermore, the water-washed orgnaic layer was dried over anhydrous magnesium sulfate and then treated under reduced pressure to distill off the solvent, thereby preparing 8.0 g of crystalline 3-(4-nitrophenylthio)-propyl bromide (compound 52). This product could be used in the subsequent reaction without purifying particularly.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(4-nitrophenyl thio)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 51):
To 30 ml of ethanol were added 2.0 g of the above compound 52, 1.68 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37) and 3 ml of triethylamine, and the solution was then heated with stirring under reflux for 3 hours.
The resulting reaction mixture was concentrated to dryness and then mixed with 100 ml of water. Afterward, the deposited material was collected by filtration and then washed with ethanol.
Furthermore, the thus washed deposit was recrystallized from methanol, collected by filtration, washed and dried to obtain 2.4 g of 1,3-dimethyl-6-{4-[3-(4-nitrophenylthio)-propyl]piperazin-1 -yl3 -2,4(1H,3H)-pyrimidinedione.
2C~1389 - 129 _ Analytical results of the resulting crystalline pyrimidinedione derivative:
Melting point: 145-147~C
In 20 ml of methanol was suspended 2.2 g of the thus obtained crystals, and 2.0 g of oxalic acid dihydrate was added thereto, followed by stirring. After complete dissolution, stirring was further continued for a while.
Afterward, 30 ml of ether was added thereto so as to deposit crystals, and the latter was collected by filtration, washed, and dried to obtain 2.0 g of 1,3-dimethyl-6-{4-[3-(4-nitrophenylthio)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 51).
Analytical results of the crystalline compound 51 thus obtained:
Melting point: 164-168~C (decomposed) Values of elemental analysis [as C1gH2sNso4s~1.5(cooH)2-H2o]
Calcd. (%): C 46.15; H 5.28; N 12.23; S 5.60 Found (%): C 45.89; H 5.25; N 12.16; S 6.12 IR V KBrmax (cm-1): 3450, 1700, 1641, 1340, 1222, 978, 851, 745, 722 Example 29 Preparation of 1,3-dimethyl-6-{4-[2-(4-nitrophenoxy)-ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 53):
NO2 ~ 0H + HOCH2CH2N N ~ ~ N-CH, (compound 41 ) C/H
HCl/CH~OH
NO2 ~ OCH2CH2N~_,N ~ N-CH~
~N ~ HCl (compound 53) C H
To 100 ml of anhydrous tetrahydrofuran were added 5.37 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1 -yl]-2,4(1H,3H)-pyrimidinedione (compound 41 ), 3.20 g of 4-nitrophenol and 6.03 g of triphenylphosphine, and the resulting mixture was treated in the same manner as in Example 20-(2) to obtain 5.40 g of crystalline 1 ,3-dimethyl-6-{4-[2-(4-nitrophenoxy)ethyl]piperazin-1 -yl3 -2,4(1 H,3H)-20 pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
IR V KBrmax (cm~1 ): 1705, 1663, 1595, 1505, 1340, 1275, 1213, 1180, 1115, 1010, 862, 805, 750 Furthermore, the thus obtained crystals were treated 2G~1389 with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6- {4-[2-(4-nitrophenoxy)ethyl]pipera-zin-1-yl~ -2,4(1 H,3H)-pyrimidinedione hydrochloride (compound 53).
Analytical results of the crystalline compound 53 thus obtained:
IR lz KBrmax (cm-1 ) 1705, 1655, 1595, 1435, 1342, 1267, 1112, 860, 755 Values of elemental analysis (as C1gH23NsOs-HCl-0.5H2O):
Calcd. (%): C 49.71; H 5.79; N 16.10; Cl 8.15 Found (%): C 49.17; H 6.05; N 16.20; Cl 8.40 Example 30 Preparation of 1,3-dimethyl-6-{4-[4-(4-nitrophenoxy)-butyl]piperazin-1-yl} -2,4(1 H,3H)-pyrimidinedione hydro-chloride (compound 54):
HOCH2CH2CH2-CH2Br + HN~N~ _~N-CH3 (compound 37) C/H
02N{~OH HCl/CH30H
~1389 C2N ~ OCH2CH2CH2CH2N N ~ N-CH3 N ~ HCl (compound 54) C H
The same procedure as in Example 20-(1) was repeated with the exception that 3-bromo-1-propanol was replaced with 12.9 g of 4-bromo-1-butanol, in order to obtain 13.1 g of 1,3-dimethyl-6-[4-(4-hydroxybutyl)piperazin-1-yl]-2,4-10 (1H,3H)-pyrimidinedione.
Furthermore, the same procedure as in Example 20-(2) was repeated with the exception that 1.05 g of this pyrimidinedione derivative was substituted for 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidine-15 dione (compound 36), in order to prepare 1.2 g of crystalsof 1,3-dimethyl-6-{4-[4-(4-nitrophenoxy)butyl]piperazine-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 54).
Analytical results of the crystalline compound 54 thus obtained:
Values of elemental analysis (as C20H27NsOs-HCl-0.5H2O) Calcd. (%): C 51.89; H 6.31; N 15.13; Cl 7.66 Found (%): C 52.01; H 6.24; N 15.41; Cl 7.56 Example 31 Preparation of 1,3-dimethyl-6-{4-[3-(2-nitrophenoxy)-propyl]piperazin-1-yl} -2.4(1H,3H)-pyrimidinedione hydro-~ ~ ~L~89 chloride (compound 55):
BrCH2CH2CH2Br (~OH ' o HN N ~ N~CHa N ~
(compound 37) CH3 HCl/CH30H
O .
OCH2CH2CH2N N~N-CH3 NO2 ~N ~ HCl (compound 55) C H 3 The same procedure as in Example 21-(1) and 21-(2) was repeated with the exception that 3-nitrophenol was replaced with 13.9 g of 2-nitrophenol, in order to obtain crystals of 1,3-dimethyl-6-{4-[3-(2-nitrophenoxy)propyl]piperazin-1-yl}-2.4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 123.5-125~C
Values of elemental analysis (as C1gH2sNsOs) Calcd. (%): C 56.57; H 6.25; N 17.36 Found (%): C 56.74; H 5.85; N 17.46 -2~9~1389 NMR (CDC13), S ppm: 2.03 (m, 2H), 2.66 (m, 6H), 2.98 (m, 4H), 3.32 (s, 3H), 3.40 (s, 3H), 4.11 (t, 2H), 5.22 (s, 1H), 6.9-7.9 (m, 4H) The thus obtained crystals were treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6- {4-[3-(2-nitrophenoxy)propyl]pipera-zin-1-yl} -2,4(1H,3H)-pyrimidinedione hydrochloride (compound 55).
Analytical results of the crystalline compound 55 thus obtained:
Melting point: 251-252~C (decomposed) Values of elemental analysis (as C1gH2sNsOs-HCl) Calcd. (%): C 51.88; H 5.96; N 15.92; Cl 8.06 Found (%): C 51.29; H 5.84; N 16.06; Cl 7.58 Example 32 Preparation of 1,3-dimethyl-6-[2-(4-nitrobenzoylamino)-ethylamino]-2,4(1 H,3H)-pyrimidinedione (compound 56):
02N ~ COCl + H2NCH2CH2NH ~ N~CHg (compound 57) CH 9 2~ 9 _ 135 --> 02N~CONHCH2CH2NH~ -CH3 (compound 56) C H
The same procedure as in Example 22 was repeated with the exception that 1,3-dimethyl-6-[4-(2-hydroxyethyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) was replaced with 0.35 g of 1,3-dimethyl-6-(2-aminoethylamino)-2,4(1H,3H)-pyrimidinedione (compound 57), in order to obtain crystals of 0.49 g of 1,3-dimethyl-6-[2-(4-nitrobenzoyl-amino)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 56).
Analytical results of the crystalline compound 56 thus obtained:
Melting point: 284-285~C (decomposed) IR V KBrmax (cm~1): 1690, 1660, 1640, 1610, 1550, 1360, 860 NMR (DMSO-d6), ~ppm: 3.3 (m, 4H), 3.36 (s, 3H), 3.28 (s, 3H), 4.98 (s, 1H), 8.18 (d, 2H), 8.41 (d, 2H) Values of elemental analysis (as C1sH17NsOs) Calcd. (%): C 51.87; H 4.93; N 20.16 Found (%): C 51.89; H 5.19; N 19.73 Example 33 Preparation of tablets containing, as an effective component, 1,3-dimethyl-6-{4-[3-(4-nitrophenoxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidine hydrochloride (compound 35) which can be obtained by the process of Example 20:
With 20 g of corn starch were mixed 1 g of the above pyrimidinedione derivative hydrochloride (compound 35) and 123 g of lactose, and the mixture was further mixed with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in 100 ml of water, so as to form grains, followed by drying the grains at 50~C for 4 hours. Afterward, 1 g of magnesium stearate was added to the dried grains and then mixed sufficiently. The mixture was then formed into tablets by the use of a tableting machine, the weight of each tablet being 150 mg.
Example 34 Preparation of capsules containing, as an effective component, 1,3-dimethyl-6-{4-[2-(4-nitrobenzoylamino)ethyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45) which can be obtained by the process of Example 25:
With 25 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (compound 45) and 120 g of lactose, and hard capsules were filled with the resulting mixture by the use of a capsule filling machine to obtain capsules, the content of the mixture in 2~0~389 each capsule being 150 mg.
Example 35 Preparation of an injection containing, as an effective component, 1,3-dimethyl-6-{4-[3-(4-nitrophenyl)-2-hydroxy-propyl]piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione oxalate (compound 49) which can be obtained by the process of Example 27:
In distilled water for injection were dissolved 20 mg of the above pyrimidinedione derivative oxalate (compound 49) and 0.85 g of sodium chloride, and the total volume of the liquid was regulated to be 100 ml, thereby preparing an n~ ectlon .
Pharmacological Test 2 Following the same procedure as in Pharmacological Test 1, APD7s and ERP of the respective compounds prepared in the above examples in Table 4 were calculated. The resluts are set forth in Table 4.
Toxicity Test 2 Following the same procedure as in Toxicity Test 1, toxicity of the respective compounds prepared in the above examples in Table 5 was tested to calculate a mortality rate of mice.
Administration was made by oral administration (p.o.) in an amount of 300 mg/kg of each compound for one mouse.
2()01389 Table 4 (results of pharmacological test) Com- APD75 (%) ER' (%) pound Dose (llg/ml)Dose mg/kg,i.v.) 5 No. 0.3 1.0 3.0 10.0 0.10. 1.0 3.0 - 17 22 30 6 12 15.8 25.3 42 - 2 10 17 4.69.411.7 18.4 10 44 - 5 13 21 0 7.719.9 27.8 51 - - 33 - 12.612.619.0 53 - 8 22 43 8.82330.1 15 55 - - 18 39 0 0 6.8 13.6 56 - - - - 6.76.76.7 Table 5 (results of toxicity test) 20Compound Number Mortality Rate (%) -~ 139 ~ 2~1389 Example 36 Preparation of 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 58):
O O
NH BrCH2CH2CH2Br ~ N-CH2CH2CH2Br o ( o H ~ ~ N-CH3 N
CHs (compound 60) hydrazine H2O
H2NCH2CH2CH2N N ~ N-CH~
f (compound 59) /N 0 02N ~ F (compound 58') Hcl/cHsoH~
~ . , .
2~389 02N ~ NHCH2CH2CH2N N ~ N-CH3 (compound 58) / 0 HCl (1) Preparation of 1,3-dimethyl-6-[4-(3-aminopropyl)-piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 59):
In 100 ml of dimethylformamide were suspended 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane, and then this suspension was heated with stirring at 120~C
for 6 hours so as to perform reaction. Next, insoluble matters were removed from the resulting reaction mixture by filtration, and the filtrate was then concentrated to dryness under reduced pressure. The residue was washed with hexane and then recrystallized from ethanol/water, and the resulting crystals were collected by filtration, washed, and dried to obtain 13.8 g of N-(3-bromopropyl)phthalimide.
Afterward, 13.0 g of this N-(3-bromopropyl)phthalimide, 10.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimi-dinedione (compound 60) and 20 g of triethylamine were suspended in 200 ml of dioxane, and the resulting suspension was refluxed for 6 hours.
Furthermore, insoluble matters were removed from the reaction mixture by filtration, and the filtrate was then concentrated to dryness under reduced pressure. The residue (concentrate) was recrystallized from ethyl 2~)01389 - 141 _ acetate/n-hexane, and the resulting crystals were collected by filtration, washed, and dried to obtain 12.5 g of 1,3-dimethyl-6-[4-(3-phthaloylaminopropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Next, 12.5 g of the thus obtained crystals and 6.0 g of hydrazine nomohydrate were suspensed in 200 ml of ethanol, and the suspension was then refluxed for 4 hours. After cooling, the resulting insoluble matters were removed therefrom by filtration, and the filtrate was then concen-trated to dryness under reduced pressure. Furthermore, the residue (concentrate) was dissolved in water, and dilute hydrochloric acid was added thereto to adjust a pH to about 3. Insoluble matters which had been formed at this time were then removed therefrom by filtration, and a great deal of potassium carbonate was added to the filtrate, followed by extracting with chloroform. After completion of the extraction, the resulting organic layer was dried over anhydrous sodium sulfate and then subjected to a treatment under reduced pressure so as to distill off the solvent, thereby obtaining 1,3-dimethyl-6-[4-(3-aminopropyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 59) as a colorless syrupy. This product was then allowed to stand, whereby it crystallized.
(2) Preparation of 1,3-dimethyl-6-~4-[3-(4-nitro-anilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 58):
To 20 ml of dimethyl sulfoxide were added 2.50 g of the above obtained compound (compound 59) and 1.90 g of 4-nitrofluorobenzene, and the resulting mixture solution was heated at 80~C for 3 hours. After cooling, the deposited crystals were collected by filteration, washed, and dried to obtain 2.75 g of 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (compound 58').
Analytical results of the crystalline compound 58' thus obtained:
IR ~ KBrmax (cm-1): 3280, 1635, 1592, 1450, 1425, 1295, 1105, 990, 840 Values of elemental analysis (as C1gH26N6O4):
Calcd. (%): C 56.70; H 6.51; N 20.88 Found (%): C 56.19; H 6.88; N 20.50 Next, the thus prepared compound 58' was treated with a hydrochloric acid/methanol solution in a usual manner to prepare 1,3-dimethyl-6-~4-[3-(4-nitroanilino)propyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 58).
Analytical results of the crystalline compound 58 thus obtained:
Melting point: 270~C or more IR V KBrmax (cm-1): 3230, 1645, 1595, 1432, -2 ~ 8 9 1315, 1105, 837, 745 Values of elemental analysis (as C1gH26N6O4-HCl):
Calcd. ~%): C 51.99; H 6.20; N 19.15; Cl 8.08 Found (%): C 52.30; H 6.56; N 18.91; Cl 8.56 Example 37 Preparation of 1,3-dimethyl-6-{2- ([1-(4-nitrophenyl)-piperidin-4-yl]amino) ethylamino} -2,4(1 H,3H)-pyrimidinedione oxalate (compound 61 ):
02N~F + HN~}0 ; 02N~N~0 (compound 62) H2NCHzCHzNH~N-CH~
N~
(compound 63) CH~
(COOH)2/CH30H
o o2N ~ -N 3 NHCH2CH2NH ~ N-CHJ
N~ (C00H) 2 (compound 61) CH~
(1) Preparation of 1 -(4-nitrophenyl)-4-oxopiperidine .~
.
2~389 _ 144 -(compound 62):
In 20 ml of acetonitrile were dissolved 2.8 g of 4-nitrofluorobenzene, 3 g of 4-piperidone hydrochloride and 6.9 ml of triethylamine, and the solution was then heated under reflux for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water, and the deposited crystals were collected by filtration. The crystals were washed with water and then with ether, and they were recrystallized from isopropanol/hexane (1/1 in terms of volume ratio), collected by filtration, washed, and dried in order to obtain 3.47 g of 1-(4-nitrophenyl)-4-oxopiperidine (compound 62).
(2) Preparation of 1,3-dimethyl-6-{2-([1-(4-nitro-phenyl)piperidin-4-yl]amino)ethylamino}-2,4-(1H,3H)-pyrimi-dinedione oxalate (compound 61):
In 30 ml of methanol were suspended 0.5 g of the aboveprepared compound 62 and 1.8 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 63), and 0.58 ml of a 4 N HCl/dioxane solution was added dropwise to the resulting suspension at 0~C, followed by stirring at the same temperature for 1 hour.
Next, the bulk temperature of the reaction mixture was maintained at 0~C, and 0.14 g of sodium cyanoborohydride was added thereto little by little and stirring was then performed at the same temperature for 3 hours.
2Q~)1389 Then, a small amount of water was added to the reaction mixture, and methanol was distilled off under reduced pressure. The resulting residue was dissolved in 0.5 N
hydrochloric acid.
Potassium carbonate was added to this hydrochloric acid solution to make it alkaline, followed by extracting with chloroform.
Afterward, the extract (organic layer) was washed with water and then dried over anhydrous sodium sulfate, and the used solvent was distilled off under reduced pressure.
Afterward, the residue was then purified through a silica gel column chromatograph (chloroform/methanol = 50/1 to 25/1 in terms of volume ratio), thereby preparing 0.6 g of 1,3-dimethyl-6-~2-([1-(4-nitrophenyl)piperidin-4-yl]amino~-ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
NMR (CDC13) ~ppm: 1.5 (m, 4H), 2.2-3.2 (m, 7H), 3.30 (s, 3H), 3.41 (s, 3H), 4.0 (m, 2H), 4.86 (s, 1H), 6.93 (d, 2H), 8.17 (d, 2H) Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.52 g of 1,3-dimethyl-6-{2-([1-(4-nitrophenyl)-piperidin-4-yl~amino)ethylamino3-2,4(1H,3H)-pyrimidinedione oxalate (compound 61).
Analytical results of the crystalline compound 61 thus obtained:
Melting point: 216-217~C (decomposed) IR V KBrmax (cm-1): 2500, 1690, 1620, 1600, 1540, 1330, 810 Values of elemental analysis [as C1gH26N604-(COOH)2]:
Calcd. (%): C 51.22; H 5.73; N 17.06 Found (96): C 51.08; H 5.69; N 16.58 Example 38 Preparation of 1,3-dimethyl-6-{2-[4-(4-nitrophenyl)-piperazin-1 -yl]ethylamino}-2,4(1 H,3H)-pyrimidinedione oxalate (compound 64):
HN NH
OzN~F ~ OzN~N~ NH
(compound 66) CH3 /3So3CHzCHzNH~N~CH3 (compound 65) CH~
(COOH)2/CH30H
2~389 -~ 02N ~ N~_,N-CH2CH2NH ~ N-CH3 N ~ (COOH) 2 (compound 64) CH3 (1) Preparation of 1,3-dimethyl-6-[2-(p-toluene-sulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 65):
o ~ ~N-CH~
Cl N O
HOCH2CH2NH2 CH3 ~ SO2Cl >
-~ CH3 ~ SO~-CH2CH2NH ~ N-CH3 (compound 65) ~N O
First, 35 g of 2-aminoethanol was heated up to 90~C, and it was then taken out of the oil bath. Afterward, 50.0 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione was added thereto, so that reaction was performed. At this time, a rate of the addition was such that reaction temperature was maintained in the range of 90 to 110~C.
2~1389 After completion of the addition, the reaction mixture was stirred for 10 minutes, and 300 ml of dioxane/methanol (10/1 in terms of volume ratio) was added thereto, followed by standing onvernight. The resulting crystals were then 5 washed with a small amount of dioxane, and dried to obtain 49.0 g of white crystalline 1,3-dimethyl-6-(2-hydroxyethyl-amino)-2,4(1 H,3H)-pyrimidinedione.
Next, 200 ml of a pyridine suspension of this white crystals (49.0 g) was cooled to -5~C, and 40.0 g of 10 p-toluenesulfonyl chloride was added at such a rate that the reaction temperature did not exceed a level of 5~C.
Furthermore, 51.0 g of p-toluenesulfonyl chloride was additionally used to completely eliminate the turbidity of the reaction mixture.
Afterward, the reaction mixture was poured into 1.5 liters of ice water containing 70 g of K2CO3 and then allowed to stand overnight. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure in order to obtain 50.5 g of light yellow 20 crystalline 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethyl-amino]-2,4(1H,3H)-pyrimidinedione (compound 65).
Analytical results of the crystalline compound 65 thus obtained:
Melting point: 146.0-149.0~C
IR ~ KBrmax (cm-1): 3270, 1682, 1615, 1550, 2C~01389 1480, 1435, 1350, 1190, 1178, 1010, 903, 780 (2) Preparation of 1 -(4-nitrophenyl)piperazine (compound 66):
A mixture of 2.8 g of 4-nitrofluorobenzene, 15 g of piperazine and 20 ml of acetonitrile was heated under reflux for 6 hours. After cooling, chloroform was added to the reaction mixture, and the resulting solution was washed with water, dried (over anhydrous sodium sulfate), and concen-trated under reduced pressure to obtain N-(4-nitrophenyl)-piperazine (compound 66).
(3) Preparation of 1,3-dimethyl-6-{2-[4-(4-nitro-phenyl)piperazin-1-yl]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 64):
With 0.6 g of the above N-(4-nitrophenyl)piperazine (compound 66) was mixed 0.5 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 65), and the mixture was then heated at 80~C for hour. After cooling, the reaction mixture was diluted with 5 ml of acetonitrile.
Next, the diluted solution was then poured into 20 ml of a dilute aqueous sodium hydroxide solution, and the resulting mixture was extracted with chloroform. The resulting organic layer was washed with water, dried (over anhydrous sodium sulfate), and concentrated to dryness.
The residue (concentrate) was purified through a silica 2~ 89 gel column chromatograph (chloroform/methanol = 30:1 in terms of volume ratio) to obtain 1,3-dimethyl-6-~2-[4-(4-nitrophenyl)piperazin-1-yl]ethylamino~-2,4(1H,3H)-pyrimi-dinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3) ~ppm: 2.8-3.8 (m, 12H), 3.36 (s, 3H), 3.41 (s, 3H), 4.86 (s, 1H), 6.87 (d, 2H), 8.16 (d, 2H) This pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 0.36 g of 1,3-dimethyl-6-{2-[4-(4-nitrophenyl)piperazine-1-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 64).
Analytical results of the crystalline compound 6 thus obtained:
IR V KBrmax (cm~1): 1680, 1640, 1600, 1540, 1320, 830 Values of elemental analysis (as C20H24N6o4-2(cooH)2 4H20) Calcd. (%): C 43.38; H 5.46; N 12.65 Found (%): C 42.91; H 5.19; N 13.24 Example 39 Preparation of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethylamino]ethylamino}-2,4(1H,3H)-2~1389 pyrimidinedione oxalate (compound 67):
CH~
CH~NHCH2CH2NCH2CH2NHCH~
02N ~ F
02N ~ NCH2CH2NCH2CH2NHCH~
(compound 68) Cl ~ -CH3 N ~ (COOH) 2 /CH 3 OH
Cl~3 Cl~3 Cl~3 0 02N~NCI12CH2NCH2CH2N~A:-CH3 N~ - (COOH~ 2 (compound 67) CH 3 (1) Preparation of N,N',N"-trimethyl-N-(4-nitro-phenyl)diethylenetriamine (compound 68):
In 7 ml of dimethyl sulfoxide were dissolved 1.41 g of p-fluoronitrobenzene and 14 g of N,N',N"-trimethyldiethylene-triamine, and the mixture was then stirred at 120~C for 3 2~01389 hours.
The solvent was then distilled off from the reaction mixture under reduced pressure, and the residue was then dissolved in chloroform. This chloroform solution was washed with a small amount of water, and then dried over anhydrous sodium sulfate. The used solvent was distilled off under reduced pressure, so that 2.1 g of N,N',N"-tri-methyl-N-(4-nitrophenyl)diethylenetriamine (compound 68) was obtained in a yellow oily state.
(2) Preparation of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethylamino]ethylamino3-2,4(1H,3H)-pyrimidinedione oxalate (compound 67):
In 10 ml of ethanol were suspended 2.1 g of the above prepared N,N',N"-trimethyl-N-(4-nitrophenyl)diethylenetri-amine (compound 68), 1.22 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione and 2 ml of triethylamine, and the suspension was then heated under reflux for 1 hour. The resulting reaction mixture was then concentrated to dryness, and the residue was purified through a silica gel column chromatograph (chloroform/methanol = 50/1 to 25/1, v/v) and then recrystallized from acetone/water (1/1 in terms of volume ratio), thereby preparing 1.87 g of 1,3-dimethyl-6-~N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethyl-amino]ethylamino~-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystals thus obtained:
2~ 389 Melting point: 65~C
NMR (CDCl3), ~ppm: 2.40 (s, 3H), 2.82 (s, 3H), 3.38 (s, 3H), 3.50 (s, 3H), 3.54 (s, 3H), 2.78 (m, 2H), 3.13 (m, 2H), 3.80 (m, 2H), 5.40 (s, 1H), 6.78 (m, 2H), 8.62 (m, 2H) Values of elemental analysis (as C1gH2gN6O4) Calcd. (~): C 56.42; H 6.98; N 20.78 Found (~): C 56.63; H 7.31; N 19.98 The thus obtained 1,3-dimethyl-6-{N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethylamino]ethylamino}-2,4-(1H,3H)-pyrimidinedione was treated with an oxalic acid/-methanol solution in a usual manner to obtain 1.91 g of 1,3-dimethyl-6-~N-methyl-2-[N-methyl-2-(N-methyl-4-nitro-anilino)ethylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 67).
Analytical results of the crystalline compound 67 thus obtained:
Melting point: 184-185~C (decomposed) IR ~ KBrmax (cm-1): 3460, 1700, 1642, 1545, 1480, 1310, 1200, 1100, 833, 722 Values of elemental analysis (as C1gH26N6O4-(cOoH)2-2H2o) Calcd. (%): C 50.09; H 6.21; N 16.69 Found (~): C 50.29; H 6.29; N 16.11 ~ ~ Q ~ 3 8 ~1 . .
_ 154 -Example 40 Preparation of 1,3-dimethyl-6-{4-[3-(N-methyl-4-nitro-anilino)propyl]piperazin-1 -yl3 -2,4(1H,3H)-pyrimidinedione oxalate (compound 69):
02N ~ NHCH2CH2CH2N~_,N ~ -CH3 (compound 58') CH~
CH~I (COOH)2/CH.OH
CH, O
02N ~ NCH2CH2CH2N N ~ -CH3j ~-~ ,N-~3 ~ (COOH)2 (compound 69) C H, At room temperature, 0.12 g of sodium hydride (60%
( dispersion in mineral oil) was added to a suspension obtained by suspending 0.1 g of 1,3-dimethyl-6-{4-t3-(4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione (compound 58') obtained in Example 36 in 15 ml of anhydrous dimethylformamide, and they were stirred for 30 minutes. Afterward, 0.29 g of methyl iodide was further added thereto.
This mixture was stirred at room temperature for 10 B
~1389 minutes, and a small amount of methanol and then 50 ml of chloroform were added thereto. Afterward, the resulting reaction mixture was poured into 50 ml of water. The separated organic layer was taken out, washed with water, and dried (over anhydrous sodium sulfate). The used solvent was distilled off, and the residue was crystallized from a methanol/ether solution (1/1 in terms of volume ratio), collected by filtration, washed, and dried in order to obtain 0.62 g of 1,3-dimethyl-6-[4-{3-(N-methyl-4-nitro-anilino)propyl3piperazin -1-yl]-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
IR V KBrmax (cm~1): 1690, 1640, 1588, 1520, 1480, 1425, 1282, 1205, 1101, 815 NMR (d6-DMSO), Sppm: 1.82 (m, 2H), 2.13-2.73 (m, 6H), 2.73-3.07 (m, 4H), 3.10 (s, 3H), 3.17 (s, 3H), 3.30 (s, 3H), 3.57 (t, 2H), 5.22 (s, 1H), 6.87 (d, 2H), 8.10 (d, 2H) Values of elemental analysis (as C20H28N6~4 2H2~) Calcd. (%): C 57.13; H 7.67; N 19.99 Found (~): C 57.49; H 7.02; N 20.16 This pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[3-(N-methyl- 4-nitroanilino)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate 2 ~ ~ ~ 3 8 ~
_ _ _ 156 (compound 69).
Analytical results of the crystalline compound 69 thus obtained:
Values of elemental analysis 5(as C20H28N6o4~(cooH)2-2H2o) Calcd. (%): C 51.76; H 6.71; N 16.46 Found (~): C 52.05; H 6.08; N 16.56 Example 41 Preparation of 1,3-dimethyl-6- {4-t3-(N-methansulfonyl-104-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 70):
02N~NHCH2CH2CH2N~_N~II-CH, (compound 58') - CH, CH,SO,Cl (COOH)2/CH,OH
SO2CH, O
2002N~NCHzCH2CH2N~ N~ ~ (COOH)z (compound 70) CH ~
In 20 ml of chloroform were dissolved 0.4 g of 1,3-dimethyl-6- {4-[3-(4-nitroanilino)propyl]piperazin-1 -yl3 -252,4(1H,3H)-pyrimidinedione (compound 58') obtained in '~
2~01;~89 _ 157 -Example 36 and 0.4 g of triethylamine, and 0.2 g of methanesulfonyl chloride was further added to the resulting solution under ice cooling.
This mixture was allowed to stand overnight at room temperature, and a small amount of water was added thereto, followed by stirring at room temperature for 30 minutes.
Furthermore, 20 ml of a dilute aqueous alkaline solution was added to the reaction mixture, and the separated chloroform layer was washed with water and then dried over anhydrous sodium sulfate. Afterward, the dried chloroform layer was treated under reduced pressure to distill off the solvent. The resulting residue was purified through a silica gel column chromatograph (chloroform/-methanol = 100/1 to 25/1 in terms of volume ratio), thereby preparing 0.35 g of 1,3-dimethyl-6-{4-[3-(N-methanesulfonyl-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione.
This pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[3-(N-methanesulfonyl-4-nitroanilino)-propyl]piperazin -1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 70).
Analytical results of the crystalline compound 70 thus obtained:
Melting point: 204.0-204.5~C
Z~ 89 _ 158 -Values of elemental analysis (as C20H28N6o6s-(cooH)2-2H2o) Calcd. (%): C 43.56; H 5.65; N 13.85; S 5.29 Found (~): C 43.81; H 5.24; N 13.35; S 5.52 IR ~ KBrmax (cm~1): 1780, 1695, 1630 (br), 1350, 1340, 1205, 1155 Example 42 Preparation of 1,3-dimethyl-6-~2-[N-ethyl-2-(4-nitro-anilino)ethylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 71):
n2N~ NHCH2CH2NH + CN ~ N-CH3 (compound 72) CH 3 HC1/CH~OH
CH2CH~ O
02N ~ NHCH2CH2NCH2CH2-NH ~ N-CH~
- N~ (CO2H)2 (compound 71) / o (1) Preparation of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 72):
2(~ 89 CH9~ SO9-CHZCH2NH~ N-CH9 (compound 6 5) CH~
NaH /DblSO CN~ N-CH3 (COmPOUnd 72) CH3 TO 150 ml of an anhydrous dimethyl sulfoxide containing 47 2 g of the compound 65 obtained in Example 38-(1) was slowly added 6. 24 g of sodium hydride (60% dispersion in mineral oil) at room temperature. This reaction mixture was stirred vigorously at room temperature for 5 hours, and then cooled. Afterward, a small amount of water was added thereto so as to bring reaction to an end. This solution was poured into 1 liter of water containing 70 g of potassium carbonate, and then extracted with 200 ml of chloroform three times. The combined organic layer was dried over anhydrous sodium sulfate and then concentrated, and 300 ml of ether was added to the resulting concentrate.
Afterward, the solution thus obtained was allowed to stand overnight.
Light yellow crystals which had been deposited by the _ 160 -overnight standing were collected by filtration, washed with ether, and dried under reduced pressure in order to obtain 15.2 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimi-dinedione (compound 72).
Analytical results of the crystalline compound 72 thus obtained:
Melting point: 126.0-126.5~C
IR ~ KBrmax (cm 1): 1705, 1650, 1612, 1470, 1440, 1305, 1150, 783, 490 lH-NMR (CDC13), sppm: 2.34 (s, 4H), 3.35 (s, 3H), 3.56 (s, 3H), 5.25 (s, 3H) (2) Preparation of 1,3-dimethyl-6-{2-[N-ethyl-2-(4-nitroanilino)ethylamino]ethylamino)-2,4(1H,3H)-pyrimidine-dione oxalate (compound 71):
In 5 ml of chloroform were dissolved 1.32 g of N-ethyl-N'-(4-nitrophenyl)ethylenediamine and 1.12 g of the above obtained 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 72), and the resulting reaction mixture was concentrated under reduced pressure. To the residue (concentrate) was added 10 mg of Amberlist 15 (trade mark; made by Rohm & Haas Co.), and the mixture was then heated at 80~C for 1 hour.
Next, the resulting reaction mixture was dissolved in 5 ml of ethyl acetate, and Amberlist 15 was then removed therefrom by filtration. Afterward, n-hexane was added to 2~ 9 the filtrate.
Furthermore, the resulting solution was allowed to stand overnight, and deposited crystals were collected by filtration, washed with n-hexane, and dried under reduced pressure in order to obtain 1.5 g of 1 ,3-dimethyl-6-{2-[N-ethyl-2-(4-nitroanilino)ethylamino]ethylamino~ -2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
1H-NMR (CDC13), ~ppm: 1.12 (t, 3H), 2.52-2.98 (m, 6H), 2.98-3.25 (m, 2H), 3.28 (s, 6H), 3.28-3.48 (m, 2H), 4.78 (s, 1H), 5.27 (m, 1H), 5.45 (m, 1H), 6.59 (d, 2H), 8.08 (d, 2H) Furthermore, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 1.4 g of 1,3-dimethyl-6-{2-[N-ethyl-2-(4-nitroanilino)ethylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 71 ).
Analytical results of the crystalline compound 71 thus obtained:
Melting point: 175.0-176.5~C
values of elemental analysis (as C18H26N6~4-(C~~H)2) Calcd. (%): C 50.00; H 5.87; N 17.49 Found (96): C 49.81; H 6.02; N 17.22 2Qal1389 Example 43 Preparation of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-nitro-anilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 73):
OZN~3~NHCH2CH2CH2NH + C N ~ N-CH3 (compound 72) CH 3 HCl/CH30H
02N ~ NHCH2CH2CH21~lCH2CH2-NH ~ N-CH3 ~ i HCl (compound 73) C/H 3 O
The same procedure as in Example 42-(2) was repeated with the exception that N-ethyl-N'-(4-nitrophenyl)ethylene-diamine was replaced with 1.45 g of N-ethyl-N'-(4-nitro-phenyl)-1,3-propylenediamine as a starting material, in order to obtain crystals of 1,3-dimethyl-6-~2-[N-methyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimi-dinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
- 2(~1389 NMR (DMSO-d6), sppm: 1.05 (t, 3H), 1.6-1.9 (m, 2H), 2.4-2.8 (m, 6H), 3.0-3.4 (m, 4H), 3.1 (s, 3H), 3.25 (s, 3H), 4.65 (s, 1H), 6.4 (br, 1H), 6.6 (d, 2H), 7.2 (br, 1H), 8.0 (d, 2H) The thus obtained crystals were treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{2-[N-ethyl-3-(4-nitroanilino)propyl-amino]ethylamino} -2,4(1 H,3H)-pyrimidinedione hydrochloride (compound 73).
Analytical results of the crystalline compound 73 thus obtained:
Values of elemental analysis (as C19H28N6O4-2HCl) Calcd. (%): C 47.80; H 6.33; N 17.60; Cl 14.85 Found (%): C 47.52; H 6.49; N 17.31; Cl 14.76 Example 44 Preparation of 1,3-dimethyl-6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1 -yl]ethylamino} -2,4(1 H,3H)-pyrimi-dinedione oxalate (compound 74):
~N-CH2CHzOH
02N ~N~JNH
(compound 66) ~n ~ ~ ~ 8 9 _ 164 --~ 02N ~ N~_N-CH2CH2NH
(compound 75) ~
Cl ~ ~ N-CHs CH, ~ (COOH)z/CH~OH
( 02N ~ N~_JN-CH2CH2N ~ (COOH)2 (compound 74) CH~
(1) Preparation of 1-[2-(2-hydroxyethylamino)ethyl]-4-(4-nitrophenyl)piperazine (compound 75):
In 20 ml of chloroform was dissolved 4 g of 1-(4-( nitrophenyl)piperazine (compound 66) and 0.52 ml of 1-(2-hydroxylethyl)aziridine, and the solvent was distilled off from the resulting reaction mixture under reduced pressure. To the residue was added 10 mg of Amberlist 15 (trade name; made by Rohm & Haas Co.), and the mixture~was then heated with stirring at 100~C for 3 hour. Afterward, the temperature of the reaction mixture was returned to room temperature. To the reaction mixture was added 20 ml of . . .
Z~0~389 - 165 _ chloroform, and insoluble matters were then removed therefrom by filtration. The filtrate was concentrated, and the resulting residue (concentrate) was purified through a silica gel column chromatograph (chloroform/methanol = 100/1 to 25/1 in terms of volume ratio), thereby preparing 1 g of 1-[2-(2-hydroxyethylamino)ethyl]-4-(4-nitrophenyl)piperazine (compound 75).
(2) Preparation of 1,3-dimethyl-6-~N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1-yl]ethylamino3-2,4(1H,3H)-pyrimidinedione oxalate (compound 74):
To 10 ml of ethanol were added 1.0 g of the thus obtained compound 75, 0.52 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidined one and 2 ml of triethylamine as starting materials, and the resulting mixture was treated in the same procedure as in Example 39-(2) to obtain 0.73 g of 1,3-dimethyl-6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)-piperazin-1-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.65 (m, 6H), 2.9-3.4 (m, 8H), 3.31 (s, 3H), 3.47 (s, 3H), 3.82 (m, 2H), 5.32 (s, 1H), 6.86 (d, 2H), 8.12 (d, 2H) Then, 0.7 g of this pyrimidinedione derivative was further treated with an oxalic acid/methanol solution in a usual manner to obtain crystals of 0.35 g of 1,3-dimethyl-Z~389 _ 166 -6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1-yl]-ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 74).
Analytical results of the crystalline compound 74 thus obtained:
Values of elemental analysis [as C20H28N6os-1.5(cooH)2-H2o]
Calcd. (%): C 47.18; H 5.68; N 14.35 Found (%): C 47.37; H 5.94; N 14.08 Example 45 Preparation of tablets containing, as an effective component, 1,3-dimethyl-6-{4-[3-(4-nitroanilino)propyl]-piperazin-1-ylJ-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 58) which can be prepared by the process of Example 36:
With 20 g of corn starch were sufficiently mixed 1 g of the above pyrimidinedione derivative hydrochloride (compound 58) and 123 g of lactose, and the mixture was further mixed with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in 100 ml of water, so as to form grains, followed by drying the grains at 50~C for 4 hours. Afterward, 1 g of magnesium stearate was added to the dried grains and then mixed sufficiently. The mixture was then formed into tablets by the use of a tableting machine, the weight of each tablet being 150 mg.
20~1389 Example 46 Preparation of capsules containing, as an effective component, 1,3-dimethyl-6-~2-~[1-(4-nitrophenyl)piperidin-4-yl]amino)ethylamino}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 61) which can be prepared by the processof Example 37:
With 25 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (compound 61) and 120 g of lactose, and hard capsules were filled with the resulting mixture by the use of a capsule filling machine to prepare capsules, the content of the mixture in each capsule being 150 mg.
Example 47 Preparation of an injection containing, as an effective component, 1~3-dimethyl-6-{2-(N-methyl-N-[3-(4-nitroanilino) propyl]amino)ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 73) which can be prepared by the process of Example 43:
In distilled water for injection were dissolved 20 mg of the above pyrimidinedione derivative hydrochloride (compound 73) and 0.85 g of sodium chloride, and the total volume of the liquid was regulated to be 100 ml, thereby preparing an injection.
Pharmacological Test 3 Following the same procedure as in Pharmacological Test 1, ADP7s and ERP of the respective compounds prepared in the above examples in Table 6 were calculated. The results are set forth in Table 6.
Toxicity Test 3 Following the same procedure as in Toxicity Test 1, toxicity of the respective compounds prepared in the above examples in Table 7 was tested to calculate a mortality rate of mice. The results are set forth in Table 7.
Administration was made by oral administration (p.o.) in an amount of 300 mg/kg of each compound for one mouse.
Table 6 (results of pharmacological test) Com- APD75 (%) ER? (%) pound Dose (lls~ml) Dose mg/kg,i.v.) 15No. 0.31.0 3.0 10.0 0.10. 1.0 3.0 61 - - - - 8.38.3 8.3 64 8 23 32 - 21.428.6 28.6 20 69 - - 11 13 6.76.7 13.3 20.0 71 - 8 15 17 6.77.7 13.4 16.6 Table 7 (results of toxicity test) Compound Number Mortality Rate (%) 2~1389 Example 48:
Preparation of 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrophenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 76) N, o BrcHzcHzcHzoH ~ HocHzcH2cH2N N ~,N-CH3 0 2 N ~ COCH3 OH(COOH) 2 /CH 3 OH
02N~ocH2CH2CH2N,~N)~N-CH3 3 CH3 ~(COOH)2 (Compound 76) (1) Preparation of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione:
14.1 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione, 11.7 g of 3-bromo-1-propanol and 13 g of triethylamine were reacted by heating them under reflux for 20 hours in 250 m~ of ethanol. After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was dissolved in 300 m~ of chloroform. The resultant solution was washed twice with 100 m~ of water. After the washing, the organic layer was dried 2~01389 over anhydrous magnesium sulfate. The organic layer was heated under reduced pressure, whereby the solvent was distilled off to obtain 20.5 g of a reaction product in a crude form. Ether was added to the crude reaction product to crystallize it. Resulting crystals were collected by filtration, washed with chilled ether, and then dried to obtain 12.4 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione(yield: 69.8%).
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 119-121~C.
NMR (CDC13), ~ ppm: 1.8 (dt,2H), 2.7(m,6H), 3.02(m,4H), 3.36(s,3H), 3.43(s,3H), 3.82(t,2H), 4.34(br,1H), 5.26(s,1H).
IR vmBax (cm 1): 3380(Br), 3180(s), 2830, 1695, 1650, 1605, 1440, 1213, 1068, 1000, 921, 760.
(2) Preparation of 1,3-dimethyl-6-~4-[3-(2-acetyl-4-nitrophenoxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 76):
Into a suspension which had been obtained by mixing 0.6 g of the pyrimidinedione derivative obtained in the above procedure (l), 0.54 g of 2-hydroxy-5-nitroacetophenone and 0.69 g of triphenylphosphine in 10 m~ of anhydrous tetrahydrofuran, 0.42 m~ of diethyl azodicarboxylate was added dropwise under stirring at room temperature.
Next, the resulting mixture was stirred for 30 minutes at room temperature and then concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/l by volume), whereby 0.7 g of 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrophenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione was obtained as an oily matter.
Analytical results of the thus-obtained pyrimidinedione derivative:
NMR (CDC13), ~ ppm: 8.47(m,1H), 7.54(m,1H), 6.91(d,1H), 5.23(s,1H), 4.26(m,2H), 3.37(s,3H), 3.30(s,3H), 2.98(m,4H), 2.60(m,6H), 2.63(s,3H), 2.16(m,2H).
Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.73 g of 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrophenoxy)propyl]-Z~6~1389 piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate tCompound 76).
Analytical results of Compound 76 thus obtained:
Melting point: 122-124~C (decomposed).
IR vmax (cm 1): 3400, 3020, 2600, 1690, 1640, 1520, 1340, 1280, 1120, 820, 750, 700.
Elemental analysis for C21H27N506 ( 2 2 Calculated (%): C, 48.33; H, 5.82; N, 12.25.
Found (~): C, 48.22; H, 5.69; N, 11.93.
Example 49:
Preparation of 1,3-dimethyl-6-{4-[3-(4-acetyl-2-nitrophenoxy1propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 77):
HOCHzCHzCH2N~JN ~ N-CH3 N o CH 3 CO~ rNOz ~ OH (COzH)2/CH30H
3CO~OCH2CH2CH2N~JN~N-CH3 CH3 ~(COOH)2 (Compound 77) Z~ 89 By a procedure similar to Example 48-(2) except for the use of 4-hydroxy-3-nitroacetophenone in lieu of 2-hydroxy-5-nitroacetophenone, 1,3-dimethyl-6-{4-[3-(4-acetyl-2-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 77) was obtained.
Analytical results of the pyrimidinedione derivative (Compound 77) thus obtained:
Melting point: 119-123~C ~decomposed).
IR vKBr (Cm-l~ 3380, 2250, 1700, 1640, max 1530, 1350, 1020, 760, 700.
Elemental analysis for C21H27N5O6 ( 2 2 Calculated (~): C, 46.86; H, 5.98; N, 11.28.
Found (~): C, 46.79; H, 5.43; N, 11.51.
Example 50:
Preparation of 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 78):
HOCH2CHzCHz~ N ~ ~-CH3 o ~, N 0 2 OH, (COOH) z/CH30H
2~0~3~39 2cH2cH2N~N~N-CH3 CH3 (COOH)2 (Compound 78) By a procedure similar to Example 48-(2) except for the use of 4-hydroxy-3-nitroacetophenone in lieu of 2-hydroxy-5-nitroacetophenone, 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 78) was obtained.
Analytical results of the pyrimidinedione derivative (Compound 78) thus obtained:
Melting point: 168-171~C (decomposed).
IR vma (cm 1): 3400, 3050, 1730, 1630, 1540, 1350, 1080, 760, 700.
Y 26 29N5~6 (COOH)2 H2O
Calculated (%): C, 54.63; H, 5.40; N, 11.38.
Found (%): C, 54.99; H, 5.29; N, 11.30.
Example 51:
Preparation of 1,3-dimethyl-6-{4-t3-(3-acetyl-4-nitrophenoxy)propyl3piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 79):
2~1389 HOCH2CHzCHzN~ - ~ N-CH3 N o CH3CO ~ OH (COOH)z/CH3OH
2N ~ 2 2 2 ~_~ ~ 3 CH3 ~(COOH)2 (Compound 79) By a procedure similar to Example 48-(2) except for the use of 5-hydroxy-2-nitroacetophenone in lieu of 2-hydroxy-5-nitroacetophenone, 1,3-dimethyl-6-{4-[3-(3-acetyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 79) was obtained.
Analytical results of the pyrimidinedione derivative (Compound 79) thus obtained:
Melting point: 223-224~C (decomposed).
IR vmax (cm 1): 3440, 3000, 2600, 1730, 1600, 1520, 1350, 1020, 810.
Elemental analysis for C21H27N5O6 ( 2 2 Calculated (%): C, 48.33; H, 5.82; N, 12.25.
Found (%): C, 48.17; H, 5.62; N, 12.05.
Example 52:
1i 389 Preparation of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 80):
OzN~CI OzN~OH
~=0 ~ ~=0 HOCHz CHz CHzN N ~-CH3 '-- N~- (COOH) z/CH~OH
CH~
02N~oCH2CH2CH2N\JN~N-CH3 ~ CH3 ~(COOH) 2 (Compound 80) (1) Preparation of 2-hydroxy-5-nitrobenzophenone:
In an autoclave, a suspension which had been obtained by suspending 3 g of 2-chloro-5-nitrobenzo-phenone and 1.1 g of potassium hydroxide in 30 mQ of water was heated under stirring at 150~C for 5 hours.
After completion of the heating, the autoclave was allowed to cool down. The resultant reaction mixture was added with 30 mQ of water, followed by the addition of hydrochloric acid to acidify the reaction mixture. Crystals precipitated upon the acidification were collected by filtration.
Z~11389 The thus-obtained crystals were recrystallized from ethanol to obtain 2.3 g of 2-hydroxy-S-nitro-benzophenone.
Analytical results of the crystals thus obtained:
Melting point: 125-126~C.
NMR (CDC13), ~ ppm: 7.21(m,2H), 7.68(m,4H), 8.41(m,2H), IR vmax (cm 1): 3040, 1600, 1520, 1330 1280, 1210, 1080, 960, 690.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 80):
By a procedure similar to Example 48-(2), 0.73 g of 2-hydroxy-5-nitrobenzophenone obtained in the above procedure (1), 0.5 g of 1,3-dimethyl-6-[4-(3-hydroxy-propyl)piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione, 0.58 g of triphenylphosphine and 0.34 m~ of diethyl azodicarboxylate were reacted in 10 m~ of anhydrous tetrahydrofuran, whereby 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione was obtained as a syrup-like matter (0.7 g).
Analytical results of the pyrimidine derivative thus obtained:
2C~)1389 NMR (CDC13), ~ ppm: 8.36(m,2H), 7.0-7.8(m,6H), 5.14(s,1H), 4.14(t,2H), 3.26(s,3H), 3.34(s,3H), 3.0 (m,4H), 2.2-2.5(m,6H), l.9(m,2H).
Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.71 g of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 80).
Analytical results of the pyrimidinedione derivative (Compound 80) thus obtained:
Melting point: 200-202~C (decomposed).
IR vmax (cm 1): 3450, 2910, 1690, 1650, 1510, 1330, 1280, 1150, 1080, 760, 700.
Elemental analysis for C26H29N5O6-~(COOH)2-~H2O:
Calculated (%): C, 57.85; H, 5.39; N, 12.49.
Found (%): C, 57.71; H, 5.54; N, 12.24.
Example 53:
Preparation of Compounds 87-92:
~ ~i13 By a procedure similar to Example 52-(1) except for the use of Compounds 81-86 of the following structural formula (1) - in which Xl means the groups set out below respectively - in place of 2-chloro-5-nitrobenzophenone, phenol derivatives of the below-described structural formula (I') in which Xl varies respectively were obtained as Compounds 81'-86'.
O2N ~ Cl (I) ~7 X
O2N ~ OH (I') xl Compound No. Xl 81, 81' -CO ~ Br 82, 82' -CO ~ NH
83, 83' -CO~
N
84, 84' -CO
85, 85' -CO ~
86, 86' -CO ~ N
2~ 389 Analytical results of Compound 81' thus obtained:
NMR (CDC13), ~ ppm: 8.38(m,2H), 7.70(m,4H), 7.41(m,1H), Elemental analysis for C13H8NO4Br:
Calculated (%): C, 48.47; H, 2.50; N, 4.35;
Br, 24.81.
Found (%): C, 48.52; H, 2.31; N, 4.45;
Br, 24.42.
Analytical results of Compound 83' thus obtained:
IR vmax (cm 1): 1690, 1560, 1400, 1310, 770, 750.
Analytical results of Compound 84' thus obtained:
IR vmax (cm 1): 1660, 1520, 1340, 1270, 1040, 730.
By a procedure similar to Example 52-(2) except that the phenol derivatives, i.e, Compounds 81'-86' were used respectively instead of 2-hydroxy-5-nitro-benzophenone, pyrimidinedione derivative oxalates (Compounds 87-92) having the following physical properties and the following structural formula (II) in which Xl means the below-described groups respective-ly were obtained.
O2N ~ lH2CH2CH2N~_~N ~ ~N_cH3 (II) CH3 ~(COOH)2 2~389 Analytical results of Compound 87 (in which Xl has the same meaning as in Compound 81):
Melting point: 134-135~C (Decomposed).
IR vmax (cm 1): 2900, 1710, 1640, 1530, 1340, 840, 790.
Elemental analysis for C26H28Ns~6Br-(C~~H)2-3H2~
Calculated (%): C, 46.04; H, 4.97; N, 9.59;
Br, 10.94.
Found (%): C, 46.26; H, 5.16; N, 9.92;
Br, 10.53.
Analytical results of Compound 88 (in which Xl has the same meaning as in Compound 82):
Melting point: 171-174~C (Decomposed).
IR vmax (cm 1): 3450, 1710, 1640, 1550, 1440, 1350, 1200, 760.
Elemental analysis for C23H27N7O6-2(COOH)2:
Calculated (%): C, 47.86; H, 4.61; N, 14.47;
Found (%): C, 47.38; H, 5.17; N, 14.40.
Analytical results of Compound 89 (in which Xl has the same meaning as in Compound 83):
Melting point: 149-151~C (Decomposed).
IR vmax (cm 1): 2550, 1700, 1660, 1520, 1340, 850, 800.
e ent n ys s 24H27N7~6 2(COo )2 2 2~
Calculated (%): C, 45.22; H, S.02; N, 13.19;
Found (%): C, 45.60; H, 5.18; N, 13.59.
2~1389 Analytical results of Compound 90 (in which Xl has the same meaning as in Compound 84):
Melting point: 177-178~C (Decomposed).
IR vmax (cm 1): 2950, 1720, 1650, 1520, 51320, 1260, 860, 760.
Element 1 na ys s 25H28N6~6 2(C )2 2 Calculated (%): C, 48.07; H, 5.01; N, 11.60.
Found (%): C, 48.02; H, 5.05; N, 11.31.
Analytical results of Compound 91 (in which Xl has the same meaning as in Compound 85):
Melting point: 104-107~C (Decomposed).
IR vKBr (cm~l~ 2700, 1690, 1630, 1540, max 1340, 1280, 800.
Y 25 28 6 6 ( )2 2 Calculated (%): C, 46.90; H, 5.16; N, 11.32.
Found (%): C, 46.88; H, 5.42; N, 11.38.
Analytical results of Compound 92 (in which Xl has the same meaning as in Compound 86):
Melting point: Amorphous.
IR vmax (cm 1): 1740, 1690, 1600, 1550, 1350, 1260, 780, 700.
Elemental analysis for C25H28N6O6 ( 2 2 Calculated (%): C, 46.29; H, 4.85; N, 11.89.
Found (%): C, 48.85; H, 4.97; N, 11.44.
Example 54:
Preparation of 1,3-dimethyl-6-{4-[2-(2-acetyl--_ - 183 - 2 n ~ 1 ~ 8 9 4-nitrophenoxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 93):
o HOCH2CH2N NH+ Cl ~N-CH3 N o ) HOCHzCH2N N ~ ~-CHs I N
02N~ COCH3 (COOH)2/CH3OH
CH3 ~(COOH)2 (Compound 93) (1) Preparation of 1~3-dimethyl-6-t4-(2-hydroxyethyl) ( piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione:
2.7 g of 6-chloro-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione, 4 ml of 1-(2-hydroxyethyl)pipera2ine and 12 ml of triethylamine were dissolved in 70 ml of isopropanol. The resultant solution was heated under reflux for 3 hours.
After completion of the heating, the reaction mixture was allowed to cool down, the solvent was removed under reduced pressure from the reaction .,, ~,...
2(~:)1389 mixture, and the residue was dissolved in 60 m~ of chloroform. The chloroform solution thus obtained was washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to obtain the reaction product in a crude form.
Next, a mixed solvent of ethanol and ethyl ether was added to the crude reaction product. Precipitated crystals were collected by filtration. Those crystals were then recrystallized from hexane/ethanol to obtain 3.72 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 5.21(s,1H), 3.69~t,2H), 3.35(s,3H), 3.26(s,3H), 2.5-3.1(m,10H).
(2) Preparation of 1,3-dimethyl-6-{4-t2-(2-acetyl-4-nitrophenoxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 93):
0.5 g of the pyrimidinedione derivative obtained by the above procedure (1), 0.65 g of 2-hydroxy-5-nitroacetophenone, 0.6 g of triphenylphosphine and 2~1389 0.36 m~ of diethyl azodicarboxylate were reacted in a similar manner to Example 48-(2) to obtain 0.65 g of 1,3-dimethyl-6-{4-[2-(2-acetyl-4-nitrophenoxy)ethyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 8.2-8.6(m,2H), 7.08(m,1H), 5.26(s,1H), 4.35(m,2H), 3.42(s,3H), 3.34(s,3H), 2.72(s,3H), 2.7-3.2(m,10H).
Next, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known Per se in the art to obtain 0.68 g of 1,3-dimethyl-6- {4-[2-(2-acetyl-4-nitrophenoxy)ethyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 93):
Analytical results of the pyrimidinedione derivative (Compound 93) thus obtained:
Melting point: 193-195~C (Decomposed~.
IR vKar (cm 1): 3290, 2650, 1720, 1640, 1520, 1340, 1270, 1120, 2~1389 830, 760, 7~0.
Elemental analysis for C20H25N5O6 (C 2 2 Calculated (%): C, 48.98; H, 5.42; N, 12.98.
Found (%): C, 49.02; H, 5.22; N, 12.90.
Example 55:
Preparation of Compounds 99-103:
Using phenol derivatives (Compounds 94-98) having the below-described structural formula (III) in which R7, R8 and R9 mean the below-described groups respectively, pyrimidinedione derivative oxalates (Compounds 99-103) having the physical properties set out below and the below-described structural formula (IV) in which R7, R8 and R9 are different from one compound to another were obtained respectively in a similar manner to Example 54-(2).
R7 ~ OH (III) 2~1389 Compound 94 -H -CO ~ -NO2 A
Compound 95 -H -CO ~ Br -NO2 Compound 96-COCH3 -H -NO2 Compound 97 -H -No2 -COCH3 Compound 98 -H -NO2 -CO
~ 2 2 ~ 3 R R CH3 ~ (COOH)2 (IV) Compound 99 (R7, R8 and R9 are as defined with respect to Compound 94):
Melting point: 160-162~C (decomposed).
IR vmBax (cm 1): 2530, 1700, 1640, 1520, 1340, 760, 700.
Elemental analysis for C25H27N5O6 ( 2 2 Calculated (%): C, 52.34; H, 5.37; N, 11.30.
Found (%): C, 52.14; H, 5.18; N, 11.42.
- 2~ 89 Compound 100 (R7, R8 and R9 are as defined with respect to Compound 95):
Melting point: 136-138~C (decomposed).
IR vKBr (cm-l) 2600, 1700, 1600, 1530, max 1340, 800, 700.
Elemental analysis for C25H26BrN5O6 (C 2 2 Calculated (%): C, 46.43; H, 4.62; N, 10.03;
Br, 11.44.
Found (%): C, 46.64; H, 4.43; N, 10.30;
Br, 11.25.
Compound 101 (R7, R8 and R9 are as defined with respect to Compound 96):
Melting point: 110~C (amorphous).
IR VKBr (cm-l~ 2990, 2550, 1700, 1630, max 1520, 1320, 1180, 800.
Y 20 25N5~6 (COOH)2 3H2O
Calculated (%): C, 45.91; H, 5.78; N, 12.17.
Found (%): C, 45.76; H, 5.54; N, 12.07.
Compound 102 (R7, R8 and R9 are as defined with respect to Compound 97):
Melting point: 139-141~C (decomposed).
IR vKBr (Cm-l~ 3300, 2950, 1700, 1640, max 1530, 1360, 1270, 800, 760.
Elemental analysis for C20H25N5~6-(COOH)2-H2~
Calculated (%): C, 48.98; H, 5.42; N, 12.98.
Found (%): C, 49.08; H, 5.97; N, 12.97.
2C~01389 Compound 103 (R7, R8 and R9 are as defined with respect to Compound 98):
Melting point: 133-135~C (decomposed).
IR vKax (cm 1): 3000, 2550, 1740, 1630, 51540, 1340, 1280, 760, 700.
Elemental analysis for C25H27N5O6 ( 2 2 Calculated (~): C, 53.91; H, 5.19; N, 11.64.
Found (%): C, 53.66; H, 4.96; N, 11.86.
Example 56:
Preparation of 1,3-dimethyl-6-{4-<3-t2-(2-hydroxybenzoyl)-4-nitrophenoxy]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 104):
~5 O
O2N ~ O-(CH2)3N N ~ -CH3 CH3 ~ (COOH)2 OH
(Compound 104) (1) Preparation of 2,2'-dihydroxy-5-nitrobenzophenone (Compound 104'):
~o ~ OH
(Compound 104') A reaction mixture, which had been obtained by suspending 3 g of 2,2'-dichloro-5-nitrobenzophenone and 1.1 g of potassium hydroxide in 30 m~ of water, was heated under stirring at 150~C for S hours in an autoclave.
After allowing the reaction mixture to cool down, 30 m~ of water were added to the reaction mixture. Hydrochloric acid was then added to acidify the reaction mixture, and precipitated crystals were collected by filtration.
Those crystals were dried under reduced pressure to obtain 1.9 g of 2,2'-dihydroxy-S-nitrobenzophenone (Compound 104'). Those crystals were used in the following reactions without any further purification.
(2) Preparation of 1,3-dimethyl-6-t4-<3-C2-(2-hydroxy-benzoyl)-4-nitrophenoxy]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 104):
In a similar manner to Example 48-(2), 0.7S g of 2,2'-dihydroxy-S-nitrobenzophenone obtained in the above procedure (1), O.S g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidine-dione, O.S8 g of triphenylphosphine and 0.34 m~ of diethyl azodicarboxylate were reacted in 10 m~ of anhydrous tetrahydrofuran, and the reaction mixture was treated to obtain 0.6 g of 1,3-dimethyl-6-{4-<3-[2-(2-hydroxybenzoyl)-4-nitrophenoxy]propyl>piperazin-1-yl}-Z6~,389 2,4(lH,3H)-pyrimidinedione.
Next, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain O.6 g of 1,3-dimethyl-6-{4-<3-[2-(2-hydroxybenzoyl~-4-nitro-phenoxy]propyl>-piperazin-l-yl}-2,4tlH,3H)-pyrimidinedione oxalate (Compound 104):
Analytical results of the pyrimidinedione derivative (Compound 104) thus obtained:
Melting point: 144-146~C (decomposed).
IR vmBr (cm~l): 3550, 2900, 2550, 1710, 1640, 1530, 1340, 840, 730, 700.
Y 2 6H29N5~7 2 ( COOH ) 2 H20 Calculated (%): C, 49.93; H, 4.89; N, 9.73.
Found (%): C, 49.83; H, 5.07; N, 9.43.
Example 57:
Preparation of 1,3-dimethyl-6-{4-[3-[2-(2-chlorobenzoyl)-4-nitrophenoxy]propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 105):
~ OCH3 ~ Cl OCH3 02N COCl > 02N ~ CO-- 192 - ~ 3 8 9 ,~,, ~~
) 02N ~ CO
Sr~ ~
HOCH2CH2CH2N N ~ N-CH3 'J N~o (COOH)z/CH30H
~0 2 ~ ~CH2cH2cH2N N ~ -C~3 lOCO ~ CH3 ~ (C~~H)2 (Compound 105) (l) Preparation of 3-(2-chlorobenzoyl)-4-methoxynitro-benzene:
4.0 g of 2-methoxy-5-nitrobenzoyl chloride were dissolved in 100 ml of anhydrous tetrahydrofuran, followed by the addition of 2.72 g of 4-(N,N-dimethyl-amino)pyridine at room temperature. The resultant mixture was then vigorously stirred for 1 hour.
Added dropwise to the reaction mixture at -10~C
after completion of the stirring were 28 ml of a Grignard reagent which had been prepared from 3.82 g of 2-chlorobromobenzene and 0.48 g of metal magnesium in ethyl ether.
After completion of the dropwise addition, the temperature of the reaction mixture was allowed to B
gradually rise to room temperature over 3 hours. Water was then added to the reaction mixture, followed by concentration to dryness. Next, the residue was dissolved in 50 mQ of chloroform and the solution thus obtained was washed with water. The solution was thereafter washed successively with 50 mQ of a 1 N
aqueous sodium hydroxide solùtion, 50 mQ of 1 N
hydrochloric acid and a saturated NaCl solution.
The thus-washed solution was dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was was purified by chromatography on a silica gel column (eluent:
chloroform/hexane = 1/50-1/20, by volume) to obtain 1.55 g of 3-(2-chlorobenzoyl)-4-methoxynitrobenzene.
Analytical results of the compound thus obtained:
NMR (CDC13), ~ ppm: 3.80(s,2H), 6.92-7.75(m,5H), 8.28-8.69(m,2H).
(2) Preparation of 3-(2-chlorobenzoyl)-4-hydroxynitro-benzene:
1.55 g of 3-(2-chlorobenzoyl)-4-methoxynitro-benzene obtained in the above procedure (1) were dissolved in 30 mQ of chloroform, followed by the addition of 5.31 g of iodotrimethylsilane. The thus-obtained solution was then heated under reflux and stirring for 2 hours. The reaction mixture was allowed 2~01389 to cool down, washed with 30 m~ of water, and then extracted twice with a 1 N aqueous sodium hydroxide solution.
Hydrochloric acid was added to the alkaline layer obtained by the above extraction, followed by extraction with chloroform. The organic layer obtained by the chloroform extraction was washed with water and dried over anhydrous sodium sulfate. The solvent was thereafter distilled off from the organic layer, thereby obtaining 0.5 g of 3-(2-chlorobenzoyl)-4-hydroxynitrobenzene in the form of a pale yellow oil.
Analytical results of the pale-yellowish oily compound thus obtained:
NMR (CDC13), ~ ppm: 7.33(d,1H,J=lO,OHz) 7.46-7.83(m,5H), 8.35(d,1H,J=2.5Hz), 8.50(dd,1H,J=2.5,10.0Hz).
(3) Preparation of 1,3-dimethyl-6-{4-<3-[2-(2-chloro-benzoyl)-4-nitrophenoxy]propyl>piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 105):
By a similar procedure to Example 4B-(2) except for the use of 3-(2-chlorobenzoyl)-4-hydroxynitro-benzene obtained by the above procedure (2) in place of 2-hydroxy-S-nitroacetophenone, 0.5 g of 1,3-dimethyl-6-{4-<3-[2-(2-chlorobenzoyl)-4-nitrophenoxy]propyl>-2~)1389 piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 105) was obtained as white crystals.
Analytical results of crystals of Compound 105 thus obtained:
Melting point: Amorphous.
IR vKax (cm 1): 1685, 1650, 1602, 1425, 1335, 1285, 1080, Y 2 6H2 8ClN506 ( COOH ) 2 H20 Calculated (%): C, 51.74; H, 4.96; N, 10.77;
Cl, 5.45.
Found (%): C, 51.50; H, 5.11; N, 10.97;
Cl, 5.71.
Example 58:
Preparation of 1,3-dimethyl-6-{4-<3-[4-nitro-2-(2-pyridinecarbonyl)phenylthio]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 106):
0 2N~Cl OzN /~SCH2CHzCHzCl ~ 0 HSCHzCHzCHzCl ~ 0 ' HN N~N-CH3 - '' N~o CH3 (COOH) z/Cl~H
2~0~389 O N~SCH2cH2cH2N\ - N~-cH3 ~ N CH ~ (COOH)2 (Compound 106) (1) Preparation of l-chloro-3-[2-(2-pyridinecarbonyl)-4-nitrophenylthio]propane:
1.58 g of 4-chloro-3-(2-pyridinecarbonyl)nitro-benzene, 0.66 g of 3-chloro-l-propanethiol and 2 m~ of triethylamine were dissolved in 5 ml of dimethyl-sulfoxide. The resultant solution was heated under stirring at 80~C for 3 hours.
After completion of the heating, the reaction mixture was concentrated and the concentrate thus obtained was dissolved in chloroform. The chloroform solution was washed with water and then dried over anhydrous sodium sulfate.
Next, the solvent was distilled off from the thus-dried solution. The residue was purified by chromatography on a silica gel column (eluent:
chloroform) and then crystallized from a mixed solvent of hexane and ether to obtain 1.0 g of 1-chloro-3-t2-(2-pyridinecarbonyl)-4-nitrophenylthio]propane.
Analytical results of crystals of the compound thus obtained:
Elemental analysis for C15Hl3ClN2O3S:
Calculated (%): C, 53.49; H, 3.89; N, 8.32, S, 9.52; Cl, 10.53.
Found (%): C, 53.29; H, 3.79; N, 8.25;
S, 9.35; Cl, 10.37.
(2) Preparation of 1,3-dimethyl-6-{4-<3-t4-nitro-2-(2-pyridinecarbonyl)phenylthio]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 10~):
0.93 g of 1-chloro-3-[2-(2-pyridinecarbonyl)-4-nitrophenylthio]propane, 0.62 g of 1,3-dimethyl-6-(piperazin-l-yl)-2,4(lH,3H)-pyrimidinedione and 2 m~
of triethylamine were dissolved in 10 ml of dimethyl sulfoxide, followed by heating under stirring at 120~C
for 4 hours.
After completion of the heating, the reaction mixture was allowed to cool down, the solvent was distilled off under reduced pressure from the reaction mixture, and the residue was dissolved in chloroform.
The thus-obtained solution was washed with water and then dried over anhydrous sodium sulfate, followed by purification by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1, by volumw) to obtain 0.69 g of 1,3-dimethyl-6-{4-<3-t4-nitro-2-(2-pyridinecarbonyl)phenylthio~propyl>piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione in a yellow solid form.
2C~)1389 Analytical results of the pyrimidinedione derivative thus obtained:
Melting point: 182~C (decomposed).
NMR (CDC13), ~ ppm: 1.89(m,2H), 2.56(m,6H), 3.01(m,4H), 3.36(s,3H), 3.42(s,3H), 3.46(m,2H), 5.28(s,lH), 7.5-8.9(m,7H).
Elemental analysis for C25H28N6O5S-~H2O:
Calculated (%): C, 56.27; H, 5.48; N, 15.75;
Cl, 6.01.
Found (%): C, 56.37; H, 5.36; N, 15.55;
Cl, 5.79.
The pyrimidinedione derivative obtained in the yellow solid form was treated in an oxalic acid/
methanol solution by a method known E~ se in the art to obtain 0.62 g of 1,3-dimethyl-6-{4-<3-t4-nitro-2-(2-pyridinecarbonyl)phenylthio]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 106).
Analytical results of Compound 106 thus obtained:
Melting point: 138~C (decomposed).
IR vKBr (cm~l) 3460, 1693, 1648, 1600, max 1454, 1435, 1346, 722, 500.
Elemental analysis for C25H28N6O5-(COOH)2 ~H2O
Calculated (%): C, 52.00; H, 5.01; N, 13.48;
2~389 S, 5.14.
Found (%): C, 51.81; H, 4.86; N, 13.24;
S, 5.06.
Example 59:
Preparation of 3-methyl-6-{4-[3-(4-nitro-2-~enzoylphenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 107):
OzN ~ ocHzcHzcH2-Br HN NH
OzN ~ OCH2CHzCHzN NH
o Cl ~ N-CH3 N~o (COOH)2/CH30H
, ~ 2 N ~O - CH 2 CH 2 CH - N/--\N ~N - CH
CO H/ O
~ ~ ( COOH ) 2 ( Compound 10 7 ) 2C~1389 (1) Preparation of 1-[3-(2-benzoyl-4-nitrophenoxy)-propyl]piperazine:
3.5 g of 3-benzoyl-4-(3-bromopropyloxy)nitro-benzene and 7.8 g of piperazine were dissolved in 5 30 m~ of chloroform. The resultant solution was heated under reflux for 4 hours.
The resultant reaction mixture was allowed to cool down, washed with water, and dried over anhydrous sodium sulfate. The solvent was thereafter distilled off from the reaction mixture and the residue was crystallized from hexane/ethanol to obtain 3.5 g of 1-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazine.
(2) Preparation of 3-methyl-6-{4-[3-(4-nitro-2-benzoyl-phenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidine-dione oxalate (Compound 107):
1 g of 1-[3-(2-benzoyl-4-nitrophenoxy)propyl]-piperazine, 0.34 g of 6-chloro-3-methyl-2,4(lH,3H)-pyrimidinedione and 0.72 m~ of triethylamine were dissolved in 3 m~ of 2-propanol, followed by heating under reflux for 6 hours.
Precipitated crystals were collected by filtration from the reaction mixture and then recrystallized from isopropanol to obtain 1.9 g of 3-methyl-6-{4-[3-(4-nitro-2-benzoylphenoxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
2~1389 Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 8.41(m, 2H), 7.1-7.9(m,6H), 4.77(s,1H), 4.13(m,2H), 3.15(s,3H), 2.0-2.4(m,10H), 1.74(m,2H).
The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.67 g of 3-methyl-6-{4-t3-(4-nitro-2-benzoylphenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 107).
Analytical results of Compound 107 thus obtained:
Melting point: 144-146~C (decomposed).
IR vmBax (cm 1): 3360, 2610, 1710, 1660, 1610, 1520, 1350, 1290, 1100, 750, 700.
Y 2 5 H2 7Ns~6 ( COOH ) 2 2 H20:
Calculated (%): C, 52.34; H, 5.37; N, 11.30.
Found (%): C, 51.89; H, 5.04; N, 11.23.
Example 60:
Preparation of 1,3-dimethyl-6-{2-t3-(2-benzoyl-4-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 108):
2~1389 02N- ~ OH BrCH2CHzCH2Br OzN ~ OCH2CHzCH2-Br ~=0 > ~0 ¢I~N - C H 3 NH2CH2CH2NH N~ tCOOH) 2/C~)H
o O2N ~ O-cH2cH2cH2NHcH2cH2NH ~ -CH
(COOH)2 (Compound 108) (1) Preparation of 3-(2-benzoyl-4-nitrophenoxy)propyl bromide:
1.5 g of 2-hydroxy-5-nitrobenzophenone, 6 ml of 1,3-dibromopropane and 3 g of anhydrous potassium carbonate were heated and reacted under reflux for 6 hours in 10 m~ of 2-butanone.
After completion of the reaction, the reaction mixture was allowed to cool down and unnecessary matters were filtered off. The filtrate was concentrated to obtain a syrup, which was purified by chromatography on a silica gel column (eluent:
hexane/ethyl acetate = 4/1, by volume) and then crystallized form hexane to obtain 1.0 g of 3-(2--benzoyl-4-nitrophenoxy)propyl bromide.
Analytical results of the propyl bromide derivative thus obtained:
Melting point: 86~C.
(2) Preparation of 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitrophenoxy)propylamino]ethylamino}-2,4(1H,3H)-pyrimidi nedione oxalate (Compound 108):
0.77 g of the propyl bromide derivative obtained in the above procedure (1), 0.5 g of 1,3-dimethyl-6-(2-aminoethylamino)-2,4(lH,3H)-pyrimidinedione and 0.7 m~ of triethylamine were reacted at 80~C for 4 hours in 10 ml of dimethylformamide. After distilling off the solvent from the resultant reaction mixture under reduced pressure, chloroform was added to the residue, and the solution thus formed was washed with water, dried and then concentrated to obtain a syrup.
The syrup was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 40/1, by volume~ to obtain 0.51 g of 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.1-8.1(m,8H), 5.14(s,1H), 4.33(t,2H), 3.22(s,3H), 3.36(s,3H), 2 ~ ~ ~ 3 8 9 2.7-3.2tm,6H), 2.1(m,2H).
The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known Per se in the art to obtain 0.43 g of 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitrophenoxy)propylamino]ethyl-amino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 108).
Analytical results of Compound 108 thus obtained:
Melting point: 111-113~C (decomposed).
IR ~max (cm 1): 3050, 1730, 1700, 1640, 1520, 1360, 770, 700.
Elemental analysis for C24H27N5O6-(COOH)2 3H2O
Calculated (%): C, 49.92; H, 5.69; N, 11.20.
Found (%): C, 50.11; H, 5.35; N, 11.00.
Example 61:
Preparation of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 109):
< ~ C ~ OH BrCHzCHzCHzBr ~ -CO ~ OCH2CH2CHzBr cH~cu2~2 r~
CO~ OCHZcH2cH2NHcHzcH3 CN~¢~NO (COOH)2/CH30H
3 ~ ~
O CH2CH3 - o <~C~O-CH2CH2CH2NcH2cH2NH~_cH3 NO2 CH3 ~
~ (COOH)2 (Compound 109) (1) Preparation of 5-benzoyl-2-(3-bromopropyloxy)-nitrobenzene:
1.5 g of 4-hydroxy-3-nitrobenzophenone and 1 g of potassium carbonate were added to 5 ml of methyl ethyl ketone. The resultant mixture was heated under stirring for 30 minutes, followed by the addition of 2.0 mQ of dibromopropane. The thus-obtained mixture was stirred for further 4 hours. After allowing the reaction mixture to cool down, insoluble matters were filtered off. The filtrate was then concentrated and cooled to 0~C. Under those conditions, the reaction mixture was added with 10 ml of hexane to conduct sludging. The resultant precipitate of 5-benzoyl-2-26~1389 (3-bromopropyloxy)nitrobenzene was collected by filtration.
Analytical results of the precipitate:
NMR (CDC13), ~ ppm: 7.2-8.3(m,8H), 4.40(t,2H), 3.69(t,2H), 2.47(m,2H).
2.0 g of the precipitate of 5-benzoyl-2-(3-bromopropyloxy)nitrobenzene were employed in the subsequent reaction without purification.
(2) Preparation of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate ~Compound 109):
1.8 g of the 5-benzoyl-2-(3-bromopropyloxy)-nitrobenzene precipitate obtained in the above procedure (1) were reacted with 10 m~ of ethylamine (70 wt.% of solution in water) at 70~C for 1 hour in an autoclave. Thereafter, excess ethylamine was distilled off. The reaction mixture was added with 30 m~ of chloroform and then washed twice with water.
The water-washed chloroform layer was then concentrated to obtain 2.1 g of 5-benzoyl-2-(3-ethyl-aminopropyloxy)nitrobenzene as a roughly-purified oily product.
1.0 g of the roughly-purified oily product, 0.4 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (Compound ~) and 0.05 g of p-toluene-2~,389 sulfonic acid were reacted at 80~C for 3 hours in a solventless state. The reaction mixture was directly subjected to chromatographic purification on a silica gel column (eluent: CHC13/CH30H = 40/1, by volume), thereby obtaining 0.61 g of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.4-8.2(m,8H), 4.99(s,1H), 4.16(t,2H), 3.36, 3.44(s,3H), 2.4-3.0(m,8H), 2.11(m,2H), l.lO(t,3H).
lS The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known per se in the art to obtain O.Sg of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 109).
Analytical results of Compound 109 thus obtained:
IR vmax (cm 1): 3400, 1690, 1620, 1530, 1360, 1250, 720, 700.
Elemental analysis for C26H31N5O6 ( 2 2 Calculated (%): C, 52.91; H, 5.87; N, 11.02.
Found (%): C, 52.50; H, 5.77; N, 10.92.
2~1389 Example 62:
Preparation of 6-{4-[2-(2-benzoyl-4-nitrophenyl-thio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione oxalate 5(Compound 110):
02N- ~ Cl HSCH2CH20H 02N ~ -SCH2CH20H
O ~ \~0 HN N ~ ~-CH3 '~ N~j (COOH)2/CH30H
o 2 ~ C~2 2 ~ ~ ~ 3 ~ (COOH)2 (Compound 110) (1) Preparation of 2-(2-hydroxyethylthio)-5-nitrobenzo-phenone:
2.0 g of 2-chloro-5-nitobenzophenone and 2.0 g of triethylamine were dissolved in 10 m~ of dimethyl-sulfoxide, followed by the addition of 0.63 g of 2-mercaptoethanol. The resultant mixture was heated under stirring at 80~C for 5 hours. The reaction mixture was poured into water and then extracted with 2~01389 100 m~ of chloroform. After washing the extract with water and then drying it over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.0 g of 2-(2-hydroxyethylthio)-5-nitrobenzo-phenone as pale yellow crystals.
Analytical results of the benzophenone derivative thus obtained:
NMR (CDC13), ~ ppm: 8.16-8.50(m,2H), 7.23-8.06(m,6H), 3.86(t,2H), 3.21(t,2H), 2.63(br.s,lH).
(2) Preparation of 6-{4-[2-(2-benzoyl-4-nitrophenyl-thio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione oxalate (Compound 110):
2.0 g of 2-(2-hydroxyethylthio)-5-nitrobenzo-phenone obtained in the above procedure (1) were dissolved in 20 m~ of chloroform, ~ollowed by the addition of 1.6 g of triethylamine. Further, 0.91 g of methanesulfonyl chloride was added at 0~C.
After stirring the resultant mixture at 0~C for 10 minutes, it was stirred at room temperature for further 16 hours. The reaction mixture thus obtained was diluted with 80 mQ of chloroform and then poured into water. The resulting mixture was allowed to separate into layers. The organic layer was washed successively with a 1 N aqueous sodium hydroxide 2C~)1389 solution, water and saturated NaCl solution. Next, the organic layer thus washed was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.50 g of a mesylate as a roughly-purified product.
To a solution of the mesylate in 15 ml of dimethyl sulfoxide, 1.80 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(lH,3H)-pyrimidinedione were added.
The resultant mixture was heated at 80~C for 6 hours.
The thus-obtained reaction mixture was poured into 100 m~ of water in which 2.0 g of potassium carbonate were contained, and was then extracted twice with 50 m~
portions of chloroform. The extracts were combined together, washed with water and then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 25/1, by volume), thereby obtaining 2.0 g of 6-{4-t2-(2-benzoyl-4-nitrophenylthio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione as pale yellow crystals.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ ppm: 8.27-8.54(m,2H), 7.44-8.07(m,6H), 5.28(s,lH), 3.39(s,3H), 20~)1389 3.35(s,3H), 2.44-3.27(m,12H).
The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 6-{4-[2-(2-benzoyl-4-nitrophenylthio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione ~Compound 110) as white crystals.
Analytical results of Compound 110 thus obtained:
Melting point: 201.0-202.5~C.
Elemental analysis for C25H27N5O4S-(COOH)2:
Calculated (%): C, 55.57; H, 5.01; N, 12.00;
S, 5.49.
Found (%): C, 55.51; H, 5.55; N, 12.16;
S, 5.38.
Example 63:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-t3-(4-benzoyl-2-nitrophenoxy)propyl]piperazin-l-yl}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 78) available by the process of Example 50:
1 g of the pyrimidinedione derivative oxalate (Compound 78), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of S g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant z~ 389 particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 64: -Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4-llH,3H)-pyrimidinedione oxalate (Compound 811 available by the process of Example 52:
5 g o~ the pyrimidinedione derivative oxalate (Compound 81), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 65:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-chlorobenzoyl-4-nitrophenoxy]propyl]piperazin-1-yl}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 105) available by the process of Example 57:
20 mg of the pyrimidinedione derivative oxalate (Compound 105) and 0.85 g of sodium chloride were 26~C)1389 weighed. They were dissolved in distilled water for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 4:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 8 and obtained in the corresponding examples described above were determined. The results are summarized in Table 8.
Table 8 Result of Pharmacological Test 75 (~) ERP (~) Compound Dose (~g/m~) Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.03.0 76 16.0 21.0 - 2.4 4.3 12.616.5 78 19.0 42.0 - 6.7 13.3 20 26.7 19.0 30.0 34.0 2.6 9.7 21.9 89 19.0 30.0 - 5.6 11.1 11.1 22.0 31.0 - 20.5 20.5 14.3 99 9.0 22.0 29.0 9.8 14.7 23.1 102 7 20.0 - - - - -104 - 16.0 25.0 105 11.0 23.0 28.0 0 0 6.36.3 Toxicity Test 4:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 9 and obtained in Z~301;~89 the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 9.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table 9 Compound No. Mortality rate (%) 100 o 105 o Example 66:
Preparation of 1,3-dimethyl-6-{4-~3-(2-benzoyl-4-nitroanilino)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 111):
O O
25 1 ~ ~NK + BrCHzCH2CHz8r ~ ~ ~NCH2CH2CH2Br O O
2~1389 HN N ~ N-CH3 N~o ~NCH2CHzCH2N~N ~Y-CH
NH2CHzCH2CH2N N ~ ~-CH302N ~ CO
(COOH)2/CH30H
>
~o O2N ~ N~CH2CH2CH2N N ~ N-CH3 CO CH3 (COOH)2 (Compound 111) (1) Preparation of 1,3-dimethyl-6-{4-(3-aminopropyl)-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione (Compound 158):
A suspension of 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane in 100 ml of dimethylformamide was heated under stirring at 120~C
for 6 hours to react them. Insoluble matters were then filtered off from the reaction mixture and the filtrate was then concentrated to dryness under reduced pressure. The residue was washed with hexane and then 2001~89 recrystallized from ethanol-water. Resulting crystals were collected by filtration, washed and then dried to obtain 13.8 g of N-(3-bromopropyl)phthalimide.
A suspension which had been obtained by suspending 13.0 g of the N-(3-bromopropyl)phthalimide, 10.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4-(lH,3H)-pyrimidinedione (Compound 157) and 20 g of triethyl-amine in 200 m~ of dioxane was heated under reflux for 6 hours.
Further, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated to dryness under reduced pressure. The residue (dry concentrate) was recrystallized from ethyl acetate/n-hexane. Resultant crystals were collected by filtration, washed and then dried, thereby obtaining 12.5 g of 1,3-dimethyl-6-t4-(3-phthaloylaminopropyl)-piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione.
Next, a suspension of 12.5 g of those crystals and 6.0 g of hydrazine hydrate in 200 m~ of ethanol was heated under reflux for 4 hours. After allowing the suspension to cool down, resultant insoluble matters were filtered off. The filtrate was concentrated to dryness under reduced pressure. The residue (dry concentrate) was then dissolved in water, to which dilute hydrochloric acid was added to adjust the pH to about 3. Insoluble matters formed by the pH
2~:;L38~3 adjustment were filtered off. After adding a large amount of potassium carbonate to the filtrate, the resultant mixture was extracted with chloroform.
Subsequent to the completion of the extraction, the resulting organic layer was dried over anhydrous sodium sulfate and then heated under reduced pressure to distill off the solvent, whereby 6.80 g of 1,3-dimethyl-6-[4-(3-aminopropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 158) were obtained as a colorless syrupy substance. The syrupy substance was crystallized when allowed to stand overnight.
(2) Preparation of 1,3-dimethyl-6-t4-[3-(2-benzoyl-4-nitroanilino)propyl~piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 111):
0.9 g of 1,3-dimethyl-6-[4-(3-aminopropyl)-piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione and 1.0 g of 2-chloro-5-nitrobenzophenone were added to 10 m~ of dimethyl sulfoxide. The resultant mixture was heated at 110~C for 20 hours. After allowing the reaction mixture to cool down, the reàction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with chloroform.
An organic layer (chloroform layer) obtained by the extraction was separated, washed with water, dried over anhydrous sodium sulfate, and then concentrated to -2~389 dryness. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 20/1, by volume), thereby obtaining 0.95 g of 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitroanilino)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as a yellow oily substance.
Analytical results of the oily substance of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.04(m,2H), 2.65(m,6H), 3.04(m,4H), 3,36(s,3H), 3.42(s,3H), 3.57(t,2H), 5.30(s,1H), 6.90(d,1H), 7.69(s,5H), 8.35(dd,lH), 8.95(d,lH), 9.50(s,1H).
Further, the oily substance was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 1.0 g of 1,3- dimethyl-6-{4-[3-(2-benzoyl-4-nitroanilino)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 111).
Analytical results of Compound 111 thus obtained:
Melting point: Amorphous.
Elemental analysis for C26H30N6O5-(COOH)2:
Calculated (%): C, 56.37; H, 5.41; N, 14.09.
Found (%): C, 56.92; H, 5.40; N, 14.20.
Example 67:
8~
Preparation of Compounds 120-127:
sy a similar procedure to Example 66-(2) except for the use Compounds 112-119 having the below-described structural formula (I) - in which R7, R8 and R9 mean the below-described groups respectively - in place of 2-chloro-5-nitrobenzophenone, pyrimidinedione derivative oxalates having the physical properties set out below and the below-described structural formula (II) in which R7, R8 and R9 are different from one compound to another were obtained as Compounds 120-127, respectively.
R8 ~ Cl (I) 2~1389 Compound 112-COCH3 -No2 -H
Compound 113-CO ~ -NO2 -H
Compound 114-CO ~ -NO2 -H
Compound 115-CO ~ -NO2 -H
Compound 116-CO ~ N -NO2 -H
Compound 117 -No2 -COCH3 -H
Compound 118 -NO2 -CO ~ -H
Compound 119 -H -NO2 -COCH3 R8 ~ NHCH2CH2CH2N N ~ N-CH3 (II) R7 R9 C/H3 .(COOH)2 -~ 2~1389 Compound 120 (R7, R8 and R9 are as defined with respect to Compound 112):
Melting point: 135-137~C (decomposed).
IR ~KBr (cm-l) 3300, 2550, 1720, 1630, max 1560, 1320, 1250, 800, 710.
enta n lysis for C21H28N6O5 (COOH)2 2H2~
Calculated (~): C, 48.42; H, 6.01; N, 14.73.
Found (%): C, 48.14; H, 5.82; N, 14.32.
Compound 121 (R7, R8 and R9 are as defined with respect to Compound 113):
Melting point: 182-183~C (decomposed).
IR vmax (cm 1): 3350, 2550, 1690, 1630, 1540, 1350, 1290, 1100, 810, 770.
Elemental analysis for C25H34N6O5 ( 2 2 Calculated (%): C, 50.46; H, 6.59; N, 13.08.
Found (%): C, 51.04; H, 6.77; N, 12.90.
Compound 122 (R7, R8 and R9 are as defined with respect to Compound 114):
Melting point: Amorphous.
Y 26 29N6O5Cl (COOH)2 ~H2O
Calculated (%): C, 52.54; H, 5.04; N, 13.13;
Cl, 5.54.
Found (%): C, 52.36; H, 5.05; N, 13.14;
Cl, 5.23.
2~01389 Compound 123 (R7, R8 and R9 are as defined with respect to Compound 115):
Melting point: 151~C (decomposed).
IR vmax (cm 1): 3440, 1706, 1645, 1588, 1496, 1441, 1333, 1200, 768, 722, 500.
Elemental analysis for C25H29N7O5~ COOH)2-H2O:
Calculated (%): C, 50.91; H, 5.19; N, 14.84.
Found (%): C, 51.12; H, 5.10; N, 14.81.
Compound 124 (R7, R8 and R9 are as defined with respect to Compound 116):
Melting point: 162-165~C (decomposed).
IR vKBr (Cm-l~ 3400, 1690, 1600, 1550, max 1350, 1260, 1150, 780, 700.
e en y 25 29 7~5 ( )2 2 Calculated (%): C, 48.00; H, 4.83; N, 13.06.
Found (%): C, 48.38; H, 4.92; N, 12.91.
Compound 125 (R7, R8 and R9 are as defined with respect to Compound 117):
Melting point: 148-150~C (decomposed).
IR vKBr (cm 1): 3350, 2600, 1690, 1640, 1530, 1330, 1240, 980, 760, 700.
Elemental analysis for C25H34N6O5-(COOH)2-3H2O:
Calculated (%): C, 50.46; H, 6.59; N, 13.08.
26g~1389 Found (%): C, 51.04; H, 6.77; N, 12.90.
Compound 126 (R7, R8 and R9 are as defined with respect to Compound 118):
Melting point: 202-203~C (decomposed).
IR vKBr (cm-l) 3560, 2550, 1700, 1610, lS30, 1320, 1280, 1110, 810, 710.
Y 26 30 6~5 (C ~ )2 2 Calculated (%): C, 54.72; H, 5.58; N, 13.67.
Found (%): C, 54.68; H, 5.21; N, 13.47.
Compound 127 (R7, R8 and R9 are as defined with respect to Compound 119):
Melting point: about 140~C (amorphous).
IR vKBr (cm~l) 3420, 2600, 1710, 1640, max 1540, 1320, 1220, 1110, 810, 710.
Y 21 28 6~5 (C ~ )2 2 2 Calculated (%): C, 48.24; H, 5.57; N, 14.06.
Found (%): C, 44.11; H, 5.90; N, 13.89.
Example 68:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitroanilino)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 111) available by the process of Example 66:
2~1389 1 g of the pyrimidinedione derivative oxalate tCompound 111), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of S g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 69:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 120) available by the process of Example 67:
5 g of the pyrimidinedione derivative oxalate (Compound 120), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 70:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitroanilino]propyl]piperazin-1-yl}-2,4-(lH,3H~-pyrimidinedione oxalate (Compound 111) available by the process of 2(~ 389 Example 66:
20 mg of the pyrimidinedione derivative oxalate (Compound 111) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 5:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 10 and obtained in the corresponding examples described above were determined. The results are summarized in Table 10 .
Table 10 15 Result of Pharmacological Test 75 (%) ERP (%) Compound Dose (~g/m~) Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.0 3.0 111 13.0 21.0 - 7.710.9 14.0 21.0 120 16.0 27.0 29.0 125 - 10.0 21.0 126 23.0 45.0 48.0 7.014.0 21.0 Toxicity Test 5:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 11 and obtained in 20~389 the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 11.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table ll Compound No.Mortality rate (%) 122 o Example 71:
Preparation of 1,3-dimethyl-6-{4-(2-benzoyl-4-nitrophenyl)piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 128):
C ~
02N~CO-~> + HN N~l-CH3 --(COOH) 2/CH30H, 2~1!~i~89 CO / O
CH3 ~(COOH)2 ~ (Compound 128) 0.5 g of 1,3-dimethyl-6-(piperazin-1-yl)-S 2,4(1H,3H)-pyrimidinedione (Compound 157) and 0.6 g of 3-benzoyl-4-chloronitrobenzene were added to S ml of dimethylsulfoxide. The resultant mixture was heated at 110~C for 20 hours. After allowing the reaction mixture to cool down, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with chloroform.
An organic layer tchloroform layer) obtained by the extraction was separated, washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 20/1, by volume), thereby obtaining 0.2 g of 1,3-dimethyl-6-[4-(2-benzoyl-4-nitrophenyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (d6-DMso)~ ~ ppm: 2.64(m,2H), 3.18(m,6H), 3.28(s,3H), 3,17(s,3H), S.OO(s,lH), 7.3-8.0(m,5H), ~1389 -8.2-8.6(m,3H).
Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.18 g of 1,3-dimethyl-6-[4-(2-benzoyl-4-nitrophenyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione oxalate (Compound 128).
Analytical results of Compound 128 thus obtained:
Melting point: 178-179~C (decomposed).
IR vmBax (cm 1): 3430, 1700, 1660, 1600, 1520, 1320, 1260, 1130, 950, 860, 760, 700.
Elemental analysis for C23H23N5O5-~(COOH)2-~H2O:
Calculated (%): C, 57.25; H, 5.01; N, 13.91.
Found (%): C, 57.55; H, 4.80; N, 13.56.
Example 72:
Preparation of 1,3-dimethyl-6-{3-[4-nitro-2-(3-pyridinecarbonyl)anilino]propylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 129):
~ Cl ~ + H2NCHzCH2CHzNH- ~ -CH3 , (COOH)2/CH30H, 2~ 389 2 ~ 2 2CH2NH ~ CH3 CH3 ~(COOH)2 N
(Compound 129) 0.67 g of 4-chloro-3-(3-pyridinecarbonyl)nitro-benzene and 0.6 g of 1,3-dimethyl-6-(3-aminopropyl-amino)-2,4(1H,3H)-pyrimidinedione were dissolved in 3 m~ of dimethylformamide, followed by the addition of 0.79 m~ of triethylamine. The resultant mixture was heated under stirring at 80~C for 5 hours.
After completion of the heating, the reaction mixture was allowed to cool down and the solvent was then distilled off. The residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume) to obtain 0.39 g lS of 1,3-dimethyl-6-{3-[4-nitro-2-(3-pyridinecarbonyl)-anilino]propylamino}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 9.40(m,lH), 8.84(m,6H), 7.86-8.S7(m,3H), 7.50(dd,1H), 6.85(d,1H), 5.90(m,1H), 4.86(s,1H), 3.23(s,3H), 3.38(s,3H), 3.40(m,4H), 2.1(m,2H).
2~31389 Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.36 g of 1,3-dimethyl-6-{3-t4-nitro-2-(3-pyridinecarbonyl)anilino~ -propylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 129).
Analytical results of Compound 129 thus obtained:
Melting point: 136-139~C (decomposed).
IR vmBax (cm 1): 3350, 2550, 1690, 1640, 1550, 1330, 1260, 1110, 770, 700.
Elemental analysis for C21H22N6O5-(COOH)2:
Calculated (%): C, 52.27; H, 4.58; N, 15.90.
Found (%): C, 52.25; H, 4.92; N, 15.51.
~5 Example 73:
Preparation of 1,3-dimethyl-6-t3-(2-benzoyl-4-nitroanilino)propylamino]-2,4(1H,3H)-pyrimidinedione oxalate (Compound 130):
~ Cl ~ NH2CHzCHzCHzNH ~ ~-CH3 >
OzN~ CO- ~ ,N~o (COOH)2/CH30H
>
2 ~ 2C 2CH2NH ~ N CH3 CH3 ~(COOH)2 (Compound 130) By a similar procedure to Example 72 except for the use of 3-benzoyl-4-chloronitrobenzene in place of 4-chloro-3-(3-pyridinecarbonyl)nitrobenzene, 1,3-dimethyl-6-[3-(2-benzoyl-4-nitroanilino)propyl-amino]-2,4(1H,3H)-pyrimidinedione oxalate (Compound 130) was obtained.
Analytical results of Compound 130 thus obtained:
Melting point: amorphous.
IR vmax (cm 1): 3300, 1690, 1620, 1540, 1330, 1110, 990, 850, 760, 700.
Elemental analysis for C22H23N505-~(COOH)2:
Calculated (%): C, 57.26; H, 5.01; N, 14.52.
Found (%): C, 57.16; H, 4.63; N, 14.76.
Example 74:
Preparation of 1,3-dimethyl-6-[2-(2-benzoyl-4-nitroanilino)ethylamino]-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 131):
~ Cl + NH2CH2CH2NH ~ -CH
ozlYJ~-~'C0 ~ N 0 -2C~0~389 02N~NHCH2CH2NH~ CH3 (Compound 131) By a similar procedure to Example 73 except tha~
1,3-dimethyl-6-(2-aminoethylamino)-2,4(lH,3H)-pyrimidinedione was reacted in place of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione with 3-benzoyl-4-chloronitrobenzene, 1,3-dimethyl-6-[2-(2-benzoyl-4-nitroanilino)ethylamino]-2,4(lH,3H)-pyrimidinedione (Compound 131) was obtained.
Analytical results of Compound 131 thus obtained:
Melting point: 207-209~C (decomposed).
IR vmBr (cm 1): 3050, 2950, 1760, 1680, 1560, 1340, 1110, 760, 700.
Y 21H21N5~5 (COOH)2 H20 Calculated (%): C, 51.98; H, 4.74; N, 13.18.
Found (%): C, 51.81; H, 4.87; N, 12.97.
Example 75:
Preparation of 1,3-dimethyl-6-{2-[4-nitro-2-(3-pyridiencarbonyl)phenylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 132):
o CO-~ + NHzCH2CH2NH ~N-CH3 2~01~89 021~NHCH2CH2NH~N--CH3 (Compound 132) By a similar procedure to Example 72 except for the use of 1,3-dimethyl-6-(2-aminoethylamino)-2,4(lH,3H)-pyrimidinedione in place of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione, 1,3-dimethyl-6-{2-[4-nitro-2-(3-pyridinecarbonyl)phenyl-amino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound 132) was obtained.
Analytical results of Compound 132 thus obtained:
Melting point: 148~C.
IR VmBax (cm ): 3380, 3200, 1692, 1630, 1587, 1333, 1265, 1155, 1115 .
Elemental analysis for C20H20N6O5-H2O:
Calculated (%): C, 54.30; H, 5.01; N, 19.00.
Found (%): C, 54.04; H, 4.71; N, 18.84.
Example 76:
- Preparation of 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-1-yl)-2,4(lH,3H)-pyrimidinedione oxalate (Compound 133):
HN NH ((CH 3 ) 3 COCO ) 2 0 02N ~ CHzCHz-Br > >
N0z ~ HzCHzN N-COC(CH 3) 3 - 234 - 20~3~9 ~N-CH3 ~COCl H~ C)~O (COOH) z/CH30H
~ 2 2~_, '1~ 3 CE13 ~ (COOEI)2 \ /
(Compound 133) (1) Preparation of l-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonylpiperazine:
1.7 g of 4-nitrophenethyl bromide and 5 g of piperazine were dissolved in 15 ml of chloroform. The ( resultant solution was heated under reflux for 3 hours.
After completion of the reaction, the reaction mixture was allowed to cool down and washed three times with water to remove excess piperazine from the reaction mixture. Then, the chloroform layer was separated.
Next, the solvent was removed under reduced pressure from the chloroform layer. The residue was dissolved in 15 me of dry tetrahydrofuran, followed by the addition of 1.6 g of di-tert-butyl dicarbonate.
~. .
2~C~1389 The mixture thus obtained was stirred at room temperature for 1 hour and the solvent was distilled off from the reaction mixture.
A hexane/ethanol mixed solvent was added to the residue. The thus-precipitated crystals were collected by filtration and then recrystallized from a hexane/ethanol mixed solvent, thereby obtaining 2.4 g of l-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonyl-piperazine.
Analytical results of the piperazine derivative thus obtained:
Melting point: amorphous.
NMR (CDC13), ~ ppm: 8.14(d,2H), 7.34(d,2H), 3.41(m,4H), 2.74(m,4H), 2.43(m,4H), 1.45(s,9H).
(2) Preparation of 1,3-dimethyl-6-{4-t2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 133):
0.8 g of 1-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonylpiperazine was dissolved in 20 m~ ofdry tetrahydrofuran, followed by the addition of 1 m~
of hexamethylphosphorus triamide. While chilling the resultant mixture at -78~C, 2.9 m~ of a 1 M solution of lithium diisopropylamide in dry tetrahydrofuran were added.
Z¢~ 89 Upon an elapsed tie of 1 hour after completion of the addition, the temperature of the reaction mixture was maintained at -78~C and 0.83 m~ of benzoyl chloride was then added dropwise.
After completion of the dropwise addition, the temperature of the reaction mixture was gradually raised to -30~C, at which the reaction mixture was stirred for 3 hours. The reaction mixture was then poured into ice water, followed by extraction with chloroform.
The extract was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a syrupy substance.
The syrupy substance was dissolved in 30 m~ of ethyl ether, followed by the addition of 2 m~ of hydrochloric acid/dioxane (4 N). The resultant mixture was stirred at room temperature for 30 minutes.
The resultant crystals were collected by filtra-tion and then washed with ether.
The crystals were next dissolved in 20 m~ of isopropanol, to which 0.5 g of 1,3-dimethyl-6-chloro-2,4(1H,3H)-pyrimidinedione and 3 m~ of triethylamine.
The thus-prepared mixture was stirred under reflux for 6 hours.
After completion of the stirring, the solvent was distilled off from the reaction mixture. The Z~1389 residue was dissolved in chloroform. The resultant chloroform solution was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.
The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1, by volume) to obtain 0.33 g of 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.3-8.2(m,8H), 5.06(s,1H), 3.28(s,3H), 3.39(s,3H), 2.4-3.0(m,12H).
Next, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.34 g of 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 133):
Analytical results of Compound 133 thus obtained:
Melting point: 183-185~C (decomposed).
IR vmax (cm 1): 3350, 2850, 2500, 1710, 1660, 1520, 1340, 1210, 840, 800, 750, 700.
Elemental analysis for C25H27N5O5 ( 2 2 2~01389 Calculated (%): C, 55.38; H, 5.34; N, 11.96.
Found (%): C, 55.16; H, 5.11; N, 12.01.
Example 77:
Preparation of 1,3-dimethyl-6-{4-t(2-benzoyl-4-nitrophenyl)methyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 134):
HN NH ((CH 3 ) 3 CO CO ) 2 0 NO2~&:H2Br > >
NO 2~3CH2N~,N-COOC (CH3 ) 3 ~N-CH3 (~COCl H~ Cl Nl o (COOH) 2/CH30H
> > > >
O ~ C ~ 4~
~ CH3 ~(COOH)2 tCompound 134) (1) Preparation of l-t(4-nitrophenyl)methyl]-4-tert-butyloxycarbonylpiperazine:
By a similar procedure to Example 76-(1) except for the use of 1.6 g of 4-nitrobenzyl bromide in place of 4-nitrophenethyl bromide, 1.1 g of 1-[(4-nitro-phenyl)methyl~-4-tert-butyloxycarbonylpiperazine.
2~
Analytical results of the piperazine derivative thus obtained:
NMR (CDC13), ~ ppm: 8.11(d,2H), 7.44(d,2H), 2.96(m,4H), 2.73(m,4H), 1.51(s,9H).
(2) Preparation of 1,3-dimethyl-6-{4-[(2-benzoyl-4 nitrophenyl)methyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 134):
In a manner similar to Example 76-(2) except for the use of 0.77 g of 1-[(4-nitrophenyl)methyl]-4-tert-butyloxycarbonylpiperazine obtained in the above procedure (1) in place of 1-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonylpiperazine, 0.10 g of 1,3-dimethyl-6-{4-[(2-benzoyl-4-nitrophenyl)methyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 134) was obtained.
Analytical results of Compound 134 thus obtained:
Melting point: amorphous.
IR vKBr (cm~l~ 3350, 1700, 1630, 1530, max 1360, 1120, 860, 760, 700.
y s 24H25N505 1/2(COOH)2 3/2H20:
Calculated (~): C, 56.42; H, 4.92; N, 12.65.
Found (~): C, 56.12; H, 4.77; N, 12.39.
Example 78:
Preparation of 1,3-dimethyl-6-{2-[(2-benzoyl-4-2~1389 nitrophenyl)methylamino]ethylamino}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 135):
OzN ~ Cl CH2(S ~ )2 HgCl2 H~
S CO~
02N ~ CHO
CO,-~>
~
HzNCHzCHzNH-y N-CH3 N~o ( co OH~2/MeOH
02N ~ CH2NHc~2cH2NH ~ -CH3 C~3 ~(COOH)2 (Compound 135) (l) Preparation of 2-benzoyl-4-nitrobenzaldehyde:
3.72 g of bisthiophenylmethane were dissolved in 40 mQ of tetrahydrofuran and the resultant solution was chilled to -20~C. 12 m~ of n-butyl lithium (1.6 M solution in hexane) were added dropwise, followed by stirring at -20~C for l hour.
After completion of the stirring, a solution of 4 g of 3-benzoyl-4-chloronitrobenzene in 20 ml of 2(~ 389 tetrahydrofuran was added dropwise while maintaining the temperature of the reaction mixture at -20~C.
Subsequent to completion of the dropwise addition, they were reacted for 1 hour while controlling the temperature of the reaction mixture within a range of from -78~C to -20~C.
After completion of the reaction, the reaction mixture was poured into water and then extracted with 400 m~ of ether. The extract layer (ether layer) was washed twice with 200 m~ of water and dried over anhydrous magnesium sulfate.
The solvent was next distilled off from the extract under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = lO/l, by volume) to obtain an oily substance.
The oily substance was dissolved in 40 m~ of acetonitrile, to which a solution of 2.0 g of mercuric chloride in 20 m~ of water was added dropwise.
Subsequent to completion of the dropwise reaction, 0.1 g of p-toluenesulfonic acid was added further and was reacted at 60~C for 4 hours.
After completion of the reaction, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated. The resultant concent-rate was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = 10/1, by volume) to obtain 1.1 g of crude 2-benzoyl-4-nitrobenzaldehyde as an oily substance.
(2) Preparation of 1,3-dimethyl-6-{2-t(2-benzoyl-4-nitrophenyl)methylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 135):
A solution of 1.0 g of 1,3-dimethyl-6-(2-amino-ethylamino)-2,4(lH,3H)-pyrimidinedione in 20 m~ of methanol, a solution of 1.1 g of the crude product of 2-benzoyl-4-nitrobenzaldehyde in 10 m~ methanol and 0O3 mQ of a 4 N solution of hydrochloric acid in dioxane were separately cooled to 0~C, mixed together and then reacted at 0~C for 1 hour.
After completion of the reaction, 0.1 g of sodium cyanoborohydride, followed by a reaction at 0 + 5~C for 3 hours.
After the reaction was completed, the reaction mixture was acidified with 1 N hydrochloric acid and then poured into ice water. The resultant mixture was rendered basic with sodium bicarbonate and then extracted twice with 50 mQ portions of chloroform.
Subsequent to completion of the extraction, the chloroform layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.
- 2~1il389 The thus-obtained concentrate was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 10/1, by volume) to obtain 0.7 g of 1,3-dimethyl-6-{2-t(2-benzoyl-4-nitrophenyl)methyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.2-8.1(m,8H), 5.68(b,1H), 4.89(s,1H), 3.61(s,2H), 3.34(s,3H), 3.39(s,3H), 3.06(m,4H).
Further, 0.5 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known Per se in the art to obtain 0.11 g of 1,3-dimethyl-6-{2-[(2-benzoyl-4-nitrophenyl)methylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 135).
Analytical results of Compound 135 thus obtained:
Melting point: hygroscopic amorphous.
IR vmax (cm 1): 3400(br), 2700, 2550, 1700, 1620, 1530, 1340, 1120, 820, 720, 700.
Y 22H23N5~5 2(cooH)2 3H20 Calculated (%): C, 46.50; H, 4.95; N, 10.43.
Found (%): C, 46.82; H, 4.65; N, 10.25.
Z~)1389 Example 79:
Preparation of 1,3-dimethyl-6-{4-t3-(4-benzoyl-2-nitrophenyl)propyl~piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 136):
O ' O
C ~ Cl I, ~ C ~ I H2C=CH-COOCH3 NOz NO2 ~ -C ~ -CH=CH-COOCH3 OH
> ~ -CH ~ -CH=CH-COOCH3 'NO2 o ~ -C ~ CH2CHzCHzOH
HN N ~ -CH3 CH3 ~ SOzCl'J N~o HCl/CH30H
CH2CH2N~ ~N~N-CH3 (Compound 136) ~1) Preparation of 4-iodo-3-nitrobenzophenone:
A mixture of 10.44 g of 4-chloro-3-nitrobenzo-phenone, 60 g of sodium iodide and 60 m~ of dimethyl-formamide was heated under reflux for 15 hours.
The reaction mixture was cooled and then poured into 800 m~ of water. Precipitated crystals were collected by filtration.
The precipitated crystals were washed with water, dried under reduced pressure and then purified by chromatography on a silica gel column (eluent:
c~loroform/hexane = 2/1 - 10/1, by volume), thereby obtaining 10.17 g of 4-iodo-3-nitrobenzophenone as yellow crystals.
Analytical results of the benzophenone derivative thus obtained:
i5 NMR (CDC13), ~ ppm: 8.35(d,1H), 8.26(d,1H), 7.40-8.10(m,6H).
(2) Preparation of methyl 4-benzoyl-2-nitrocinnamate:
10.17 g of 4-iodo-3-nitrobenzophenone obtained in the above procedure (1), 4.10 g of methyl acrylate and 4.70 g of triethylamine were dissolved in 130 m~
of acetonitrile and then degasified. The resultant solution was added with 0.65 g of palladium (II) acetate and heated under reflux for 6 hours under a nitrogen gas stream, whereby a reaction was conducted.
After allowing the reaction mixture to cool down, the 2~1389 solvent was distilled off from the reaction mixture under reduced pressure. Benzene was added to the residue. The resultant solution was washed successively with water, 1 N hydrochloric acid, a saturated solution of sodium bicarbonate and a saturated NaCl solution.
The thus-washed organic layer was dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The residue was thereafter purified by chromatography on a silica gel column (eluent: chloroform) to obtain 7.12 g of methyl 4-benzoyl-2-nitrocinnamate as pale yellow crystals.
Analytical results of the cinnamic acid derivative thus obtained:
NMR (CDC13), ~ ppm: 8.43(d,1H), 7.48-8.38(m,8H).
6.51(d,1H), 3.84(s,3H).
(3) Preparation of 2-nitro-4-(a-hydroxybenzyl)-cinnamic acid:
7.12 g of methyl 4-benzoyl-2-nitrocinnamate obtained in the above procedure (2) were dissolved in 120 m2 of methanol, followed by the addition of 0.90 g of sodium borohydride at room temperature. After stirring the resultant mixture at the same temperature for 10 hours, a small amount of water was added to terminate the reaction.
2~ 89 The solvent was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in benzene. The resultant solution was washed successively with 200 m~ of water and 200 mQ
of a saturated NaCl solution.
The thus-washed organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, thereby obtaining 7.12 g of methyl 2-nitro-4-(a-hydroxybenzyl)cinnamate as an pale yellow oily substance.
Further, 7.12 g of the pale yellow oily substance were dissolved in 60 m~ of methanol, followed by the addition of 40 m~ of a 1 N aqueous solution of potassium hydroxide at room temperature.
The resultant solution was vigorously stirred for 3 hours at the same temperature. After completion of the stirring, the reaction mixture was poured into water and then neutralized with 1 N hydrochloric acid.
Precipitated crystals were collected by filtration and then washed with water.
The crystals thus obtained were dried under reduced pressure to obtain 6.95 g of 2-nitro-4-(a-hydroxybenzyl)cinnamic acid in a purified form.
Analytical results of the product thus obtained in the purified form:
Elemental analysis for C16H13NO5:
Calculated (%): C, 64.21; H, 4.38; N, 4.68.
Found (%): C, 63.79; H, 4.95; N, 4.21.
(4) Preparation of 3-(4-benzoyl-2-nitrophenyl)-1-propanol:
3.54 g of 2-nitro-4-(a-hydroxybenzyl)cinnamic acid obtained in the above procedure (3), 13.38 g of hydroxyamine-O-sulfonic acid and 9.69 g of hydroxyl-amine sulfate were suspended in 180 m~ of water. The resulting suspension was cooled and while maintaining its internal temperature at 20-30~C, a 50% aqueous solution of sodium hydroxide (about 22 m~ in total) was added dropwise thereto.
After the mixture was stirred at the same temperature for 3 hours to react them, the reaction mixture was ice-cooled. The reaction mixture was then added with 6 N sulfuric acid to acidify same, and precipitated crystals were collected by filtration.
The thus-obtained crystals were washed with water and then dried under reduced pressure to obtain 3.48 g of 3-[2-nitro-4-(a-hydroxybenzyl)phenyl]propionic acid as crystals.
3.3 g of the crystals of the phenylpropionic acid derivative thus obtained were dissolved in 70 mQ
of tetrahydrofuran. The resultant solution was added with 1.4 me of boran-dimethylsulfide complex, followed by stirring. Upon an elapsed time of 6 hours, 2~01389 5 mQ of water was added to the reaction mixture to terminate the reaction. The solvent was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in 100 m~ of chloroform.
The chloroform solution was washed successively with water, a lN aqueous solution of sodium hydroxide and a saturated saline solution. The thus-washed organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 2.90 g of crude 3-[2-nitro-4-(~-hydroxybenzyl)phenyl]propanol.
2.90 g of the crude product were dissolved in 100 m~ of chloroform, followed by the addition of 20 g of celite and 9.0 g of manganese dioxide. The resultant mixture was vigorously stirred for 24 hours at room temperature.
After completion of the stirring, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 2.87 g of 3-(4-benzoyl-2-nitro-phenyl)-l-propanol.
Analytical results of the phenylpropanol derivative thus obtained:
NMR (CDC13), ~ ppm: 8.12(d,1H), 7.80(dd,1H), 7.00-7.72(m,6H).
3.64(t,2H), 3.00(t,2H), 1.92(m,2H), 1.84(brs,1H).
2~ 89 (5) Preparation of 1,3-dimethyl-6-{4-~3-(4-benzoyl-2-nitrophenyl)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 136):
1.0 g of 3-(4-benzoyl-2-nitrophenyl)-1-propanol obtained in the above procedure(4) and 1.38 g of pyridine were dissolved in 20 m~ of chloroform. The resultant mixture was added under ice-cooling with 1.34 g of p-toluenesulfonyl chloride. The resultant mixture was stirred for 10 minutes at the same temperature and for additional 16 hours at room temperature.
The thus-obtained reaction mixture was added with 2 m~ of water and then stirred for 3 hours at room temperature. After addition of 50 m~ of chloroform, the reaction mixture was poured into 50 mQ
of water. The thus-formed mixture was allowed to separate into layers. The organic layer was washed successively with 1 N hydrochloric acid, a 1 N aqueous solution of sodium hydroxide and a saturated saline solution and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.51 g of 3-(4-benzoyl-2-nitro-phenyl)-l-propyl p-toluenesulfonate as an oily yellow substance.
Z~)1389 1.51 g of the oily yellow substance were dissolved in 10 m~ of dimethyl sulfoxide. The resultant solution was added with 1.10 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(lH,3H)-pyrimidinedione and then heated at 80~C for 6 hours to react them.
The resultant reaction mixture was poured into a solution which had been obtained by adding 2.0 g of potassium carbonate to 100 m~ of water. The thus-prepared mixture was extracted twice with 50 m~
portions of chloroform.
The organic layers separated by the two extraction operations were combined, washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 20/1, by volume), thereby obtaining 0.92 g of 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenyl)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione as pale yellow crystals.
Analytical results of the pyridine derivative thus obtained:
NMR (CDC13), ~ppm: 8.23(d,1H), 7.16-8.10(m,7H), 5.21(s,1H), 3.36(s,3H), 3.29(s,3H), -- - 252 - 2 ~ O ~ 3 8 9 2.26-3.26(m,12H), 1.96(m,2H).
Next, the pyrimidinedione derivative was treated in a hydrochloric acid/methanol solution by a method S known per se in the art to obtain 0.9 g of 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenyl)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-( chloride (Compound 136) as white crystals:
Analytical results of Compound 136 thus obtained:
Elemental analysis for C26H29N5O5-HCl:
Calculated (%): C, 59.14; H, 5.73; N, 13.26;
Cl, 6.71.
Found (~): C, 59.56; H, 6.09; N, 13.16;
Cl, 6.21.
Example 80:
Preparation of 1,3-dimethyl-6-{4-[2-(4-benzoyl-- 2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 137):
O O
--'~ ~ HOCHzCH2CH20H ~ \/ ~
25'~CO-,/,~Cl ~ ~C~Cl _ - 253 - 2 G ~ ~ ~ 8 9 ~rCH 2 CO OCzH 5 \ / 1) HCl > ~ C- ~ CH2COOC2H5 >
NOz ~)NdOH
C ~ CHzCOOH ~ ~ C ~ CHzCH20H
HN N- ~ N-CH3 10 CH3- ~ SOzCl '' ~o (COOH)2/CH30H
CH3 >
C ~ C 2CH2N~_~N~ N-CH3 CH3 ~(COOH)2 ( Compound 137) (1) Preparation of 2-(4-chloro-3-nitrophenyl)-2-phenyl-1,3-dioxane:
10 g of 4-chloro-3-nitrobenzophenone, 15 ml of 1,3-propanediol and 0.5 g of camphorsulfonic acid were dissolved in 50 ml of benzene and while eliminating water by a molecular sieve ("Molecular Sieves 3A", trade mark; 1/16 pellets; product of Junsei Chemical Co., Ltd.), were reacted under reflux for 12 hours.
The resultant reaction mixture was allowed to cool down, washed with a 1 N aqueous solution of sodium , ~ .
Z~)1389 hydroxide, washed further with water, dried and then concentrated, thereby obtaining an oily substance.
Next, the oily substance was purified by chromatography on a silica gel column (eluent:
hexane/ethyl acetate = 4/1, by volume) to obtain 7.8 g of 2-(4-chloro-3-nitrophenyl)-2-phenyl-1,3-dioxane.
Analytical results of the compound thus obtained:
Elemental analysis for C16H13NO4Cl:
Calculated (%): C, 60.29; H, 4.11; N, 4.39;
Cl, 11.12.
Found (%): C, 60.09; H, 4.56; N, 4.01;
Cl, 11.29.
(2) Preparation of ethyl 4-(2-phenyl-1,3-dioxan-2-yl)-2-nitrophenylacetate:
lS 5.2 g of zinc powder were suspended in a mixed solution of 10 m~ of benzene and 10 m~ of trimethyl borate. In a nitrogen gas atmosphere, 9 m~ of ethyl bromoacetate were added dropwise at room temperature to the suspension to react them.
Upon an elapsed time of 1 hour, the reaction mixture was added further with a solution of 7.8 g of 2-(4-chloro-3-nitrophenyl)-2-phenyl-1,3-dioxane in 40 m~ of benzene, 0.9 m~ of dimethylformamide and 0.22 g of tris(triphenylphosphine) palladium(II) chloride. The resultant mixture was allowed to stand overnight at room temperature to react them.
Z6~1389 Insoluble matters were then filtered off and the filtrate was concentrated. The thus-obtained filtrate was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = 3/1, by volume), thereby obtaining 4.4 g of ethyl 4-(2-phenyl-1,3-dioxan-2-yl)-2-nitrophenylacetate in an oily form.
Analytical results of the ethyl phenylacetate derivative thus obtained:
NMR (CDC13), ~ppm: 7.3-8.2(m,8H), 4.15(q,2H), 3.22(s,2H), 1.40(t,3H).
(3) Preparation of 4-benzoyl-2-nitrophenylacetic acid:
4.4 g of ethyl 4-(2-phenyl-1,3-dioxan-2-yl)-2-nitrophenylacetate obtained in the above procedure (2) were dissolved in 30 m~ of methanol, followed by the addition of 15 m~ of 1 N hydrochloric acid. They were reacted under reflux for 1 hour.
After completion of the reaction, the reaction mixture was allowed to cool down and the solvent was distilled off. The residue was extracted with ether.
The organic layer obtained by the extraction was washed with water and then concentrated, whereby 3.5 g of an oily crude substance.
Next, the oily substance was dissolved in 20 m~
of ethanol. The resulting solution was added with 5 m~ of a 10% aqueous solution of sodium hydroxide, 2~3~1389 and they were reacted overnight at room temperature.
The solvent was distilled off from the reaction mixture. The residue was added with 10 m~ of water, followed by the addition of 3 N hydrochloric acid to acidify the resultant solution. Precipitated crystals were collected by filtration, thereby obtaining 2.8 g of 4-benzoyl-2-nitrophenylacetic acid.
Analytical results of the nitrophenyl acetic acid derivative thus obtained:
NMR (CDC13), ~ppm: 7.2-8.3(m,8H), 3.73(s,2H).
(4) Preparation of 2-(4-benzoyl-2-nitrophenyl)ethyl alcohol:
A solution of 2.8 g of 4-benzoyl-2-nitrophenyl-acetic acid, which had been obtained in the above procedure (3), in SO m~ of tetrahydrofuran was ice-cooled, to which 2.3 mQ of borane-methyl sulfide complex were added dropwise. The resultant mixture was left over.
Upon an elapsed time of 1 hour, water was added to terminate the reaction. The solvent was distilled off from the reaction mixture. The residue was added with ether and the resulting ether solution was washed with a dilute hydrogen peroxide solution.
After the washing, the ether solution was concentrated. The resulting syrup was added along with Z~}0~8~
17 g of activated manganese dioxide into S0 m~ of chloroform. The mixture was vigorously stirred for 30 hours.
After completion of the stirring, manganese dioxide was filtered off from the reaction mixture and the filtrate was concentrated. The concentrate was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = 3/1, by volume), thereby obtaining 1.9 g of 2-(4-benzoyl-2-nitrophenyl)-ethyl alcohol in an oily form.Analytical results of the compound thus obtained:
NMR (CDC13), ~ppm: 7.2-8.3(m,8H), 4.05(t,2H), 3.11(t,2H).
(5) Preparation of 1,3-dimethyl-6-{4-[2-(4-benzoyl-2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 137):
1.9 g of 2-(4-benzoyl-2-nitrophenyl)ethyl alcohol obtained in the above procedure (4), 1.5 g of p-toluenesulfonyl chloride and 1.8 m~ of pyridine were dissolved in 30 mQ of chloroform and reacted at room temperature for 24 hours. Water was then added to the reaction mixture. After vigorously stirring the reaction mixture for 3 hours, the chloroform layer was separated, washed first with a 1 N aqueous solution of hydrochloric acid and then a 1 N aqueous solution of sodium hydroxide, washed with water, concentrated over Z~ .89 sodium sulfate, and then concentrated to obtain a brown oily substance.
The brown oily substance, 0.6 g of 1,3-dimethyl~
6-(1-piperazLnyl) -2,4(lH,3H)-pyrimidinedione and 3 mQ of triethylamine were reacted for 6 hours under reflux in 20 m~ of isopropanol.
The reaction mixture was allowed to cool down, concentrated, and then dissolved in chloroform~ The resultant chloroform solution was washed with water, concentrated and then purified by chromatography on a silica gel column (eluent: chloroform/methanol ~ 40~1 by volume), thereby obtaining 0.7 g of 1,3-dime~yl~6 {4-[2-(4-benzoyl-2-nitrophenyl)ethyl]piperazin-l~yl~
2,4(lH,3H)-pyrimidinedione in an oily form.
Analytical results of the pyrimidinedione deriva~i~e thus obtained:
NMR (CDC13), ~ppm: 8.01(d,1H), 7.3-7.8(m,7H), 5.12(s,1H), 4.55(m,2H), 3.22(s,3H), 3.30(s,2H), 2.6-3.3(m,10H).
Next, the oily pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.6 g of 1,3-dimethyl-6-{4-t2-(4-benzoyl-2-nitrophenyl)ethyl]-2C~
piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 137).
Analytical results of Compound 137 thus obtained:
IR vmBax (cm 1): 2550, 1740, 1700, 1650, 1530, 1340, 1200, 1030, 830, 760, 700.
Elemental analysis for C25H27N5O5-(COOH)2-3H2O:
Calculated (~): C, 52.17; H, 5.68; N, 11.27.
Found (%): C, 52.57; H, 6.01; N, 11.30.
~0 Example 81:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl~piperazin-l-yl}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 133) available by the process of Example 76:
1 g of the pyrimidinedione derivative oxalate (Compound 133), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of 5 g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 82:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-t2-(2-benzoyl-4-nitroanilino)ethylamino]-2,4(1H,3H)-pyrimidinedione (Compound 131) available by the process of Example 74:
5 g of the pyrimidinedione derivative oxalate (Compound 131), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 83:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{3-[4-nitro-2-(3-pyridinecarbonyl)anilino]propylamino}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 129) available by the process of Example 72:
20 mg of the pyrimidinedione derivative oxalate (Compound 129) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 6:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 12 and obtained in the corresponding examples described above were determined. The results are summarized in Table 12.
2~ 8g Table 12 Result of Pharmacological Test 75 ( ) ERP (%) 5 Compound Dose (~g/ml)Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.0 3.0 133 - - - 6.3 6.318.8 136 11.0 14.0 - - 7.715.4 15.4 137 32.0 51.0 - 6.3 6.312.5 18.8 Toxicity Test 6:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 13 and obtained in the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 13.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table 13 Compound No.Mortality rate (%) 26~ 89 Example 84:
Preparation of 1,3-dimethyl-6-{4-[3-(3-methyl-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4~
(lH,3H)-pyrimidinedione hydroxide (Compound 138):
r-~ ~ 2 2 2 . (Compound 157) ~ ~
--/ N~o (Compound 139) ~3 O2N ~ OH Hcl/cH3oH
> >
3 ,O
2 ~ 2C~2CH2~ ~ -CH3 HCl C~3 (Compound 138) (1) Preparation of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139):
14.1 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157), 11.7 g of 3-2~
bromo-l-propanol and 13 g of triethylamine were reacted under reflux for 20 hours in 250 ml of ethanol. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was dissolved in 300 m~ of chloroform. The chloroform solution was washed twice with 100 m~ portions of water and the thus-washed organic layer was dried over anhydrous magnesium sulfate. The organic layer was heated under reduced pressure to distill off the solvent, whereby 20.5 g of a crude product were obtained. Ether was added to the crude product to have it crystallized.
The resultant crystals were collected, washed and then dried, thereby obtaining 12.4 g of 1,3-dimethyl-6-[4-(3-hydroxylpropyl)piperazin-1-yl]-2,4(lH,3H)-pyridine-dione ICompound 139) (yield: 69.8%).
Analytical results of crystals of Compound 139 thus obtained:
Melting point: 119-121~C.
NMR ( CDC13), ~ppm: 1.8(d,lH), 2.7(m,6H), 3.02(m,4H), 3.36(s,3H), 3.43(s,3H), 3.82(t,2H), 4.34(br.1H), 5.26(s,1H), IR vmax (cm 1): 3380, 3180, 2830, 1695, 1650, 1605, 1440, 1213, 1068, 1000, 921, 750.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(3-methyl-4-2~1389 nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 138):
1.13 g of Compound 139 obtained in the above procedure, 1.21 g of triphenylphosphine and 0.70 g of 3-methyl-4-nitrophenol were suspended and mixed in 15 m~ of anhydrous tetrahydrofuran. Into the resultant suspension, a solution of 0.8 g of diethyl azodicarboxylate in 10 m~ of anhydrous tetrahydrofuran was added at room temperature.
After stirring the resultant mixture for 10 minutes, it was concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent: methanol/ethyl acetate = 1/15 - 1/7, by volume), thereby obtaining 0.92 g of 1,3-dimethyl-6-{4-[3-(3-methyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 178.5-181~C.
Elemental analysis for C20H27N5O5:
Calculated (%): C, 57.54; H, 6.52; N, 16.78.
Found (%): C, 57.30; H, 6.56; N, 16.64.
NMR (CDC13), ~ppm: 1.9-2.3(m,2H), 2.6-2.8(m,9H), 3.0-3.2(m,4H), 3.44(s,3H), 3.54(s.3H), 4.28(t,2H), 5.44(s,1H), 7.0-7.16(m,2H), Z00~89 8.40(d,lH).
Next, 0.80 g of 1,3-dimethyl-6-{4-[3-(3-methyl-4-nitrophenyloxy)propyl~-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione was treated in an HCl/methanol solution by a method known per se in the art to obtain 0.60 g of 1,3-dimethyl-6- {4-[3-(3-methyl-4-nitrophenyloxy)-propyl]piperazin- l-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 138).
Analytical results of Compound 138 thus obtained:
Melting point: 224~C (decomposed1.
Elemental analysis for C2oH27N5O5-HCl-2H2O:
Calculated (%): C, 49.03; H, 6.58; N, 14.29;
Cl, 7.24.
Found (%): C, 48.82; H, 6.88; N, 14.18;
Cl, 7.31.
Example 85:
Preparation of 1,3-dimethyl-6-{4-[3-(4-chloro-2-nitrophenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 140):
C1 ~ OH+HOC~2CH2CH2N N ~ -CH3 (Compound 139 HCl/CH3OH
2~389 Cl ~ OCH2CH2CH2N~_~N ~ N--CH3 HC1 NO2 c~3 (Compound 140) 0.80 g of 4-chloro-2-nitrophenol, 1.13 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 139) and 1.21 g of triphenylphosphine were suspended in 15 mQ of anhydrous tetrahydrofuran, followed by the addition of 0.80 g of diethyl azodicarboxylate. The resultant mixture was treated in a similar manner to Example 84-(2~, thereby obtaining 1.43 g of 1,3-dimethyl-6-{4-[3-(4-chloro-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 162-163~C.
Elemental analysis for ClgH24N5O5Cl-~H2O:
Calculated (%): C, 51.07; H, 5.64; N, 15.67;
Cl, 7.93.
Eound (%): C, 51.11; H, 5.68; N, 15.64;
Cl, 7.94.
NMR (CDC13), ~ppm: 1.8-2.2(m,2H), 2.4-2.8(m,6H), 2.8-3.04(m,4H), 3.2-3.4(m,2H), z~
3.52(s.3H), 3.80(s,3H), 4.18(t,2H), 5.20(s,1H), 7.20(d,lH), 7.45(dd,lH).
7.81(d,1H).
5Next, 1.2 g of the pyrimidinedione derivative were treated in a 15% HCl/methanol solution by a method known E~ se in the art to obtain 1.13 g of 1,3-dimethyl-6-{4-[3-(4-chloro-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 140).
Analytical results of Compound 140 thus obtained:
Melting point: 271~C (decomposed).
Elemental analysis for ClgH24N5O5Cl-HCl:
Calculated (%): C, 48.11; H, 5.31; N, 14.76;
Cl, 14.95.
Found (%): C, 47.80; H, 5.33; N, 14.62;
Cl, 14.86.
Example 86:
Preparation of 1,3-dimethyl-6-{4-[3-(2-chloro-4-20nitrophenyloxy)propyl~piperazin-1-yl}-2,4-(lH,3H)-pyrimidinedione hydrochloride (Compound 141):
O2N ~ OH+HOCR2CH2C~2N N ~ O-CH3 (Compound 139) HCl/CH3OH
~00~389 2 ~ Oc~2cH2cH2N~-~N ~ -CH
(Compound 141) 2.4 g of 2-chloro-4-nitrophenol, 3.38 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 3.62 g of triphenylphosphine were suspended in 70 me of anhydrous tetrahydrofuran, followed by the addition of 2.4 g of diethyl azodicarboxylate. The resultant mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.5 g of pale yellow crystals. Those crystals were recrystallized from ethanol so that 2.07 g of 1,3-dimethyl-6-{4-t3-(2-chloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione were obtained as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 133-134~C.
Elemental analysis for ClgH24N5O5Cl:
Calculated (%): C, 52.12; H, 5.52; N, 15.99;
C1, 8.10.
Found (%): C, 51.99; H, 5.72; N, 15.70;
ZQ~89 Cl, 8.06.
NMR (CDC13), ~ppm: 1.8-2.3(m,2H), 2.3-3.1(m,10H), 3.33(s,3H), 3.41(s,3H), 4.24(t,2H), 5.26(s,1H), 7.0-8.4(m,3H).
Next, 0.5 g of the pyrimidinedione derivative was treated in a 15% HCl/methanol solution by a method known ~ se in the art to obtain 0.5 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 141).
Analytical results of Compound 141 thus obtained:
Melting point: 115-120~C.
Elemental analysis for ClgH24N5O5Cl-HCl-H2O:
Calculated (%): C, 46.35; H, 5.53; N, 14.22;
Cl, 14.40.
Found (%): C, 46.25; H, 5.29; N, 14.46;
Cl, 14.69.
IR vmaBr (cm 1): 1700, 1345, 1285, 1200, 1130, 1055, 900, 830, 750.
Example 87:
Preparation of 1,3-dimethyl-6-{4-t3-(4-methane-sulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 142~:
Z(~01389 H2N ~ OH ~CH3CONH ~ OH
(Compound 143) s BrCH2CH2CH2Br ) CH3CONH ~ 2 2 2 1) 2N HCl 2) CH3S02Cl CH3S02NH~OCH2CH2CH2C
HN N ~ N-CH
~-~ N-~o 3 CH3 HCl/CH30H
(Compound 157) CH3S02NH ~ O~H2CH2C~2N~_~N ~ N CH3 (Compound 142) (1) Preparation of 4-acetamido-2-nitrophenol (Compound 143):
Z~i1389 10.1 g of 4-amino-2-nitrophenol were dissolved in 80 m~ of acetic acid, followed by the addition of 6.7 g of acetic anhydride over 5 minutes. After stirring the resultant mixture for 1 hour, the solvent S was distilled off under reduced pressure. Water was added to the residue, whereby a solid of a dark brown color precipitated. The solid was collected by filtration. The solid was washed with water and then recrystallized from water-containing ethanol, thereby obtaining 10.2 g of 4-acetamido-2-nitrophenol (Compound 143) as crystals.
Analytical results of crystals of Compound 143 thus obtained:
Melting point: 158-159~C.
(2) Preparation of 3-(4-acetamido-2-nitrophenyloxy)-propyl bromide:
A mixture consisting of 10.2 g of 4-acetamido-2-nitrophenol (Compound 143) obtained by the above procedure, 13.9 g of potassium carbonate, 100 m~ of methyl ethyl ketone and 40.2 g of 1,3-dibromopropane was reacted under reflux for 6 hours. Insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure.
The residue was dissolved in chloroform. The chloroform solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent Z~0~389 was distilled off under reduced pressure. The residue was then purified by chromatography on a silica gel column leluent: chloroform/methanol = 100/1, by volume), followed by recrystallization from dichloro-s methane-hexane to obtain 5.2 g of 3-(4-acetamido-2-nitrophenyloxy)propyl bromide as crystals.
Analytical results of crystals of the propyl bromide derivative thus obtained:
Melting point: 134~C.
Elemental analysis for CllH13N2O3Br:
Calculated (%): C, 41.66; H, 4.13; N, 8.83;
Br, 25.13.
Found (%): C, 41.84; H, 4.35; N, 8.92;
Br, 24.73.
(3) Preparation of 3-(4-methanesulfonamido-2-nitro-phenyloxy)propyl chloride:
1.0 g of 3-(4-acetamido-2-nitrophenyloxy)propyl bromide obtained by the above procedure was suspended in 15 m~ of 2N hydrochloric acid. After heating the resultant mixture under reflux for 30 minutes, 10 m~
of acetic acid were added, followed by heating under reflux for additional 4 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. Sodium carbonate was added to the resultant aqueous mixture to adjust the pH to 7-8.
The aqueous mixture was then extracted with chloroform.
~i1;389 The extract was dried over anhydrous sodium sulfate.
The drying agent was filtered off. The filtrate was added with 1 m~ of pyridine. A solution of 0.5 g of mesyl chloride in 5 m~ of chloroform was added dropwise under ice-cooling. After stirring the thus-obtained mixture for 2 hours under ice-cooling, it was stirred at room temperature for 2 hours and then extracted twice with a 2 N solution of sodium hydroxide. The resultant aqueous layer was washed with chloroform. This aqueous layer was acidified with 6 N
hydrochloric acid and then extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was recrystallized from ethanol, thereby obtaining 0.7 g of 3-(4-methanesulfon-amido-2-nitrophenyloxy)propyl chloride as crystals.
Analytical results of crystals of the propyl chloride derivative thus obtained:
Elemental analysis for CloH13ClN2O5S:
Calculated (%): C, 38.90 H, 4.24; N, 9.07;
Cl, 11.49; S, 10.38.
Found (%): C, 38.90; H, 4.30; N, 8.94;
Cl, 10.72; S, 10.03.
(4) Preparation of 1,3-dimethyl-6-{4-t3-(4-methane-sulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 142):
2~1389 0.31 g of 3-(4-methanesulfonamido-2-nitro-phenyloxy)propyl chloride, 0.22 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157) and O.S ml of triethylamine were dissolved under heat S in 10 m~ of ethanol to give a uniform solution. The solvent was distilled off under reduced pressure.
After heating the residue at 110~C for 2 hours, 10 m~
of n-butanol were added and the resulting mixture was heated under stirring at 110~C for S hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a dilute aqueous solution of sodium hydroxide. The thus-prepared solution was washed with chloroform. The water layer was then adjusted to pH 1-2 with dilute lS hydrochloric acid, washed with ethyl acetate, and then added with sodium hydrogencarbonate to raise the pH to 7-8. Precipitated insoluble matters were collected by filtration. The thus-collected substance was dried under reduced pressure and then dissolved in methanol.
15% HCl/methanol was added to convert it into the hydrochloride by a method known per se in the art, thereby obtaining 0.2 g of 1,3-dimethyl-6-{4-[3-(4-methanesulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 142) as crystals.
- Z~01389 Analytical results of crystals of Compound 142 thus obtained:
Melting point: 239~C.
Elemental analysis for C20H28N607S~HCl-~H20:
Calculated (%): C, 44.32; H, 5.58; N, 15.51;
Cl, 6.54; S, 5.92.
Found (%): C, 44.30; H, 5.58; N, 15.45;
Cl, 6.96; S, 5.94.
Example 88:
Preparation of 1,3-dimethyl-6-{4-[3-(4-acetamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 144):
CH3CONH ~ OH+HOCH2CH2CH2N N ~ N-CH3 2 C~3 (Compound 143) (Compound 139) HCl/CH30H
>
CH3CONH ~ ~C~2c~'2c~'2N ~ h-C~3 (Compound 144) 2.71 g of 4-acetamido-2-nitrophenol (Compound 143) o~tained in Example 87-(1), 3.38 g of 1,3-- Z~01~89 dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl3-2,4(1H,3H)-pyrimidinedione (Compound 139) and 3.62 g of triphenylphosphine were suspended in 70 mQ of anhydrous tetrahydrofuran, followed by the addition of 2.4 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.7 g of pale yellow crystals. 2.0 g of the crystals were treated in a 15% HCl/methanol solution by a method known ~er se in the art to obtain 2.5 g of 1,3-dimethyl-6-{4-[3-(4-acetamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 144).
Analytical results of Compound 144 thus obtained:
Melting point: 228.5-230~C.
Elemental analysis for C21H28N6O6-HCl:
Calculated (%): C, 50.76; H, 5.88; N, 16.91;
Cl, 7.13.
Found (%): C, 50.67; H, 6.27; N, 17.07;
Cl, 6.81.
Example 89:
Preparation of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 145):
O2N ~ OH+HOCH2CH2C~2N N ~ -CH3 (Compound 139J
02N ~ OCH2CH2CH2N~ N CH3 (Compound 145 - free form) H2~ ~ ~ -C~3.
(Compound 145) 0.63 g of 2-nitrocatechol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 1.06 g of triphenylphosphine were suspended in 15 ml of anhydrous tetrahydrofuran, followed by the addition of 0.71 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 0.65 g of pale yellow crystals. The crystals were recrystallized form ethanol to obtain 0.55 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 145 - free form) as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 171-173~C.
Elemental analysis for C19H25N5O5:
Calculated (%): C, 54.40; H, 6.00; N, 16.69.
Found (%): C, 54.40; H, 6.28; N, 16.48.
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.6-3.2(m,10H), 3.2(m,10H), 3.3(s,3H), 3.4(s,3H), 4.1(t,2H), 5.24(s,1H), 6.88-7.08(m,lH), 7.60-7.80(m,2H).
IR vKBr (cm~l) 1700, 1620, lS00, 1340, 1285, max 1280, 1140, 990, 870.
Next, 0.5 g of the pyrimidinedione derivative were treated in a 20% HCl/methanol solution by a method known per se in the art to obtain 0.5 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 145) as crystals.
Analytical results of crystals of Compound 145 thus obtained:
Melting point: 246-249~C.
Elemental analysis for ClgH25N5O5-HCl-2H2O:
Calculated (%): C, 46.39; H, 6.15; N, 14.24;
Cl, 7.21.
~ - 279 - ~ a ~ 89 -Found (%): C, 46.83; H, 5.97; N, 14.55;
Cl, 7.77.
Example 90:
Preparation of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 146):
( ~0CH2CR2CH2N~N~N-C~3 (Compound 145 - free form) HCl/CH30H
> >
02N ~ OC~2C~2C~2~_JN ~ N CB3 HC
( OCH2CH=CH2 H3C
(Compound 146) 1 g of 1,3-dimethyl-6-{4-13-(2-hydroxy-5-nitro-phenyloxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidine-dione (Compound 145 - free form), 0.31 g of allyl bromide and 0.36 g of potassium carbonate were suspended in 10 ml of dry acetone and heated under reflux for 5 hours. The reaction mixture was poured , ~ .....
Z~1389 into 60 m~ of water and then extracted three times with 30 m~ portions of chloroform. The extract was washed first with a 0.5 N aqueous solution of sodium hydroxide and then with water. The chloroform solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 20/1, by volume).
The resulting oily substance was crystallized from ethanol, thereby obtaining 0.78 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 120-121~C.
NMR (CDC13), ~ppm: 2.08(t,2H), 2.5-3.0(m,10H), 3.3(s,3H), 3.36(s,3H), 4.16(t,2H), 4.5-4.7(m,2H), 5.2(s,1H), 5.16-5.6(m,2H), 5.8-6.24(m,1H), 6.9(d,lH), 7.68-7.92(m,2H).
IR vmaBxr (cm 1): 1690, 1630, 1510, 1330, 1280, 1000.
Next, 0.5 g of the pyrimidinedione derivative was treated in a 20~ HCl/methanol solution by a method known per se in the art to obtain 0.5 g of 1,3-dimethyl-6-{4-t3-(2-allyloxy-5-nitrophenyloxy)propyl]-2~)1389 piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydro-chloride (Compound 146) as crystals.
Analytical results of Compound 146 thus obtained:
Melting point: 161.5-180~C.
~xample 91:
Preparation of 1,3-dimethyl-6-{4-[3-(4-methylthio-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 147):
o CH3S ~ OH+HOCH2C~2CH2N~--J~ ~ CH3 N~2 CH3 (Compound 139) HCl/CH30H
CH3S ~ 0cH2cH2cH2N~~ C~3 HC
N~2 C/H3 (Compound 147) 1.5 g of 4-methylthio-2-nitrophenol, 2.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 2.2 g of triphenylphosphine were suspended in 30 m~ of 2~1389 anhydrous tetrahydrofuran, followed by the addition of 1.35 m~ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.9 g of 1,3-dimethyl-6-{4-[3-(4-methylthio-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.48(s,3H), 2.4-2.7(m,6H), 2.8-3.0(m,4H), 3.28(s,3H), 3.36(s,3H), 4.14(m,2H), 5.16(s,1H), 7.0(d,1H), 7.36(dd,1H), 7.62(d,1H).
Next, 0.5 g of the pyrimidinedione derivative were treated in a 20% HCl/methanol solution by a method known E~ se in the art to obtain 0.4 g of 1,3-dimethyl-6-{4-t3-(4-methylthio-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (Compound 147) as crystals.
Analytical results of crystals of Compound 147 thus obtained:
Melting point: 224-226~C.
Elemental analysis for C20H27N5O5S-HCl:
Calculated (%): C, 49.43; H, 5.81; N, 14.41;
Cl, 7.30; S, 6.60.
Found (%): C, 49.20; H, 5.97; N, 14.28;
2()0~389 Cl, 7.23; S, 6.84.
Example 92:
Preparation of 1,3-dimethyl-6-{4-<3-t2~
hydroxybenzyl)-4-nitrophenyloxy]propyl>pipera-zin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 148):
o2~ ~ o~+~oC~2c~2c~2~ C~3 (Compound 139) 2 ~ 2 2 ~2N~ J ~ ~ C~3 ~ C~3 (Compound 149) Oxalic acid/CH30H
02N ~ OCH2CH2CE2N~_~N ~ N CH3 ( 2 OH c~3 (Compound 148) (1) Preparation of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenyloxy)propyllpiperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 149) 3.74 g of 2-benzoyl-4-nitrophenol, 3.5 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 3.3 g of triphenylphosphine were suspended in 50 m~ of anhydrous tetrahydrofuran, followed by the addition of 2.40 m~ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 3.9 g of 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 149) as crystals.
Analytical results of crystals of the pyrimidinedione derivative (Compound 149) thus obtained:
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.4-2.7(m,6H), 2.8-3.0(m,4H), 3.26(s,3H), 3.36(s,3H), 4.14(m,2H), 5.14(s,1H), 7.0-7.8(m,8H), 8.36(d,2H).
(2) Preparation of 1,3-dimethyl-6-{4-<3-[2-(a-hydroxy-benzyl)-4-nitrophenyloxy]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 148):
0.2 g of the pyrimidinedione derivative (Compound 149) obtained in the above procedure and 15 mg of sodium borohydride were dissolved in ethanol.
The resultant solution was stirred at room temperature for 6 hours. The reaction mixture was poured into water and then extracted with chloroform. The 2~0~389 chloroform layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume), thereby obtaining 0.15 g of 1,3-dimethyl-6-{4-<3-[2-(a-hydroxy-benzyl)-4-nitrophenyloxy]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.0(m,2H), 2.5-2.9(m,10H), 3.26(s,3H), 3.37(s,3H), 4.11(m,2H), 5.16(s,1H), 6.04(s,1H), 6.88(d,1H), 8.14(dd,lH), 8.52(d,lH).
Next, 0.15 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.15 g of 1,3-dimethyl-6-{4-<3-[2-(~-hydroxybenzyl)-4-nitrophenyloxy]-propyl>piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 148) as crystals.
Analytical results of crystals of Compound 148 thus obtained:
Melting point: 111-115~C.
Elemental analysis for C26H31N5O6 2 2 Calculated (%): C, 52.91; H, 5.87; N, 11.02.
Found (%): C, 52.74; H, 5.65; N, 10.94;
IR vKBr (cm-l) 3460, 1700, 1640, 1610, 1510, max 2~1389 1340, 760, 700.
Example 93:
Preparation of 1,3-dimethyl-6-{4-[3-(3-trifluoromethyl-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 150):
~2N ~ 2 2 2N~_~N ~ ~ C~3 CF3 c/~3 (Compound 139) Oxalic acid/CH3OH
>
O2N ~ OC~2CH2C~2U N ~ N-C~3-(COOH)2 3 C~3 (Compound 150) l.9 g of 4-nitro-3-trifluoromethylphenol, 2.25 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 2.41 g of triphenylphosphine were suspended in 60 m~ of anhydrous tetrahydrofuran, followed by the addition of 1.6 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 2~ 389 84-(2), thereby obtaining 3.50 g of pale yellow crystals. The crystals were recrystallized from ethanol to obtain 3.31 g of 1,3-dimethyl-6-{4-[3-(3-trifluoromethyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.5-2.75(m,6H), 2.9-3.1(m,4H), 3.3(s,3H), 3.4(s,3H), 4.15(t,2H), 5.3(s,1H), 7.1-7.4(m,2H), 8.15(d,1H).
Next, 3.2 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method ~nown Per se in the art to obtain 3.22 g of 1,3-dimethyl-6-{4-[3-(3-trifluoromethyl-4-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 150) as crystals.
Analytical results of crystals of Compound 150 thus obtained:
Melting point: 187-189~C.
Elemental analysis for C20H24F3N5O5-(COOH)2:
Calculated (%): Ct 47.06; H, 4.67; N, 12.47;
F, 10.15.
Found (~): C, 47.51; H, 5.24; N, 12.67;
F, 10.49.
- 288 - ~ O ~ ~ 3 8 ~
Example 94:
Preparation of 1,3-dimethyl-6-{4-13-(2-methoxycarbonyl-4-nitrophenyloxy)propyl~-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 151):
02N~OH ~ 02N~OH
~ ~~
2 2 2 ~ ~0 3 c~3 (Compound 139) ; >
02N ~ OC~2C~2CH2N~_~N ~ N--C~3 (Compound 151 - free form) Oxalic acid/CH30H
2 ~ OC-2CH2C22N~_~N ~ -C~3~(COOH)2 (Compound 151) (1) Preparation of methyl 5-nitrosalicylate:
,~ .
. " . . ~
Z~389 80 m~ of methanol and 10 g of concentrated sulfuric acid were added to 5 g of 5-nitrosalicylic acid. The resultant mixture was heated under stirring for 8 hours whlle distilling methanol off. The solvent was then distilled off under reduced pressure and the residue was dissolved in chloroform. The resultant chloroform solution was washed with water and then concentrated to dryness. The resultant residue was purified by chromatography on a silica gel column (eluent: chloroform), followed by recrystallization from chloroform-ether to obtain 5.1 g of methyl 5-nitrosalicylate as crystals.
Analytical results of crystals-of methyl 5-nitro-salicylate thus obtained:
Melting point: 114-116~C.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-carbonyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 151):
2.96 g of methyl 5-nitrosalicylate obtained by the above procedure, 4.23 g of 1,3-dimethyl-6-t4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidine-dione (Compound 139) and 3.93 g of triphenylphosphine were suspended in 50 m~ of anhydrous tetrahydrofuran, followed by the addition of 2.6 g of diethyl azo-dicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby -~9~ 89 obtaining 6.5 g of pale yellow crystals. The crystals were recrystallized from methanol to obtain 5.74 g of 1,3-dimethyl-6-{4-~3-(2-methoxycarbonyl-4-nitro-phenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidine-d ione (Compound 151 - free form) as crystals.
Analytical results of crystals of the pyrimidinedione derivative (Compound 151 - free form) thus obtained:
Melting point: 145-146~C.
NMR (CDC13), ~ppm: 1.8-2.2(m,2H), 2.4-3.0(m,10H), 3.27(s,3H), 3.36(s,3H), 3.87(s,3H), 4.17(t,2H), 5.24(s,1H), 7.0-8.7(m,2H).
Next, 5.5 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 5.6 g of 1,3-dimethyl-6-{4-[3-(2-methoxycarbonyl-4-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 151) as crystals.
Analytical results of crystals of Compound 151 thus obtained:
Melting point: 186-187~C (decomposed).
Y 21 27 5 7 ( )2 3 Calculated (%): C, 47.92; H, 5.86; N, 11.64.
Found (%): C, 47.74; H, 5.66; N, 11.43.
IR vmax ~cm 1): 1655, 1520, 1345, 1200, 1130, 1080, 820, 765, 750.
c~l3~9 Example 95:
Preparation of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 152):
2 ~ 0C~2C~2C~2N~_~N ~ _CH3 (Compound 151 - free form) Oxalic acid/CH30H
2 ~ 2C 2CH2~_~N ~ CH3 (Compound 152) 1.38 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-carbonyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione (Compound 151 - free form) were dissolved in 200 ml of methanol, followed by the addition of 100 m~ of a 1.5 N aqueous solution of sodium hydroxide. The resultant mixture was stirred at 60~C for 30 minutes. The reaction mixture was allowed to cool down, neutralized with dilute hydrochloric acid, and then concentrated to a total volume of 50 mQ
under reduced pressure. The concentrate was ice-cooled 6)1389 and precipitated crystals were collected by filtration, thereby obtaining 1.16 g of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 155-158~C.
NMR (DMSO-d6), ~ppm: 1.8-2.3(m,2H), 2.4-3.2(m,10H), 3.13(s,3H), 3.27(s,3H), 4.2(t,2H), 5.2(s,1H), 7.3-8.5(m,3H).
Next, 1.0 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per _ in the art to obtain 0.9 g of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 152) as crystals.
Analytical results of crystals o~ Compound 152 thus obtained:
Melting point: 191-193~C (decomposed).
Elemental analysis for C20H25N5O7-(COOH)2-H2O:
Calculated (~): C, 47.57; H, 5.26; N, 12.61.
Found (~): C, 47.85; H, 5.32; N, 12.49.
IR vmax (cm 1): 1700, 1650, 1500, 1345, 1290, 1135, 1075, 760, 750.
Example 96:
Preparation of 1,3-dimethyl-6-{4-[3-(2-amino-4--2~01389 -nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 153):
o 2 ~ 2 2 2 ~_~ ~ 3 NH2 c~3 (Compound 139) Oxalic acid/CH30H
. o 2 ~ OC~2CH2C~2N~ N--CB3~(COOH)2 NH2 c/~3 (Compound 153) 1.54 g of 2-amino-4-nitrophenol, 2.82 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 2.88 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 1.92 g of diethyl azodicarboxylate. The thus-prepared mixture was stirred for 1 hour at room temperature and a precipitate was collected by filtration. The precipitate was washed with chloroform-ether to obtain 1.44 g of crytals. The crystals were recrystallized from ethanol-chloroform, thereby obtaining 0.6 g of 1,3-dimethyl-6-{4-[3-(2-amino-4-nitrophenyloxy)propyll-- 29i~QO1389 piperazin-l-yl}-2, 4tlH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 188~C.
NMR (DMSO-d6), ~ppm: 1.9-2.0(m,2H), 2.4-3.0(m,10H), 3.1(s,3H), 3.24(s,3H), 4.08(m,2H), 5.15(s,1H), 5.35(br.2H), 6.8-7.5(m,3H).
Next, 0.2 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.21 g of 1,3-dimethyl-6-{4-[3-(2-amino-4-nitrophenyloxy)propyl]
piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 153) as crystals.
Analytical results of crystals of Compound 153 thus obtained:
Melting point: 145~C.
Elemental analysis for ClgH26N6O5-(COOH)2:
Calculated (~): C, 49.60; H, 5.55; N, 16.53.
Found (%): C, 49.53; H, 5.96; N, 16.49.
IR vmax (cm 1): 3430, 3340, 2940, 1690, 1650, 1510, 1435, 1340, 1290, 1235, 1075.
Example 97:
Preparation of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)propyl]--- 2~Q~3as piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 154):
Ho~CoocH3+HocH2cH2cH2N~N~ - cH3 (Compound 139) Oxalic acid/CH30H
H300C ~ OC~2CH2C~2N~_~N ~ -C~3 ~COOH)2 (Compound 154) 0.84 g of methyl 4-hydroxy-3-nitrobenzoate, 1.5 n . 8 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-l~yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 0.88 g of triphenylphosphine were suspended in 14 m~
of anhydrous tetrahydrofuran, followed by the addition of 0.54 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 1.1 g of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
ZO~)138~
NMR (CDC13), ~ppm: 2.1(m,2H), 2.3-3.0(m,10H), 3.3(s,3H), 3.4(s,3H), 3.95(s,3H), 4.3(t,2H), 5.25(s,1H), 7.25(d,1H), 8.27(dd,lH), 8.61(d,lH).
Next, 1.0 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per _ in the art to obtain 1.0 g of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate ~Compound 154) as crystals.
Analytical results of crystals of Compound 154 thus obtained:
Melting point: 190-193~C (decomposed).
Elemental analysis for C21H27N5O7-(COOH)2-3H2O:
Calculated (%): C, 45.62; H, 5.83; N, 11.57.
Found (%): C, 45.92; H, 5.21; N, 11.84.
IR vmax (cm 1): 2900, 2500, 1740, 1720, 1700, 1640, 1620, 1530, 1340, 800.
Example 98:
Preparation of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 155):
2~1389 02N ~ Cl+HOCX2C~2Ca2N~_~N ~ C 3 CN C~3 (Compound 139) Oxalic acid/CH30H
02N ~ OCH2CX2C~2N~_~N ~ N C~3 (C )2 (Compound 155) 0.82 g of 2-chloro-5-nitrobenzonitrile, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and O.Z2 g of sodium hydride were reacted at 0~C for 1 hour in 5 m~
of dimethylformamide. Water was then added.
Precipitated crystals were collected by filtration and washed with water. The thus-obtained crystals were dried in vacuum, thereby obtaining 0.9 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.1(m,2H), 2.6-3.0(m,10H), 3.3(s,3H), 3.35(s,3H), 4.6(t,2H), 5.1(s,1H), 7.5(d,1H), 8.6(m,2H).
2~)1389 Next, 0.9 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.87 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 155) as crystals.
Analytical results of crystals of Compound 155 thus obtained:
Melting point: 191-193~C (decomposed).
Elemental analysis for C20H24N6~5-(C~~H)2-3H2~
Calculated (%): C, 46.15; H, 5.63; N, 14.68.
Found (%): C, 45.89; H, 5.38; N, 14.29.
IR Vmax (cm ): 2200, 1680, 1630, 1600, 1580, 1520, 1340, 840.
~5 Example 99:
Preparation of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 156):
O O
BrCH2CH2CH2Br ~J~
NII ~ ~ N-CH2CH2cH2sr O O
- 2~ )1389 ~ ~4 N
(Compound 157) Hydrazine H2O
> >
H2NCH2CH2CH2N~_~N N_~N CH3 (Compound 158) Oxalic acid/CH OH
O2N ~ NHCH2C~2C~2~_~N ~ ~N-C~3 (COOH)2 (Compound 156) (1) Preparation of 1,3-dimethyl-6-t4-(3-aminopropyl)-piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione (Compound 158):
A solution in which 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane were suspended in 100 mQ of dimethylformamide was heated under stirring at 120~C for 6 hours, so that potassium ;~;)0~L389 phthalimide and 1,3-dibromopropane were reacted. Next, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with hexane and then recrystallized from ethanol-water.
Crystals-thus obtained were collected by filtration, washed and then dried, thereby obtaining 13.8 g of N-(3-bromopropyl)phthalimide.
Next, 13.0 g of N-(3-bromopropyl)phthalimide, 10.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157) and 20 g of triethyl-amine were suspended in 200 m~ of dioxane. The suspension was thereafter heated under reflux for 6 hours.
Further, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated to dryness under reduced pressure. The residue (dry concentrate) was recrystallized from ethyl acetate/n-hexane. Resultant crystals were collected by filtration, washed and then dried, thereby obtaining 1.25 g of 1,3-dimethyl-6-[4-(3-phthaloylaminopropyl)-piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione.
12.5 g of the crystals and 6.0 g of hydrazine hydrate were next suspended in 200 m~ of ethanol. The suspension was heated for 4 hours under reflux. After allowing the suspension to cool down, resultant Z~0~389 ~ - 301 -insoluble matters were filtered off. The filtrate was concentrated to dryness under reduced pressure. Then, the residue (dry concentrate) was dissolved in water, to which dilute hydrochloric acid was added to adjust the pH to about 3. Insoluble matters formed upon the pH adjustment were filtered off. The filtrate was added with a large amount of potassium carbonate and then extracted with chloroform. After completion of the extraction, the resultant organic layer was dried over anhydrous sodium sulfate and then heated under reduced pressure to distill the solvent off, whereby 6.80 g of 1,3-dimethyl-6-[4-(3-aminopropyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione (Compound 158) were obtained as a colorless syrupy substance. The syrupy substance was crystallized when allowed to stand overnight.
Analytical results of crystals of Compound 158 thus obtained:
Melting point: 85-88~C.
NMR (CDC13), ~ppm: 1.58(br.2H), 1.66(m,2H), 2.48(t,2H), 2.59(m,4H), 2.78(t,2H), 2.97(m,4H), 3.32(s,3H), 3.38(s,3H), 5.24(s,1H).
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 156):
0.3 g of Compound 158 obtained beforehand, 0.3 g of 2-chloro-5-nitrobenzonitrile and 0.31 m~ of triethylamine were stirred at 80~C for 1 hour in 5 m~
of dimethylformamide. The reaction mixture was concell~dLed under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume), thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-t3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.0(m,2H), 2.6-3.3(m,12H), 3.35(s,3H), 3.45(s,3H), 5.33(s,1H), 7.28(m,1H), 8.4-8.6(m,2H).
Next, 0.4 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per _ in the art to obtain 0.41 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 156) as crystals.
Analytical results of crystals of Compound 156 thus obtained:
Melting point: 156-158~C (decomposed).
Elemental analysis for C20H25N7O4 2 2 Calculated (%): C, 49.41; H, 5.43; N, 17.94.
Z~
Found (~): C, 49.34; H, 5.46; N, 18.31.
IR vmax (cm 1): 3300, 2250, 2200, 1530, 1340, 1160, 800, 750, 700.
Example 100:
Preparation of 1,3-dimethyl-6-{4-t3-(2-chloro-4-nitroanilino)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 159):
10 0 N~Cl+H2NCH2 CH2CE~2N~N~N--CH3 (Compound 158) Oxalic acid/CH30H
>
O2N ~ NHCH2CH2CH2N~_~N ~ C~3 (C )2 (Compound 159) A mixture consisting of 0.4 g of Compound 158 obtained in Example 99-(1), 0.4 g of 3,4-dichloro-nitrobenzene, 0.43 ml of triethylamine and 6 ml of dimethylformamide was treated in a manner similar to Example 99-(2), thereby obtaining 0.55 g of 1,3-Z~1389 dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.0(m,2H), 2.5-3.3(m,10H), 3.28(s,3H), 3.39(s,3H), 5.23(s,1H), 6.77(m,1H), 8.11(m,1H), 8.20(m,1H).
Next, 0.5 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.53 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 159) as crystals.
Analytical results of crystals of Compound 159 thus obtained:
Melting point: 153-155~C (decomposed).
Y 19 2sC 6 4 (C )2 ~ 2 Calculated (%): C, 44.10; H, 5.64; N, 14.69;
Cl, 6.20.
Found (%): C, 44.14; H, 5.20; N, 14.63;
Cl, 6.13.
IR vmBax (cm 1): 2250, 1690, 1640, 1630, 1590, 1530, 1330, 800, 740.
Example 101:
Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-200138~
2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 160) OH~HOC~2CH2CH2N~_J~ ~ -CH3 (Compound 139) HCl/CH30H
02N ~ ~
OC~2C~2C~2N~ N Ca3 H
~ (Compound 160) 0.9 g of 2-methoxy-5-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 1.1 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 0.67 m~ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a simila-r manner to Example 84-(2), thereby obtaining 1.2 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-5-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
2~
NMR (CDC13), ~ppm: 2.15(m,2H), 2.5-3.2(m,10H), 3.3(s,3H), 3.4(s,3H), 3.97(s,3H), 4.23(t,2H), 5.26(s,1H), 6.96(d,1H), 7.86(m,2H).
Next, 1.1 g of the pyrimidinedione derivative was treated in a 10% HCl/methanol solution by a method known per se in the art to obtain 1.17 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-5-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydro-chloride (Compound 160) as crystals.
Analytical results of crystals of Compound 160 thus obtained:
Melting point: 158-162~C (decomposed).
Elemental analysis for C20H27N5O6-HCl-H2O:
Calculated (%): C, 49.23; H, 6.20; N, 14.35;
Cl, 7.27.
Found (%): C, 49.04; H, 6.28; N, 14.26;
Cl, 7.54.
IR vKBr (cm~l) 3400, 2950, 1660, 1620, 1540, max 1350, 1260, 1010, 810, 770.
Example 102:
Preparation of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 161):
~ 307 ~ ~ O ~ ~ ~ 89 02N ~ OH + H~CH2CH=CH2 2 ~
OH OCH2CH=cH2 HOCH2CH2CH2N N ~ N-CH3 (Compound 139) 3 02N ~ OCH2CH2CH2N~_~N ~ C~3 OCH2CH=CH2 c~3 (Compound 161 - free form) HCl/CH30H
( 2 ~ 2C~2c~2~ N ~ N-C~3 HC1 OCH2CH=CH2 CH~
(Compound 161) (1) Preparation of 2-allyloxy-4-nitrophenol:
1.7 g of 4-nitrocatechol, 0.74 ml of allyl alcohol and 2.4 g of triphenylphosphine were suspended in 40 ml of anhydrous tetrahydrofuran, followed by the addition of 1.5 m~ of diethyl azodicarboxylate. The resultant mixture was stirred at room temperature for B
2Q~1389 11 hours, followed by the addition of 5 g of silica gel. The thus-prepared mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent:
hexane/ethyl acetate = 3/1, by volume), thereby obtaining 1.5 g of 2-allyloxy-4-nitrophenol as an oily substance.
Analytical results of the phenol derivative thus obtained:
NMR (CDC13), ~ppm: 4.76(m,2H), 5.22(m,lH), 5.35(m,1H), 5.96(m,1H), 6.99(d,1H), 7.91(m,2H).
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 161):
1.5 g of 2-allyloxy-4-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 1.1 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 0.67 mQ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 1.1 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 161 - free form) as an oily substance.
0~389 Analytical results of the pyrimidinedione derivative (Compound 161 - free form) thus obtained:
NMR (CDC13), ~ppm: 2.1(m,2H), 2.5-3.3(m,10H), 3.35(s,3H), 3.43(s,3H), 4.76(m,2H), 5.3(s,lH), 5.6(m,2H), 6.15(m,lH), 7.0(m,1H), 7.8(m,2H).
Next, 0.5 g of the pyrimidinedione derivative was treated in a 10% HCl/methanol solution by a method known E~ se in the art to obtain 0.4 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (Compound 161) as crystals.
Analytical results of crystals of Compound 161 thus obtained:
Melting point: 134-136~C (decomposed).
Elemental analysis for C22H29N5O6-HCl-2~H2O:
Calculated (%): C, 48.84; H, 6.52; N, 12.95;
Cl, 6.55.
Found (%): C, 48.97; H, 6.27; N, 12.74;
Cl, 6.75.
IR vmax (cm 1): -~3350, 2900, 1700, 1640, 1510, 1340, 1280, 1090, 810, 760.
Example 103:
Preparation of 1,3-dimethyl-6-{4-t3-(2-hydroxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride 2~01389 (Compound 162):
2 ~ OCH2CH2CH2N N ~ N-CH
OCH2CH=CH2 C/H3 (Compound 161 - free form) HCl/CH30H
~
02N ~ oc~2c~2c 2N N ~ -C~3 HC
(Compound 162) 0.6 g of 1,3-dimethyl-6-~4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione (Compound 161 - free form) was dissolved in 10 ml of methanol, followed by the addition of 0.1 g of 10~ Pd/activated carbon, 0.1 g of p-toluenesulfonic acid monohydrate and 2 ml of water.
The resultant mixture was heated for 15 hours under stirring and reflux. After allowing the reaction mixture to cool down, insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column 2 ~3Q~ ~ 8 9 (eluent: chloroform/methanol = 50/1, by volume), thereby thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.15(m,2H), 2.7-3.3(m,10H), 3.34(s,3H), 3.43(s,3H), 4.13(t,2H), 5.34(s,1H), 7.0(m,1H), 8.03(m,2H).
Next, 0.4 g of the pyrimidinedione derivative was treated in a 10% HCl/methanol solution by a method known ~ se in the art to obtain 0.33 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (Compound 162) as amorphous powder.
Analytical results of amorphous powder of Compound 162 thus obtained:
Elemental analysis for ClgH25N5O6-HCl-l~H2O:
Calculated (%): C, 47.26; H, 6.05; N, 14.05;
Cl, 7.34.
Found (%): C, 47.53; H, 6.21; N, 13.75;
Cl, 7.59.
IR Vmax (cm ) 3350, 1680, 1630, 1530, 1340, 1220, 1000, 750, 710.
Example 104:
Preparation of 1,3-dimethyl-6-{4-[3-(2-benzyl-2n ~ ~ 3 8 9 ~i amino-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 163):
02N ~ OH + ~ CHO ~ 02N ~ OH
NH2 HCH2 ~
o (, IOCH2C~2CF12 ~ N~N--cH3 c~3 (Compound 139) Oxalic acid/CH30H
02N ~ OC~2C zCH2N~ CH3~(COOH)2 (Compound 163) (1) Preparation of 2-benzylamino-4-nitrophenol:
4.4 g of 2-amino-4-nitrophenol, 5.2 g of benzaldehyde and 0.4 g of p-toluenesulfonic acid monohydrate were dissolved in 300 ml of benzene. The resultant mixture was heated under reflux for 5 hours while removing water. The solvent was distilled off under reduced pressure and hexane is added to the residue. Precipitated crystals were collected by filtration to obtain 6.6 g of crystals. The crystals were dissolved in S5 ml of dimethylformamide, followed ~....
. ~ , - Z~1~)138~
by the addition of 2.2 g of sodium borohydride under ice-cooling. The resultant mixture was stirred at the same temperature for 2 hours. Ether was added to the reaction mixture. The resultant ether solution was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 4-.2 g of 2-benzylamino-4-nitrophenol. This product was provided for the subsequent reaction without purification.
Analytical results of 2-benzylamino-4-nitrophenol thus obtained:
NMR (CDC13), ~ppm: 4.5(s,2H), 6.8-7.0(d,1H), 7.3-7.6(m,2H), 7.4(s,1H).
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 163):
0.7 g of 2-benzylamino-4-nitrophenol, 0.8 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 0.9 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 0.65 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 0.93 g of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy~propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
2Q~ 8~
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.05(m,2H), 2.6(m,6H), 2.95(m,4H), 3.3(s,3H), 3.35(s,3H), 4.15(t,2H), 4.35(d,2H), 4.8(m,1H), 5.25(s,1H), 6.75(d,1H), 7.2-7.45(m,1H), 7.35(s,5H), 7.6(m,1H).
Next, 0.8 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.81 g of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy)-propyl~piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 163) as crystals.
Analytical results of crystals of Compound 163 thus obtained:
Y 26 32N6 5 (COO )2 ~ 2~
Calculated (%): C, 55.35; H, 5.81; N, 13.83.
Found (%): C, 55.73; H, 5.78; N, 13.87.
Example 105:
Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 164):
~01389 . - 315-~ 2 N ~ OH
\-- N~~o c~3 (Compound 139) HCl/CH30H
~2N ~ 2C''2C~2N~_J~ ~ C 3 HCl (Compound 164) (1) Preparation of 2-methoxy-4-nitrophenol:
50 g of 2-amino-5-nitroanisole, 50 g of sodium hydroxide were dissolved in 450 ml of water. The resultant mixture was heated under reflux for 3 hours and then ice-cooled. Precipitated crystals were collected by filtration, followed by dissolution in water. The thus-prepared solution was neutralized with 6 N hydrochloric acid and crystals thus precipitated were collected by filtration. The crystals were dissolved in chloroform. The resultant solution was washed with water and dried over anhydrous sodium - 316 2 ~ ~ 1 3 8 9 sulfate. By concentrating the chloroform layer under reduced pressure, 4.5 g of 2-methoxy-4-nitrophenol were obtained as crystals.
Analytical results of 2-methoxy-4-nitrophenol thus 5 obtained: -Melting point: 102-103~C.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 164):
0.68 g of 2-methoxy-4-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 1.1 g of triphenylphosphine were suspended in 20 mQ of anhydrous tetrahydrofuran, followed by the addition of 0.71 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), followed by recrystallization from methanol, whereby 1.35 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.9-3.3(m,12H), 3.43(s,3H), 3.5(s,3H), 4.06(s,3H), 4.26(t,2H), 5.35(s,1H), 7.05(d,1H), 7.8-8.15(m,2H).
Next, 1.3 g of the pyrimidinedione derivative was treated in a lO~HCl/methanol solution by a method known per se in the art to obtain 1.17 g of 1,3-dimethyl-6-{4-t3-(2-methoxy-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 164) as crystals.
Analytical results of crystals of Compound 164 thus obtained:
Melting point: 135-138~C.
Elemental analysis for C20H27N5O6-HCl-l~H2O
Calculated (%): C, 48.34; H, 6.29; N, 14.09;
Cl, 7.13.
Found (%): C, 48.20; H, 6.61; N, 14.27;
Cl, 7.38.
Example 106:
Preparation of 1,3-dimethyl-6-{4-[3-(2,6-dichloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 165):
02N~OH + BrCH2CH2CH2Br Cl 02N~OCH2CH2CH2Br ~1389 ~0 HCl/CH30H
(Compound 157) ~C , / 11~
(Compound 165) (1) Preparation of l-bromo-3-(2,6-dichloro-4-nitro-phenyloxy)propane:
A mixture of 4.16 g of 2,6-dichloro-4-nitrophenol, 40.4 g of 1,3-dibromopropane, 2.76 g of potassium carbonate and 2.46 ~-of potassium t-butoxide was heated under reflux for 4 hours in 50 ml of methyl ethyl ketone. The reaction mixture was allowed to cool down and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform. The thus-prepared chloroform solution was washed with water, and the chloroform was then distilled off. The residue was purified by chromatography on a silica gel column (eluent: chloroform/hexane = 4/1, by volume) to obtain 6.24 g of 1-bromo-3-(2,6-dichloro-4-nitrophenyloxy)-propane. This compound was employed in the nextreaction without any further purification.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2,6-dichloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 165):
4.94 g of 1-bromo-3-(2,6-dichloro-4-nitro-phenyloxy)propane obtained by the above procedure, 3.36 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(lH,3H)-pyrimidinedione (Compound 157) and 4 ml of triethyl-amine were dissolved in 100 m~ of dioxane. The thus-prepared mixture was heated for 2 hours under stirring and reflux. The reaction mixture was allowed to cool down and then filtered to remove insoluble matters. ~he filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in chloroform. The resultant chloroform solution was washed with water and the solvent was distilled off.
The residue was purified by chromatography on a silica gel column (eluent: chloro~orm/methanol = 100/0-2, by volume), followed by recrystallization from ethanol, whereby 3.57 g of 1,3-dimethyl-6-{4-[3-(2,6-dichloro-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.95-2.25(m,2H), 2.5-2.8(m,6H), 2.9-3.1(m,4H), 3.3(s,3H), 3.4(s,3H), 4.2(t,2H), 5.35(s,1H), 8.25(s,2H).
Next, 0.5 g of the pyrimidinedione derivative was treated in a 10%HCl/methanol solution by a method known ~ se in the art to obtain 0.45 g of 1,3-dimethyl-6-{4-t3-(2,6-dichloro-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydro-chloride (Compound 165) as crystals.
Analytical results of crystals of Compound 165 thus obtained:
Melting point: 200-202~C.
~0 Elemental analysis for ClgH23cl2N5O5-Hcl-4H2o:
Calculated (%): C, 44.46; H, 4.81; N, 13.64;
Cl, 20.72.
Found (%): C, 44.47; H, 4.87; N, 13.55;
Cl, 20.73.
~5 Example 107:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-[3-t4-chloro-2-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 140) available by the process of Example 85:
1 g of the pyrimidinedione derivative hydrochloride (Compound 140), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of 5 g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant -particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 108:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride ~Compound 141) available by the process of Example 86:
5 g of the pyrimidinedione derivative hydro-chloride ~Compound 141), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Bxample 109:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{4-[3-~4-methanesulfonamido-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4~lH,3H)-pyrimidinedione hydrochloride ~Compound 142) available by the process of Example 87:
20 mg of the pyrimidinedione derivative hydro-25 chloride (Compound 142) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water Z~ 389 for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 7:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 14 and obtained in the corresponding examples described above were determined. The results are summarized in Table 14.
Table 14 Result of Pharmacological Test Effects to duration Effects to refractory time of myocardinal period of ventricular action potential muscle Compound75 t ) ERP (%) ~Dose (~g/m~) Dose (mg/kg, i.v.) 1.0 3.0 10.0 0.1 0.3 1.0 3.0 140 6 17 29 0 3.55 3.55 141 27 41 - 0 2.1 2.1 15 145 7 16 23 0 6.7 6.7 20 150 - 16 - 0 0 6.3 6.3 153 20 25 - 6.1 9.1 18.3 154 9 12 20 0 0 5.9 11.8 161 26 39 - 0 6.7 6.7 6.7 164 - 8 12 0 7.7 15.4 15.4 2(~1389 Toxicity Test 7:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 15 and obtained in the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 15.-Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table 15 Results of Toxicity Test on Novel Pyrimidine Derivative Compounds Compound No. Mortality rate (%) .
~0 Example 110:
Preparation of 1,3-dimethyl-6-{2-[N-methoxy-carbonylmethyl-3-(4-nitroanilino)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 166):
-o o ~C:~3 HocH2cH2NH2 CH3 ~ 2 ~ N~C~3 cl N~o ~ ~ CH3~S03CH2cH2NH N~o c~3 CH3 > C ¢N~o CH3 ~ ~ -CH
(Compound a) N ~ 3 N02-0-F T NH2-CH2CH2CH2NH2 ~I N~2-~- NHCH2CH2CH2NH2 N~2 ~ 2 2 2NHcH2cH2NH ~ CH Cl-CH2COOCH3 HCl/MeOH
(Compound b) CH3 ~
N~2 ~ CH2coocH3 ~ 3 HCl (Compound 166) CH3 ~
(1) Preparation of 1,3-dimethyl-6-[2-(p-toluene-sulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione:
35.0 g of 2-aminoethanol were heated to 90~C
and then removed from an oil bath. 50.0 g of 6-chloro-1,3-dimethyl-2,4-(lH,3H)-pyrimidinedione were then added to react them to each other. The addition was conducted at such a rate that the reaction temperature was maintained within the range of 90-110~C. After completion of the addition, the reaction mixture was stirred for 10 minutes, followed by the addition of 300 m~ of dioxane/methanol (= 10/1, by volume). The resultant mixture was allowed to stand overnight.
2~:)1389 Crystals thus obtained were washed with a small amount of dioxane and then dried to obtain 49.0 g of 1,3-dimethyl-6-(2-hydroxyethylamino)-2,4-(lH,3H)-pyrimidinedione as white crystals.
Next, a suspension of 49.0 g of the white crystals in 200 ml of pyridine was chilled to -5~C, to which 40.0 g of p-toluenesulfonyl chloride were added at a rate slow enough to maintain the reaction temperature below 5~C. To eliminate cloudiness from the reaction mixture, 51.0 g of p-toluenesulfonyl chloride were used additionally.
The reaction mixture was poured into 1.5 1 of ice water in which 70 g of K2CO3 were contained.
The thus-obtained mixture was allowed to stand overnight. Resulting crystals were collected by filtration, washed with water, and then dried under reduced pressure, thereby obtaining 50.5 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(lH,3H)-pyrimidinedione as pale yellow crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 146.0-149.0~C.
IR vmax (cm ): 3270, 1682, 1615, 1550, 1480, 1435, 1360, 1190, 1178, 1010, 903, 780.
(2) Preparation of 6-(1-aziridinyl)-1,3-dimethyl-ZC~01389 _ 326 -2,4(lH,3H)-pyrimidinedione (Compound a):
To a solution of 47.2 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(lH,3H)-pyrimidinedione, which had been obtained in the above procedure, in 150 mQ of anhydrous dimethylsulfoxide, 6.24 g of 60% oil-base sodium hydride were gradually added at room temperature. The resultant mixture was vigorously stirred at room temperature for 5 hours and then cooled. A small amount of water was added to terminate the reaction. The thus-obtained mixture was poured into 1 ~ of water which contained 70 g of potassium carbonate. The resultant mixture was extracted 3 times with 200 m~ portions of chloroform.
The extracts were combined into an organic layer. The lS organic layer was dried over anhydrous sodium sulfate and then concentrated. The concentrate thus prepared was added with 300 m~ of ether and the resulting solution was allowed to stand overnight.
Pale yellow crystals which had precipitated by while the solution was allowed to stand overnight were collected by filtration, washed with ether and then dried under reduced pressure, whereby 15.2 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione (Compound a) were obtained.
Analytical results of crystals of Compound a thus obtained:
- 327 - a o Q 1 3 8 9 Melting point: 126.0-126.5~C.
I~ vmBax (cm 1): 1705, 1650, 1612, 1470, 1440, 1305, 1160, 783, 490.
lH-NMR (CDC13), ~ ppm: 2.34(s,4H), 3.35(s,3H), 3.56(s,3H), 5.25(s,1H).
(3) Preparation of 1,3-dimethyl-6-{2-[3-(4-nitro-anilino)propylamino]ethylamino}-2,4(lH,3H)-pyrimidine-dione (Compound b):
2.8 g of 4-nitrofluorobenzene were heated to 80~C in 29.6 g of propylenediamine and then stirred for 1 hour at the same temperature. The reaction mixture was poured into water and precipitated crystals were collected by filtration, thereby obtaining 3.6 g of N-(4-nitrophenyl)propylenediamine as crystals.
After dissolving 1.2 g of N-(4-nitrophenyl)-propylenediamine and 1.1 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione (Compound a), which were obtained in the above procedure (2), in 5 ml of chloroform, the resultant mixture was concentrated under reduced pressure. The residue was added with 10 mg of "Amberlist 15" (trade mark; product of Rohm & Hass Co.) and stirred at 80~C for 1 hour.
The thus-obtained mixture was dissolved in 20 ml of chloroform and "Amberlist 15" was filtered off. The filtrate was washed with water and dried over anhydrous sodium salfate. The solvent was then distilled off -under reduced pressure to obtain 1,3-dimethyl-6-{2-[3-(4-nitroanilino)propylamino~ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound b) in a crude form. Although the reaction product obtained by the above procedure contained impurities, it was provided for the next reaction without purification.
(4) Synthesis of 1,3-dimethyl-6-{2-~N-methoxycarbonyl-methyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 166):
1.5 g of 1,3-dimethyl-6-{2-[3-(4-nitroanilino)-propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound b) obtained in the above procedure (3) were dissolved in 12 m~ of DMSO, followed by the addition of 1.2 g of methyl chloroacetate and 1.5 m~ of triethylamine. The resultant mixture was stirred at 50~C for 2 hours, dissolved in chloroform, washed with water and then dried over anhydrous sodium sulfate.
The solvent was thereafter distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol =
30/1, by volume), thereby obtaining 1.8 g of 1,3-dimethyl-6-{2-[N-methoxycarbonylmethyl-3-(4-nitro-anilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
- 2~0138~
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (DMSO-d6), ~ ppm: 1.70(m,2H), 2.6-2.9(m,4H), 2.95-3.4(m,4H), 3.25(s,3H), 3.3(s,3H), 3.45(s,2H), 3.65(s,3H), 4.6(s,1H), 6.45(m,1H), 6.6(d,2H), 7.2(m,1H), 7.95(d,2H).
Further, 1.5 g of the pyrimidinedione derivative were treated in an HCl/methanol solution by a method known ~ se in the art to obtain 1.4 g of 1,3-dimethyl-6-{2-[N-methoxycarbonylmethyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 166) as amorphous powder.
Elemental analysis for C20H28N6O6-HCl-H2O:
Calculated (%): C, 47.76; H, 6.21; N, 16.71;
Cl, 7.05.
Found (%): C, 47.06; H, 5.91; N, 16.05;
Cl, 7.58.
Example 111:
Preparation of 1,3-dimethyl-6-{2-[N-(2-acetoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 167~:
;~0~3~9 N02 ~ CH2CH2C~~H > ' N02 ~ cH2CH2coNHcH2CH20H
> N02 ~ CH2CH2CH2NHCH2CH20H
O O
~C%3 NH2CH2~H2~H CH35~2Cl ~N~CH3 K2C03 cl I ~o > CH3502-ocH2cH2NH N~o >
CH3 (Compound c) c~3 No2~CH2CH2cH2NHcH2cH20 CH2CH20H ,~11~
No2~cH2cH2cH2N-cH2cH2 N~o (Compound dJ C~3 o (CH3CO)20 (COOH)2/MeOH ¦ ~ N,CH3 > ~ N02~CH2CH2CH2NCH2cH2NH N~o ~ ( COOH)2 (Compound 167) CH3 (1) Preparation of N-(2-hydroxyethyl)-3-(4-nitro-phenyl)propionamide:
60 g of 3-(4-nitrophenyl)propionic acid were suspended in 360 m~ of chloroform, followed by the addition of 2.25 g of dimethylformamide. The thus-prepared reaction mixture was heated at 50-60~C, to which 33.5 m~ of thionyl chloride were gradually added dropwise. After the dropwise addition, the resultant mixture was heated under reflux for 1 hour, the solvent was distilled off under reduced pressure, and the resultant oily substance was dissolved in 150 m~ of chloroform. The chloroform solution was added dropwise Z~)0~38~3 under ice cooling into a solution which had been formed by dissolving 28.2 g of ethanolamine and 42.5 g of potassium carbonate in 450 m~ of water. After completion of the dropwise addition, the resultant mixture was stirred for 1 hour. Precipitated crystals were collected by filtration and then recrystallized from 1 ~ of ethyl acetate, thereby obtaining 56.1 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propionamide as - crystals.
Melting point: 122-125~C.
(2) Preparation of N-(2-hydroxyethyl)-3-(4-nitro-phenyl)propylamine:
50 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propionamide obtained in the above procedure and 31.8 g of sodium borohydride were suspended in 500 m~ of tetrahydrofuran, followed by the dropwise addition of 50.5 g of acetic acid under ice-cooling. After completion of the dropwise addition, the resultant mixture was heated under reflux for 2 hours. It was again ice-cooled, followed by the dropwise addition of 500 m~ of water. 4 N hydrochloric acid was added to adjust the pH to 5-6 and tetrahydrofuran was distilled off under reduced pressure. The resultant aqueous solution was added with 425 m~ of 4 N hydrochloric acid and the mixture thus prepared was heated at 60-70~C for 1 hour under stirring. The reaction ~ 9 mixture was allowed to cool down to room temperature and washed with chloroform. The resultant aqueous solution was adjusted to pH 11 with a 16% aqueous solution of sodium hydroxide and then extracted twice with 500 mQ portions of chloroform. The chloroform extracts were combined together and then concentrated under reduced pressure. The residue was crystallized from 900 mQ of toluene, thereby obtaining 38.6 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine as crystals.
Melting point: 82.5-84.5~C.
(3) Preparation of 1,3-dimethyl-6-(2-methanesulfonyl-oxyethylamino)-2,4(1H,3H)-pyrimidinedione (Compound c):
52.4 g of 6-chloro-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione were dissolved in 280 mQ of pyridine, followed by the addition of 45.5 g of triethylamine and 21.3 g of aminoethanol. The thus-prepared mixture was heated under reflux at 90~C for 4 hours. The reaction mixture was ice-cooled and while maintaining the internal temperature at 0-4~C, 55.8 g of methane-sulfonyl chloride were added dropwise. The resultant mixture was stirred for 3 hours at the same tempera-ture. 1.2 Q of methanol were added, followed by stirring for additional 2 hours. Crytals precipitated in the reaction mixture were collected by filtration and then recrystallized from 3.5 ~ of methanol, thereby obtaining 70.0 g of 1,3-dimethyl-6-(2-methane-sulfonyloxyethylamino)-2,4(lH,3H)-pyrimidinedione (Compound c) as crystals.
Melting point: 169-170~C.
(4) Preparation of 1,3-dimethyl-6-{2-tN-(2-hydroxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound d):
20.2 g of 1,3-dimethyl-6-(2-methanesulfonyloxy-ethylamino)-2,4(1H,3H)-pyrimidinedione (Compound c), which had been synthesized in the above procedure (3), and 15.1 g of potassium carbonate were suspended in 300 m~ of acetonitrile. The resultant mixture was heated under reflux for 4 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure to the total volume of about 60 m~, followed by the addition of 18 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine obtained in the above procedure (2), 36 m~ of DMF and 0.69 g of p-toluenesulfonic acid monohydrate. Under reduced pressure, acetonitrile was distilled off. The residue was heated under stirring at 80~C for 2 hours. The reaction mixture was cooled to room temperature, to which 900 m~ of 0.1 N hydrochloric acid were added to dissolve insoluble matters. Thereafter, a 0.5 M
aqueous solution of potassium carbonate was added to ~1389 render the mixture alkaline. The thus-prepared mixture was stirred at room temperature for 3 hours.
Precipitated crystals were collected by filtration, dried and then recrystallized from ethanol, thereby obtaining 26.6 g of 1,3-dimethyl-6-{2-[N-(2-hydroxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound d) as crystals.
Melting point: 125-126~C.
(5) Preparation of 1,3-dimethyl-6-{2-[N-(2-acetoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 167):
1.6 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound d) and 0.8 g of acetic anhydride were dissolved in 5 m~ of pyridine. The resultant mixture was stirred at room temperature for 24 hours and then at 60~C for 1 hour. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and then concentrated. The residue was purified by chromato-graphy on a silica gel column (eluent: chloroform/
methanol = 25/1-10/1, by volume), thereby obtaining 1.65 g of 1,3-dimethyl-6-{2-[N-(2-acetoxyethyl~-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 90.5-92.0~C.
NMR (CDC13), ~ ppm: 1.85 (m,2H), 2.15(s,3H), 2.5-3.3(m,10H), 3.26(s,3H), 3.37(s,3H), 4.3(t,2H), 4.78(s,1H), 7.2-8.2(m,4H).
- Further, 1.5 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 1.6 g of 1,3-dimethyl-6-{2-tN-(2-acetoxyethyl)-3-(4-nitrophenyl)-propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 167) as crystals.
Analytical results of crytals of Compound 167 thus obtained:
Y 21 29N5~6 (COOH)2 H2O
Calculated (%): C, 49.73; H, 5.99; N, 12.61.
Found (%): C, 50.22; H, 5.75; N, 12.98.
Example 112:
Preparation of 1,3-dimethyl-6-{2-[N-(2-benzoyl-oxyethyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 168):
2~1389 CH2c~20~ ~( ~ CO)2o HCl/MeOH
No2~cH2cH2cH2N-cH2cH2 N~o >
(Compound d) CH3 C~12CH20C~
o N~2 ~ CH2CH2CH2NCH2cH2NH ~N ~ .(COOH)2 (Compound 168) c~3 In a similar manner to Example 111-(5) except for the use of 1.6 g of benzoic anhydride in place of acetic anhydride, 1.85 g of 1,3-dimethyl-6-{2-[N-(2-benzoyloxyethyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(1H,3H)-pyrimidinedione were obtained.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.93 (m,2H), 2.5-3.4(m,10H), 3.29(s,3H), 3.38(s,3H), 4.45(t,2H), 4.77(s,1H), 7.0-8.2(m,9H).
Further, 1.5 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 1.4 g of 1,3-dimethyl-6-{2-[N-(2-benzoyloxyethyl)-3-(4-nitro phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 168) as crystals.
Analytical results of crytals of Compound 168 thus obtained:
ement na ysis for C26 31N5~6 (C ~ )2 2 Calculated (%): C, 54.45; H, 5.71; N, 11.34.
Found (%): C, 54.90; H, 5.55; N, 11.55.
Example 113:
Preparation of 1,3-dimethyl-6-{2-<N-[2-(4-fluorobenzoyloxy)ethyl]-3-(4-nitrophenyl)propyl-amino>ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 169):
I NH ~ N_CH
N02~CH2CH2cH2NcH2cH2 N~o CH2cH2oc ~ F
(COOH)2/MeOH ~ N_CH3 N02~CH2CH2CH2N-cH2cH2 I~N~O ~ ( COOH)2 (Compound 169) CH3 1.0 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound d), which had been obtained in Example 111-(4), and 0.8 g of p-fluorobenzoyl chloride were dissolved in 5 ml of pyridine. The resultant mixture was stirred at room temperature for 12 hours, poured into water, and then extracted with Z~1389 chloroform. The extract was washed with water and then concentrated. The residue was purified by chromato-graphy on a silica gel column (eluent: chloroform/
methanol = 40/1, by volume), thereby obtaining 1.0 g of S 1,3-dimethyl-6-{2-<N-[2-(4-fluorobenzoyloxy)ethyl]-3-(4-nitrophenyl)propylamino>ethylamino}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.9-3.1(m,12H), 3.29(s,1H), 3.38(s,3H), 4.59(t,2H), 4.78(s,1H), 7.1-8.0(m,8H).
Further, 0.95 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 1.07 g of 1,3-dimethyl-6-{2-<N-[2-(4-fluorobenzoyloxy)ethyl]-3-(4-nitrophenyl)propylamino>ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 169) as crystals.
Analytical results of crytals of Compound 169 thus obtained:
Melting point: 96-99~C (decomposed).
Y 26 30 5~6 (COO )2 2H2o Calculated (%): C, 51.45; H, 5.55; N, 10.71.
Found (%): C, 51.82; H, 5.40; N, 10.82.
IR vmax (cm 1): 3350, 2950, 1740, 1700, 1620, 1530, 1330, 1000, 850, 760.
200~389 Example 114:
Preparation of 1,3-dimethyl-6-{2-<N-[2-(4-methoxybenzoyloxy)ethyl]-3-(4-nitrophenyl)-propylamino>ethylamino}-2,4(lH,3H)-pyrimidine-dione oxalate (Compound 170):
CH2CH2OH l~U~ CH3O~COCl No2~cH2cH2cH2NcH2cH2 N~o CH2CH20C ~ oCH3 ( COOH ) 2 /MeOH ¢I~N~CH 3 N02~CH2CH2CH2NcH2cH2NH N~o ~ ~ COOH ) 2 ( C~ ~und 170 ) C~3 In a similar manner to Example 113 except for the use of 0.63 g of p-methoxybenzoyl chloride instead of p-fluorobenzoyl chloride, 1.1 g of 1,3-dimethyl-6-{2-<N-[2-(4-methoxybenzoyloxy)ethyl]-3-(4-nitrophenyl)-propylamino>ethylamino}-2,4(lH,3H)-pyrimidinedione were obtained.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.4-3.0(m,10H), 3.31(s,3H), 3.42(s,3H), 3.50(s,3H), 4.4(t,2H), 4.77(s,1H), 5.31(br,1H), 2~01389 7.18(m,4H~, 8.0(m,4H).
Further, 1.0 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 1.05 g of 1,3-dimethyl-6-{2-<N-[2-(4-methoxybenzoyloxy)ethyl]-3-(4-nitrophenyl)propylamino>ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate ~Compound 170) as crystals.
Analytical results of crytals of Compound 170 thus obtained:
Elemental analysis for C27H33N5O7-(COOH)2-~H2O:
Calculated (%): C, 54.54; H, 5.68; N, 10.97.
Found (%): C, 54.21; H, 5.99; N, 10.92.
IR vmBx (cm 1): 3300, 2950, 1690, 1600, 1520, 1350, 1250, 1020, 850, 760.
Example 115:
Preparation of 1,3-dimethyl-6-{2-[N-(2-methoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 171):
O
¢)~N--CH3 3 2 2 2 CH3 ( Compound a ) No2~cH2cH2cH2oso2~ 3 >
( COOH ) 2/MeCH fH2CH2~CH~
~, NO 2 ~ CH 2 CH 2 CH 2 NCH 2 C 2 N~o ~ ( COOH ) 2 ( Compound 171 ) CH3 200~389 A mixture consisting of 1 g of 3-(4-nitro-phenyl)propyl p-toluenesulfonate, 6.5 ml of 2-methoxy-ethylamine and 5 m~ of dioxane was heated under reflux for 3 hours, followed by the addition of 100 m~ of chloroform. The resultant mixture was washed with water and then dried over anhydrous sodium sulfate.
The thus-prepared chloroform solution was added with 10 mg of p-toluenesulfonic acid and 0.54 g of 6-(1-- aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (Compound a) obtained in Example 110-~2), followed by the distillation of the solvent under reduced pressure.
The mixture was then heated at 80~C for 2 hours and then cooled down to the room temperature. The thus-obtained mixture was directly subjected to chromato-graphic purification on a silica gel column (eluent:chloroform/methanol = 40/1, by volume), thereby obtaining 0.82 g of 1,3-dimethyl-6-{2-[N-(2-methoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione thus obtained:
NMR (CDC13), ~ ppm: l.9(m,2H), 2.4-3.6(m,12H), 3.23(s,3H), 3.30(s,3H), 3.33(s,3H), 4.71(s,1H), 5.74(br,1H), 7.19(d,2H), 8.03(d,2H).
Further, 0.80 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.85 g of 1,3-dimethyl-6-{2-[N-(2-methoxyethyl)-3-(4-nitrophenyl)-propylamino~ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 171) as crystals.
Analytical results of crytals of Compound 171 thus obtained:
Elemental analysis for C20H29N5O5-(COOH)2-H2O:
Calculated (~): C, 50.09; H, 6.31; N, 13.28.
Found (%): C, 50.14; H, 6.39; N, 13.30.
IR vmax (cm 1): 3300, 3000, 1680, 1630, 1510, 1430, 1350, 1200, 770, 700.
Example 116:
Preparation of 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 172):
2 0 ~ 2 2 ¢U'N~CH3 No2~CHzCH2CH20502~CH3 > >
O
( COOH ) 2 /MeOH ICH2 ~N~CH 3 > N02~CH2CH2cH2N-cH2cH2 ~N~o ~(COOH)2 ( Compound 172 ) CH3 In a similar manner to Example 115 except for the use of 0.36 m~ of benzylamine instead of 2-methoxyethylamine and the addition of 1 ml of tri-ethylamine, 1.6 g of 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione were obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.4-3.3(m,8H), 3.21(s,3H), 3.25(s,3H), 3.58(s,2H), 4.67(s,1H), 5.22(br,1H), 7.22(d,2H), 7.30(s,5H), 8.03(d,2H).
Further, 1.50 g of the pyrimidinedione deriva-tive were treated in an oxalic acid/methanol solutionby a method known E~ se in the art to obtain 1.55 g of 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 172) as crystals.
Analytical results of crytals of Compound 172 thus obtained:
Y 24 29 5 4 (C ~ )2 ~ 2~
Calculated t%): C, 56.72; H, 5.86; N, 12.72.
Found (%): C, 56.41; H, 5.82; N, 12.24.
IR vmax (cm 1): 3300, 2950, 1680, 1630, 1540, 1340, 1200, 770, 700.
- 344 - ~ 3 8 9 Example 117:
Preparation of 1,3-dimethyl-6-{2-[N-(t-butoxy-carbonyl)-3-(4-nitrophenyl)propylamino~ethyl-amino}-2,4(1H,3H)-pyrimidinedione (Compound 173):
~ NH4OH/H O N~ElH
N02~3CH2CH2CC1 2 ~ N02~CH2CH2CH2NH2 C ~N
l O O
C~3 ~(CH3)3Coc0120 1 ~Y3 ~N~ 3 ~,~ NC2~CH2CH2C~2N-cH2cH2NH I~N~O
(C~ 173)CS~3 (1) Preparation of 3-(4-nitrophenyl)propylamine:
A solution of 21 g of 3-~4-nitrophenyl)propionyl chloride in 30 ml of chloroform was added dropwise into a mixture of 75 ml of concentrated aqueous ammonia and 75 ml of ice water. The resultant mixture was then stirred for 2 hours under ice-cooling. The resultant precipitate was collected by filtration, dried in air and recrystallized from ethyl acetate, thereby obtaining 13.7 g of 3-(4-nitrophenyl)propan-amide.
10.0 g of the amide compound and 9.S g of sodium borohydride were suspended in 250 ml of dioxane, followed by the dropwise addition of 15 ml of acetic acid. The resultant mixture was stirred for 10 hours under reflux. The reaction mixture was added with B
~r, .
10 mQ of methanol and then concentrated to dryness.
The residue was dissolved in chloroform. The solution thus obtained was washed with water and then concentrated to dryness, thereby obtaining 6.0 g of 3-(4-nitrophenyl)propylamine as an oily substance.
This compound was provided for the next reaction without any further purification.
NMR (CDC13), ~ ppm: l.9(m,2H), 2.4-3.0(m,4H), - 6.70(br,2H), 8.31(d,2H), 8.10(d,2H).
(2) Preparation of 1,3-dimethyl-6-{2-[N-(t-butoxy-carbonyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound 173):
6.0 g of 3-(4-nitrophenyl)propylamine obtained in the above procedure (1) and 3.98 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (Compound a) obtained in Example 110-(2) were dissolved in 50 ml of chloroform, and the resultant mixture was concentrated to dryness under reduced pressure. The residue was added with 50 mg of p-toluenesulfonic acid monohydrate and the mixture thus prepared was stirred at 90~C for 2 hours. The mixture was dissolved in 60 ml of tetrahydrofuran, followed by the addition of 3.0 g of di-tert-butyldicarbonate. The thus-obtained mixture was stirred at room temperature ~or 1 hour and then concentrated. The residue was 26:~1389 purified by chromatography on a silica gel column (eluent: chloroform/methanol = 40/1, by volume), thereby obtaining 5.0 g of 1,3-dimethyl-6-{2-[N-(t-butoxycarbonyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(lH,3H)-pyrimidinedione (Compound 173) as crystals.
A~alytical results of Compound 173 thus obtained:
Melting point: 111-112~C.
NMR (CDC13), ~ ppm: 1.51(s,9H), l.9(m,2H), 2.5-3.0(m,6H), 3.3-3.4(m,2H), 3.28(s,3H), 3.36(s,3H), 4.68(s,1H), 6.54(br,1H), 7.39(d,2H), 8.20(d,2H).
Elemental analysis for C22H31N5O6:
Calculated (%): C, 57.25; H, 6.77; N, 15.17.
Found (%): C, 57.29; H, 6.76; N, 15.13.
Example 118:
Preparation of 1,3-dimethyl-6-{2-[N-(4-methoxy-benzyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 174):
COOC~ CH3 ) 3 ~
N02~ 2CH2CH2N-CH2CH2NH-~,~ 3 HCl/O/--\O
( Compound 173 ) - 2~1~1389- - 347 -Z~CH2cH2cH2NH-cH2cH2NH~
(Compound e)~HCl ~H3 O
1 ~ CH2Br (COOH)2/MeOH NO2 ~ CH2CH2CH2N-CH2cH2NH ~ ~ ~(COOH) (Compound 174) CH3 (1) Preparation of 1,3-dimethyl-6-{2-[3-(4-nitro-phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione hydrochloride (Compound e):
30 m~ of 0.-5 N HCl/dioxane were added to 4.9 g of 1,3-dimethyl-6-{2-[N-(t-butoxycarbonyl~-3-(4-nitro-phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione (Compound 173). The resultant mixture was stirred at room temperature for 24 hours. Precipitated crystals were collected by filtration and then washed with a chilled solvent consisting of a 1:2 mixture (by volume) of ethanol and ether, thereby obtaining 3.9 g of 1,3-dimethyl-6-{2-[3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e).
Analytical results of crystals of Compound e thus obtained:
Melting point: 230-231~C (decomposed).
Elemental analysis for C17H23N5O4-2HCl-H2O:
Calculated (%): C, 45.14; H, 6.02; N, 15.48;
26~389 Cl, 15.68.
Found (%): C, 45.31; H, 5.87; N, 15.54;
Cl, 15.67.
(2) Preparation of 1,3-dimethyl-6-{2-[N-(4-methoxy-benzyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 174):
1.4 g of 1,3-dimethyl-6-{2-[3-~4-nitrophenyl)-propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e) were dissolved in 5 m~ of water, followed by the addition of potassium carbonate to render the solution alkaline. The solution was then extracted with chloroform. The thus-obtained chloro-form solution was concentrated to dryness, followed by the addition of 0.6 g of p-methoxybenzyl bromide, 3 m~
of triethylamine and 20 m~ of isopropanol. The resultant mixture was heated for 8 hours under reflux.
The solvent was distilled off under reduced pressure and the residue was directly subjected to chromato-graphic purification on a silica gel (eluent: chloro-form/methanol = 40/1, by volume), thereby obtaining0.55 g of 1,3-dimethyl-6-{2-[N-(4-methoxybenzyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.5-3.1(m,8H), 3.24(s,3H), 3.30(s,3H), 3.64(s,2H), 4.59(s,1H), 5.16(m,1H), 7.16(m,4H), 7.94(m,4H).
Further, 0.52 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.54 g of 1,3-dimethyl-6-{2-[N-(4-methoxybenzyl)-3-(4-nitro-phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 174) as crystals.
Analytical results of crytals of Compound 174 thus obtained:
Melting point: 104-106~C (decomposed).
IR vmax (cm 1): 3300, 2950, 1710, 1700, 1630, 1520, 1340, 1250, 1070, 770, 700.
Y 25 31 5 5 ( )2 2 Calculated (%): C, 54.18; H, 6.06; N, 11.70.
Found (%): C, 54.74; H, 5.97; N, 11.37.
Example 119:
Preparation of 1,3-dimethyl-6-{2-tN-ethoxy-carbonylmethyl-3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 175):
N02 ~ CH2CH2CH2NHCH2cH2NH ~N
(Compound e) HCl C 3 Br-CH COOC H (COOH) /MeOH CH2cooc2H5 ~
2 2 5 2 > NO2 ~ C~2cH2cH2NcH2cH2NH ~N~ ~ (COOHJ
(Compound 175) 1~3~ 2 In a similar manner to Example 118-(2) except for the use of 0.4 m~ of ethyl bromoacetate in place of p-methoxybenzyl bromide, 0.77 g of 1,3-dimethyl-6-~2-[N-(2-ethoxycarbonylmethyl-3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.30(t,3H), l.9(m,2H), 2.4-3.0(m,6H), 3.0-3.4(m,4H), 3.3(s,3H), 3.5(s,3H), 4.22(q,2H), 4.74(s,1H), 7.31(d,2H), 8.12(d,2H).
Further, 0.7 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.72 g of 1,3-dimethyl-6-{2-[N-ethoxycarbonylmethyl-3-(4-nitro-phenyl)propylamino]ethylamino~-2,4(lH,3H)-pyrimidine-26~389 dione oxalate (Compound 175) as crystals.
Analytical results of crytals of Compound 175 thus obtained:
Melting point: 148-149~C (decomposed).
IR Vmax (cm ): 2930, 2450, 1730, 1700, 1600, 1540, 1340, 1250, 1200, 850, 750.
Element ana ys s r 21 29N5O6 ( )2 ~ 2 Calculated (%): C, 50.55; H, 5.90; N, 12.81.
- Found (%): C, 50.89; H, 5.81; N, 12.62.
Example 120:
Preparation of 1,3-dimethyl-6-{N-(2-phenyl-ethyl)-2-[3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 176):
o Cl ~¢DN~o CH 2CH2-~
NH2CH2 2 CH3 HocH2cH2N~
~>-cH2cH2-Br ~ 3 O
(COc1)2-DMso 02N~CH2CH2CH2NH2 HCl/MeOH
? ~ >
o 02N~CH2CH2CH2NHcH2cH2N -~N~ ~ HCl (Compound 176) CH3 (1) Preparation of 1,3-dimethyl-6-[N-(2-hydroxyethyl)-2-phenylethylamino]-2,4(1H,3H)-pyrimidinedione:
A mixture consisting of 3 mO of phenethyl bromide, 13 m~ of ethanolamine and 15 m~ of isopropanol was heated for 2 hours under reflux. After allowing the reaction mixture to cool down, 50 mQ of chloroform were added. The thus-prepared mixture was washed with water and then concentrated to obtain an oily substance. To the oily substance, 3.5 g of 6-chloro-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione and 3.3 m~ of triethylamine were added. The resultant mixture was dissolved in 15 m~ of dimethylformamide and stirred at 110~C for 4 hours. The solution was cooled down to room temperature, followed by the addition of 150 mQ of chloroform. The resultant chloroform solution was washed with water and then concentrated to obtain an oily substance. By crystallizing the oily substance from ether, 4.1 g of 1,3-dimethyl-6-[N-(2-hydroxyethyl)-2-phenyl-ethylamino]-2,4(lH,3H)-pyrimidinedione were obtained as crystals.
~nalytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 77-78~C.
NMR (CDC13), ~ ppm: 2.4-3.2(m,6H), 3.18(s,3H), 3.22(s,3H), 3.50(t,2H), 5.28(s,1H), 7.18(br,5H).
Elemental analysis for C16H21N3O3:
Calculated (%): C, 63.35; H, 6.98; N, 13.85.
Found (%): C, 63.01; H, 6.78; N, 13.91.
(2) Preparation of 1,3-dimethyl-6-{N-(2-phenylethyl)-2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 176):
0.26 m~ of oxalyl chloride was dissolved in 5 m~ of dichloromethane. The resultant mixture was - chilled to -78~C, followed by the dropwise addition of a solution of 0.21 m~ of dimethylsulfoxide in 5 m~ of dichloromethane. The thus-prepared mixture was stirred for 15 minutes at the same temperature, followed by the dropwise addition of a solution of 0.6 g of 1,3-dimethyl-6-[N-(2-hydroxyethyl)-2-phenylethylamino]-2,4(1H,3H)-pyrimidinedione in 10 m~ of dichloro-methane. The mixture was stirred for further 15 minutes. After adding 0.84 ml of triethylamine, the mixture was gradually cooled to room temperature and then stirred for 5 minutes. 30 m~ of chloroform were added. The mixture thus obtained was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.51 g of an oily substance.
The oily substance was dissolved in 10 m~ of methanol, followed by the addition of 0.72 g of 3-(4-nitrophenyl)propylamine obtained in Example 117-(1) and 0.5 mQ of 4 N-HCl/dioxane. The resulting mixture was stirred at room temperature for 30 minutes and 1 g of sodium cyanoborohydride was added in several small portions. After stirring the mixture at room temperature for 12 hours, 1 N hydrochloric acid was added to acidify the reaction mixture. Methanol was distilled off and potassium carbonate was added to neutralize the residue. The thus-prepared solution was extracted with chloroform and the chloroform layer was concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume), thereby obtaining 0.2 g of 1,3-dimethyl-6-{N-(2-phenylethyl)-2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: l.9(m,2H), 2.6-3.6(m,12H), 3.18(s,3H), 3.26(s,3H), 5.28(s,1H), 7.18(br,5H), 7.30(d,2H), 8.09(d,2H).
Further, 0.19 g of the pyrimidinedione deriva-tive was treated in a 1 N-HCl/methanol solution by a method known ~ se in the art to obtain 0.12 g of 1,3-dimethyl-6-{N-(2-phenylethyl)-2-[3-(4-nitrophenyl)-26~C)1389 propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 176) as crystals.
Analytical results of crystals of Compound 176 thus obtained:
Elemental analysis for C25H31N5O4-HC1-3H2O:
Calculated (%): C, 54.00; H, 6.89; N, 12.59;
Cl, 6.38.
Found (%): C, 53.81; H, 6.74; N, 12.11;
- Cl, 5.91.
10IR vKBr (cm~l) 3420, 2610, 1700, 1650, 1620, 1550, max 1320, 1010, 820, 780, 750.
Example 121:
Preparation of 1,3-dimethyl-6-{2-tN-allyl-3-(4-nitrophenyl)propylamino]ethylamino}-15 2,4(lH,3H)-pyrimidinedione oxalate (Compound 177):
~ N_CH3 ~\" Br (COOH)2/MeOH
N02~CH2CH2cH2NHcH2cH2NHJ~N~o (Compound e) HCl CH3 N02~ CH2-CH-CH2~
~Compound 177) CH3 In a similar manner to Example 118-(2) except Eor the use of 0.38 m2 of allyl bromide in place of p-methoxybenzyl bromide, 0.9 g of 1,3-dimethyl-6-{2-2~1389 [N-allyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione was obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 109-111~C.
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.5-3.1(m,10H), 3.26(s,3H), 3.34(s,3H), 4.75(s,1H), 5.16(m,2H), 5.63(m,1H), 7.25(d,2H), 8.04(d,2H).
Further, 0.80 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.75 g of 1,3-dimethyl-6-{2-[N-allyl-3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 177) as crystals.
Analytical results of crytals of Compound 177 thus obtained:
Melting point: 85-90~C.
Elemental analysis for C20H27N5O4-(COOH)2-l~H2O:
Calculated (%): C, 50.96; H, 6.22; N, 13.51.
Found (%): C, 51.30; H, 6.26; N, 13.24.
IR vmax (cm 1): 3250, 2940, 1690, 1620, 1540, 1340, 1160, 990, 850, 770, 700.
Example 122:
Preparation of 1,3-dimethyl-6-{2-[N-propargyl-3-~ 357 ~ 2~Q~38g (4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 178):
~ N_cH3 ~r-CH2-C~CH (COOH)2/MeOH
N02~C~2CH2c~2NHcH2c~2NH N~o (C. ,-~nd e) CH3 ~HCl C~12-C-CH ~
N02 ~ CH2cH2cH2NcH2cH2NH ~ ~COOH~
(C~ , ~ 178~ CN3 In a similar manner to Example 118-(2) except for the use of 0.37 ml of propargyl bromide in place of p-methoxybenzyl bromide, 0.85 g of 1,3-dimethyl-6-{2-tN-propargyl-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(1H,3H)-pyrimidinedione was obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 156-157~C.
NMR (CDC13), ~ ppm: l.9(m,2H), 2.23(m,1H), 2.4-3.1(m,10H), 3.25(s,3H), 3.34(s,3H), 4.73(s,1H), 5.22(br,1H), 7.27(d,2H), 8.04(d,2H).
Further, 0.80 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by ~=
2~ 389 a method known per se in the art to obtain 0.75 g of 1,3-dimethyl-6-{2-[N-propargyl-3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 178) as crystals.
Analytical results of crytals of Compound 178 thus obtained:
Melting point: 170-172~C.
Element n y 20 25 5 4 ( 2 ~ 2 Calculated (%): C, 53.01; H, 5.66; N, 14.05.
Found (%): C, 53.31; H, 5.63; N, 14.18.
IR vmax (cm 1): 3250, 2600, 1640, 1620, 1530, 1340, 770, 700.
Example 123:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{2-[N-(2-acetoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 167) available by the process of Example 111:
1 g of the pyrimidinedione derivative oxalate (Compound 167), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of 5 g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The 2~1389 thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 124:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 172) available by the process of Example 116:
5 g of the pyrimidinedione derivative oxalate (Compound 172), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 125:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{2-[N-ethoxycarbonylmethyl-3-(4-nitrophenyl)propyl-amino]ethyl-2,4~1H,3H)-pyrimidinedione oxalate (Compound 175) available by the process of Example 119:
20 mg of the pyrimidinedione derivative oxalate (Compound 175) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water for injection to give a total volume of 100 mQ, thereby preparing a formulation suitable for injection.
Z~01389 Pharmacological Test 8:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 16 and obtained in the corresponding examples described above were determined. The results are summarized in Table 16.
Table 16 Results of Pharmacological Test 75 ( ) ERP (%) CompoundDose (~g/m~)Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.0 3.0 166 8 18 - 6.7 6.7 6.7 6.7 Toxicity Test 8:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 17 and obtained in the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 17.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
2~)01389 Table 17 Compound No.Mortality rate (%) 165 ~
166 ~
167 ~
23~1389 Example 126 Preparation of 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl) propylaminoJethylamino}-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedlone hydrochloride Cl N ~ HOCHzCHzNH N ~
CH CH3 CH3 1l 'CH3 CH3SO2-OCHzCHzN N ~
> ~
CH3 o CH3 NOz ~ CH2CH2CH2NHCH2CH20H HCI/CH30H
> >
NOz ~ CH2CH2CHzNCH2CH2NH ~ NCH3 HCl CH3 0 (Compound 179) (1) Preparation of 6-~2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1~,3H)-pyrimidinedione 6-chloro-1,3,5-trimethyl-2,4(1H,3H~-pyrimidinedione (3.4g) was suspended in 30 ml of isopropanol, and the suspension was added with 1.26 ml of ethanolamine and 3.8 ml of triethylamine and then the resultant mixture was refluxed fvr 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and thereafter crystals formed were collected by filtration, washed with water and then recryst~llized l}sing a water-ethanol solution (1:1, vJv~, thereby 2.9g of 5-(2-hydroxyethylamino)~ ,5-trimethyl-2,4(1H,3H)-pyrimidinedione being obtained.
Results of analysis of the pyrimidinedione derivative thus obtained:
Melting point: ]59-160~C
N'MR (CDCI3), ~ ppm: 4.71 (t,2H), 3.55 (m, 2H), 3.21 (s, 3H), 3.39 (s, 3H), 1 93 (s, 3H) Elemental analysis: CgH15N303 Calculated (X): C, 50.69; H, 7.09: N, 19.71 10- Analyzed (x): C, 50.89; H, 7.11: H, 19.90 (2) Preparation of 6-(2-methanesulfonyloxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione 6-(2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (2.9g) was dissolved in 20 ml of pyridine and added with 1.20 ml of methanesulfonyl chloride drop by drop at 0~C. After the reaction at 0~C for 4 hours, the reaction mixture was poured into lO ml of ice water and then subjected to chloroform extraction. The extract was washed with water, dried over sodium sulfate anhydrous, concentrated ln vacuo. The resultant oily substance was subjected to silica gel column chromatograph (chloroform/methanol = 30:1, v/v) for purification. Thus, 3.0 g of 6-(2-methanesulfonyloxyethylamino~-1,3,5-trimethyl-2,4~1H,3H)-pyrimidinedione was obtained.
Results of analysis of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 5.02 (t,2H), 3.~ (m, 2H), 3.30 (s, 3H), 3.41 (s, 3H), 2.14 (s, 3H), 1.99(s, 3H) Elemental analYSiS C10~17N3~5S
Calculated ~): C, 41.23; H, 5.88: N, 14.42;S, 11.01 Analy7.ed (x~: C, 40.97; H, 5.91: N, 14.65; S, 11.07 (3) Preparation of 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-1,3,5-trimethyl-2,4~1H,3H)-pyrimidinedione hydrochloride ~compound 179) 6-(2-methanesulfonyloxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (3.0 g)-was dissolved in 3~ ml of acetonitrile, added with 2.1 g potassium carbonate and then allowed to react under heating with reflux for 6 hours.
After the reaction, the reaction mixture was allowed to stand overnight at room temperature. Insoluble materials were removed by filtration and the filtrate was made to 100 ml by addition of acetonitrile. A portion of 10 ml was taken, and 0.23 g of N-~2-hydroxyethyl)-3-t4-nitrophenyl~propylamine and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in this portion. The solution was concentrated in vacuo and the resultant oily substance was allowed to react at 80~C for 6 hours. The reaction mixture was then subjected to silica gel column chromatograph (chloroform/methanol = 40:1, v/v~ for purification. Thus, 0.29 g of 6-{2-~N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-1,3,5-trimethyl-2,4(1~,3~)-pyrimidinedione was obtained.
Results of the analysis of the pyrimidinedivne derivative thus obtained:
NMR (CDCl~ ppm: 8.05 (d, 2H), 7.30 (d, 2H), 4.32 (m, 2H), 3.25 ~s, 3H), 3.31 (s, 3H), 2.6-3.1(m, lOH), 2.06 (S, 3H), 1.9 (m, 2H) Next, this pyrimidlnedione derivative was treated with HCl/methanol in an ordinary method and thereby 0.12 g o~ a hygroscopic amorphous compound, 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-1,3,5-trimethyl-10- 2,4(1H,3H?-pyrimidinedione hydrochloride (compound 179), was obtained.
Results of the analysis of the compound 179 thus obtained:
IR ~ KBr max (cm 1): 3300, 2640, 1690? 1590, 1550, 1340, 1220, 930, 750, 700 Elemental analysis: C20H2~N505 HCl H20 Calculated (x): C, 50.68; H, 6.81: N, 14.78; Cl, 7.48 Analyzed (x): C, 51.22; H, 6.94: N, 14.29; Cl, 7.73 Example 127 Preparation of 1,3-dimethyl-6-~2-~N-(2-hydroxyethyl~-3-(4-nitrophenyl)propylamino~ethylamino~-5-nitro-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 180) Cl ~ O CH3SO2-OCH2CH2N ~ O
NO2 CH3 NO 'CH
2~01389 ,0 No2~CH2CH2CH2NHcH2CH20H
N0 \CH
N02~CH2CH2CH2NCH2CH2NH~NCH3 ~HCl (Compound 180) (1) Preparation of 6-~2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione 6-chloro-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione (4.0 g) was dissolved in a solution of 13 ml of dichloromethane and added to a solution of 1.26 ml of ethanolamine and 3.8 ml of triethylamine in dichloromethane (13 ml) gradually drop by drop at 0~C. The reaction was carried out at 0~C for 1 hour; the reaction mixture was allowed to stand at room temperature for 5 hours.
The reaction mixture was again cooled down to 0~C and added with 3.8 ml of triethylamine and with 2.28 ml of methanesulfonyl chloride drop by drop. After the reaction at 0~C for 5 hours, 30 ml of ice water was added, and the mixture was stirred vigorously for 30 minutes. The dichloromethane layer fraction was removed, and the water layer fraction was subiected to extraction with chloroform.
The extract combined with the organic layer fraction was washed with water. dried over sodium sulfate anhydrous and X~1389 then concentrated in _a~uo. The resultant oily substance was subjected to silica gel column chromatograph (chloroform/methanol = 30:1 (v/v)~ for purification. Thus, 5.8 g of 6-(2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidlnedione was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 5.12 (t, 2~, 3.44 (s, 3H), 3.22 (m, 2H~, 3.16 (s, 3H) (2) Preparation of 6-(aziridin-1-yl)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione 6-(2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione ~5.8 g) was dissolved in 70 ml of acetonitrile and added with 3.8 g of potassium carbonate. The reaction was carried out under heating with reflux for 3 hours. The reaction mixture was cooled down to room temperature; insoluble materials were removed by filtration. The filtrate was concentrated to a volume of 20 ml, added with 100 ml of ether and then stored refrigerated for 2 days. Crystals formed were collected by filtration and washed with hexane, thus 1.0 g of a powdery compound, 6-(aziridin-l-yl)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione, was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR C~C13, ~ ppm: 3.37 (s, 3H), 3.18 (s, 3H), 2.1-2 2 (m, ~lH) ~3) Preparation of 1,3-dimethYl-6-~2-~N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-5-nitro-2,4(lH,3H)-pyrimidinedione hydrochloride (compound 180) An oily substance obtained by dissolving 1.0 g of 6-(aziridin -l-yl)-1,3-dimethyl-5-nitro-2,4~1H,3H)-pyrimidinedione, 0.99 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine and 50 mg of p-toluenesulfonic acid in l.V ml of dimethylformamide was allowed to react at 90~C
for 3 hours. The reaction mixture was cooled down to room temperature, added with 10 ml of water and then vigorously stirred. Crystals formed were collected by filtration, dissolved in chloroform and then subjected to silica gel chromatograph (chloroform/methanol = 40:1 (v/v)) for purification. Thus, 0.44 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino~-5-nitro-2,4(1H,3H)-pyrimidinedione (a free form of compound 180) was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 8.01 (d, 2H), 7.31 (d, 2H), 3.66 (t,2H) 3.45 (5, 3H), 3.35 (s, 3H), 2.6-3.6 (m, lOH), 2.0(m, 2H) Next, this pyrimidinedione derivative was treated with HCI/methanol in an ordinary method; thus 0.11 g o~ a hygroscopic amorphous compound, 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenYl)propylamino]ethylamino}-5-2(~01389 nitro-2,4(1H,3H)-pyrimidinedione hydrochloride ~compound 180), was obtained.
Results of the analysis of the compound 180 thus obtained:
IR ~ KBr max (cm 1): 3300, 2550, 1700, 1650, 1530, 1350, 1110, 930, 750 Elemental analysis: C1gH26N607 HCl 3H20 Calculated (x): C, 42.19; H, 6.15: N, 15.54; Cl, 6.55 Analyzed ~X): C, 41.79; H, 6.41: N, 14.83; CI, 6.02 Example 128 Preparation of tablets containing, as an active ingredient, 1,~-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-5-nitro-2,4(1H,3H)-pyrimidinedione (free form of compollnd 180), which can be obtained by the method of Example 127.
Said pyrimidinedione derivative (free form of compound 180) ~1 g), 123 g of lactose and 20 g of corn starch were thoroughly mixed. The mixture was mixed in an aqueous solution of 5 g of hydroxypropylcellulose (100 ml) was granulated and dried at 50~C for 4 hours. The granules were 20 thoroughly blended with 1 g of magnesium stearate and then compressed into tablets using a tablet machine with a pressure of 150 mg/tablet.
Example 129 Production of capsules containing, as an active ingredient, 6-~2-[N-(2-hydroxyethyl~-3-(4-nitrophenyl)propylamino]
ethylamino}-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione ZQ~1389 hydrochloride (compound 179), which can be obtained by the method of Example 12~
Said pyrimidinedione hydrochloride derivative (compound 179) (5 g), 120 g of lactose and 25 g of corn starch were thoroughly mixed, and the resultant mixture was formulated into hard capsules (150 mg per capsule~ using a capsule filling machine.
Example 130 Production of an injection containing, as an active ingredient, 1,~-dimethyl-6-~2-~N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino~ethylamino}-5-nitro-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 180) which can be obtained by the method of Example 127.
Said pyrimidinedione derivative hydrochloride (compound 180) (20 mg) and 0.85 g of sodium chloride were dissolved in an appropriate amount of distilled water for injection to total the volume 100 ml and thus formulated into an injection.
Pharmacological test example 9:
A pharmacological tests with the compound 180 obtained by the method of Example 127 was carried out in the same manner as described in Pharmacological test 1. As a result, the ADP75 values as shown in Table 18 were obtained.
- 371 - ~ 3 8 9 Table 18 ADP75 (~) Compound No.Concentration (Jug/ml ) 0.3 1.0 3.0 10.0 Examele 131 Preparation of 1,3-dimethyl-6-~4-<3-~2-nitro-4-(2-pyridinecarbonyl)phenoxy]propyl>piperazin-l-yl~-2~4~1H,3H~-pyrimidinedione oxalate (compound 181) Cl 'o~ C
CN
15z z ~ ~N~ (COOH)2/cH3oH
(Compound 36) CH3 >
<~C~-OCHzCH2CHzN N ~NCH3 (COOH) 2 (Com~ound 181) ... ... . ..
2~11389 (1~ Preparation of 2-chloro-5-(2-pyridinecarbonyl) nitrobenzene 2-bromopyridine ~3.3 ml) was dissolved in 30 ml of ether and added with 22.1 ml of butyllithium (1.6M, in hexane~ drop by drop at -30~C. To this mixture were added a solution of 5.0 g of 4- chlorobenzonitrile in ether (10 ml) drop by drop at the same temperatllre. The reaction mixture was stirred for 1 hour and then poured into ice water.
Ether was removed In vacuo. The resultant water-layer fraction was acidified by adding 6N HCl, stirred at 100~C
for 1 hour, cooled, alkalized by adding sodium hydroxide and then extracted with ether. The resultant ether-layer fraction was concentrated and the oil thus obtained was dissolved in 10 ml of fuming sul~uric acid at 0~C. To this solution, added 1.2 ml of fuming nitric acid drop by drop and the resultant solution was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water and crystals formed were collected by filtration. The crystals were further recrystallized using ethanol, and 3.6 g of crystalline 2-chloro-5-(2-pyridinecarbonyl)nitrobenzene was thus obtained.
(2) Preparation of 1,3-dimethyl-6-~4-<3-[2-nitro-4-(2-pyridinecarbonYl)PhenoXy]propyl>piperazin-l-yl}-2~4(lH~3H) pyrimidinedione oxalate (compound 181) Sodium hydride (60 ~ dispersion in mineral oil) (0 17 g) was washed with hexane to remove oil and added with 8 ml of DMF.
200:~389 The mixture was cooled down to V~C, added with 1.0 g of 1,3-dimethyl-6-[4-~3-hydroxypropyl>piperazin-1-yl]-2,4~lH,3H)-pyrimidinedione (compound 36) and stirred for 30 minutes. To this mixture was added 1.1 g of 2-chloro-5-(2-pyridinecarbonyl)nitrobenzene, and the resultant mixture wasstirred for 1 hour. The reaction mixture was poured into ice water and crystals formed were collected by filtration, washed with water, dried and 1.0 g of 1,3-dimethyl-6-{4-<3-t2-nitro-4-(2-pyridinecarbonyl)phenoxy]propyl>piperazin-1-yl~-2,4~1H,3H)-pyrimidinedione in an amorphous powder form was thus obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR ~CDCI3~, ~ ppm: 2.1 (m, 2H), 2.4-3.1 (m, lOH), 3.25 (s, 3H), 3.34 (s, 3H), 4.28(t, 2H), 5.14 (s, lH), 7.1-8.9 (m, 7H) Next, this pyrimidinedione deri~ative (0.98 g) was treated with an oxalic acid/methanol solution in the ordinary method; thus 0.76 g of crystals of 1,3-dimethyl-6-{4-<3-t2-nitro-4-(2-pyridinecarbonyl)phenoxy~propyl>
piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 181) was obtained.
Results of the analysis of the compound 181 thus obtained:
lR ~ KBr max (cm 1): 3450, 2500, 1700, 1650, 1600, 1520, 1310, 1280, 800, 740, 700 Elemental analYSis: C2~H28~6~6 (C~~~)2 2 - 374 - ~ ~ Q~ 389 -Calculated (X): C, Sl.10; H, 5.40: N, 13.24;
Analyzed (X): C, 51.32; H, 5.40: N, 13.15 Example 132 Preparation of 1,3-dimethyl-6-~2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino~ 2,4(1H,3H)-pyrimidinedione oxalate (compound 182) N02 ~ CH2CH2CH20S- ~ CH 3 ~ ~o N02 ~ ~ CH2CH2CH2NHCH2CH2CH20H >
(Compound 6) (COOH)/~OH
S CH2CH2CHz0H o N02 ~ CH2CH2CH2NCH2CHzNH- ~ CH3 CH 3 ' (C 00H) 2 (Compound 182) ( (1) Preparation of N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamine 3-(4-nitrophenyl)propyl p-toluenesulfonate (1 g) and 4.1 ml of 3-hydroxypropylamine were dissolved in 10 ml of dioxane and the solution was stirred at 80~C for 30 minutes.
To the solution was added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for separation. The chloroform-layer fraction was taken. washed , ., .~
_ - 375 -with water and then dried over sodium snlfate anhydrous.
The solvent was removed in _acuo and 0.7 g of an oil of N-~3-hydroxypropyl)-3-(4-nitrophenyl)propy1amine was vbtained.
Results of the analysis of the amine derivative thus obtained:
NMR (CDC13), ~ ppm: 1.9-2.1 (m, 4H), 2.8-3.2 (m, 6H), 4.18 (t, 2~), 7.62 (d, 2H), 8.01 (d, 2H) (2) Preparation of 1,3-dimethyl-6-{2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H~-pyrimidinedione oxalate (compound 182) N-(3-hydroxypropyl~-3-(4-nitrophenyl)propylamine ~0.7 g), 0.53 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4~1H,3H)-pyrimidinedi.one (compound 6) and 50 m~ of p-toluenesul.fonic acid monohydrate were dissolved in 30 ml acetonitrile, and then the solvent was removed ln vacuo. The resultant oil was allowed to react at 80~C for 3 hours and subjected to silica gel column chromatograph (chloroform/ methanol = 40:1 (vJv)) for purification: 0.68 g of 1,3-dimethyl-6-~2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1.H,3H)-pyrimidinedione was thus obtained.
Results of the analysis of the pyrimidinedione derivative . .
thus obtained:
NMR (CDCl~ ppm: 1.7 (m, 4H}, 2.4-3.1 (m, 8H), 3.21 (s, 3H~, 3.34 (s, 3~), 3.70 (br, 2H), 4.0 (m, 2H), 4.71 (s, IH), 5.81 (br, lH~, 7.25 (d, 2H), 8.06 (d, 2H) Next, this pyrimidinedione derivative (0.65 g) was 376 - ~ 0 0 ~ 3 8 9 ~
treated with an oxalic acid/methanol solution in the ordinary method; thus 0.62 g of crystalline 1,3-dimethyl-6-{2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl~propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate ~compound 182) was obtained.
Results of the analysis o~ the compound 182 thus obtained:
IR ~ KBr max (cm 1): 3300, 1690, 1620, 1540, ~410, 1330, 1050, 850, 770, 740, 690 Elemental analysis: C20H29N5o5 (C~~~)2 H20 Calculated (%): C, 50.09; H, 6.31: N, 13.28 Analyzed (%): C, 50.37; H, 6.25: N, 12.79 Example 133 Preparation of 1,3-dimethyl-6-~2-~N-(l-methylethyl~-3-(4-nitrophenyl)propylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione oxalate (compound 183) N0z ~ CH2CH2CHIoll ~ CH3 ~N- ~ NCH3 ,N~o N0z ~ CHzCHzCH2NHCH2(CH3~2 CH3 (Compound 6) (COOH)2/CH3oH
) CH(CH3~2 0 N02- ~ CH2CH2CHzNCH2CH2NH ~ NCH3 IN~o CH3 ~(C00H~ 2 (C~mpound 183) - Z~01389 (1) Preparation of N-(1-methylethyl)-3-(4-nitr()phenyl)propylamine 3-(4-nitrophenyl~propyl p-toluenesulfonate (1 g) and 5 ml of isopropylamine were dissolved in 15 ml of dioxane, and the solutlon was stirred under heating with reflux for 4 hours. To the solution were added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for extraction. The chloroform-layer fraction was taken, washed with water and dried over sodium sulfate anhydrous. The solvent was removed in vacuo, and thus 0.61 g of an oil of N~ methylethyl)-3-~4-nitrophenyl)propylamine was obtained.
Results of the analysis of the amine derivative thus obtained:
NMR ~CDC13), ~ ppm: 1.22 (d, 6H), 2.0 (m, 2H), 2.9-3.3 (m, i5 5H), 7.28(d. 2H), 8.0g (d, 2~) (2~ Preparation of 1,3-dimethyl-6-{2-[N-(l-methylethyl)-3-(4 nitrophenyl)propylamino~ethylamino}-2,4(1H,3H)-Pyrimidinedione oxalate (compound 183) N-~l-methylethyl~-3-(4-nitrophenyl)propylamine (0.6 g), 0.5 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3~)-pyrimidinedione (compound 6) and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in 30 ml acetonitrile, and then the solvent was removed in vacuo. The resultant oil was alLowed to react at 80~C for 3 hours and subiected to silica gel column chromatograph (chloroform/ methanol = 40:1 (v/v)~ for purification. Thus, 1 0 g of 1,3-dimethyl-6-12-~)1389 [N-~1-methylethyl)-3-~4-nitrophenyl)propylamino]ethyl~mino~-2,4(1H,3H)-pyrimidinedione was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR ~GDCl3), ~ ppm: I.45~d, 6~), 2.0 ~m, 2H), 3.29 (s, 3H), 3.40 (s, 3H), 2.5-3.1 (m, ~H), 3.8-4.1 ~m, 4H), 4.80 (s, lH), 5.5 (m, lH), 7.31 (d, 2H), 8.00 (d, 2H) This pyrlmidinedione derivative ~0.95 g) was treated with an oxalic acid/methanol solution in the ordinary method; thus 0.88 g of crystals of 1,3-dimethyl-6-~2-[N-(1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 183) was obtained.
Results of the analysis of the compound 183 thus obtained:
IR ~ KBr max ~cm 1) 3250, 2600, 1700, 1640, 1590, 1510, 1~30, 1220, 760, 750, 700 Elemental analysis: C20ff29N50~ 1.5~COOH)2 0.5H20 Calculated (X): C, 50.45; H, 6.08: N, 12.79 Analy~ed (X): C, 50.25; H, 5.81: N, 12.52 Example 134 Preparation of 1,3-dimethyl-6-{2-rN-(2-hydroxy-1-methylethyl~-3-(4-nitrophenyl)propylamino]ethylamino~-2,4~1H,3H)-pyrimidinedione hydrochloride (compound 187) _ - 379 ~ a 0 n ~ ~ 8 9 NOz ~ CHzCHzCOzH ~NO2 ~ CHzCHzCNHCHCHzOH >
C ~J
r~ I CH3 NOz- ~ CH2CH2CHzNHCHCHzOH
(Compound 6) HCl /CH30H
> CH(CH3)cH2oH O
NO2 ~ CHzCHzCHzNCHzCHzN~ ~ NC~3 ~HCl (Compound 187) (1) Preparation of N-(2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propionamide 3-(4-nitrophenyl)propionic acid (5 g) was suspended in 40 ml of thionylchloride, and the suspension was stirred under heating with reflux for 2 hours. Excessive thionylchloride was removed in vacuo and the oil thus ( obtained was dissolved in 15 ml of chloroform.
Separately, 3.8 g of 2-amino-1-propanol and 3.5 g of potassium carbonate were dissolved in 35 ml water, and the resultant solution was cooled down to 0~C and added drop by drop with the chloroform solution which had been obtained previously. The mixture was stirred maintaining at ~~C for 1 hour. Crystals formed were collected by filtration and washed with water. Furthermore, the crystals were , ~ .. .
2~)1389 recrystallized using an ethyl acetate/chloroform ~1:1 (v/v)~, and thus 3.46 g of crystalline N-(~-hydroxy-l-methylethyl)-3-(4-nitrophenyl)prupionamide was obtained.
Results of the analysis of the amine derivative thus obtained:
Melting point: 174~C
(2) Preparation of N-(2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamine N-(2-hydroxy-1-methylethyl)-~-(4-nitrophenyl) propionamide obtained in (1) above (3.4 g) and sodium borohydride (2.1 g) was suspended in 32 ml of THF. To the mixture was added drop by drop with a solution of 3.3 g acetic acid in THF ~32 ml~. The mixture was stirred under heating with reflux for 10 hours. The reaction mixture was then cooled down to 5~C, added with 20 ml of methanol, stirred for 30 minutes and then concentrated by drying. To the resultant residue was added 50 ml of lN-HCl and 50 ml of chloroform, and the mixture was vigorously stirred. The mixture was allowed to stand for extraction then fractionated. The water-layer fraction was alkalinized with sodium hydroxide and extracted with chloroform. The chloroform-layer fraction was washed with water, dried over sodium sulfate anhydrous and then concentrated by drying;
thus, 2.96 g of an oily compound, N-(2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamine, was obtained.
This was used for the following reaction without further 2C~1389 purification.
~3) Preparation of 1,3-dimethyl-6-{2-[N-(3-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-?~4(lH~3H)-pyrimidinedione hydr-ochloride (compound 187) N-(2-hydroxy-1-methylethyll-3-~4-nitrophenyl) propylamine (2.2 g) obtained in ~2~ above, 1.6 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3HS-pyrimidinedione (compound 6) and 0.1 g of p-toluenesulfonic acid mono-hydrate were dissolved in 100 ml of acetonitrile, and then the solvent was removed n vacuo. The resultant oil was allowed to react at 80~C for 3 hours and subjected to silica gel column chromatograph tchloroform/ methanol = 40:1 ~v/v)) for purification; thus, 3.0 g of 1,~-dimethyl-6-{2-~N-(2-hydroxy-l-methylethyl~-3-(4-nitrophenyl)propylamino~
ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Results of the analysis o~ the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.04 (d, 3H), 1.9 (m, 2H), 2.5-3.0 (m, 9H), 3.28 (s, 3H), 3.40 (s, 3H), 4.13 (m, 2H), 4.69 (s, lH), 6.47 (m, lH), 7.29 (d, 2H), 8.0fi (d, 2H) This pyrimidinedione derivative (2.95 g) was treated with a HCI/methanol solution in the ordinary method; thus 3.02 g of crystalline 1,3-dimethyl-fi-~2-rN-~2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamlno]ethylamino}-2,~(lH,3H)-pyrimidinedione hydrochloride (compound 187) was obtained.
200~389 Resul ts of the analysis of the compound 187 thus obtained:
Melting point: 154 - 155~C
IR ~ KBr max (cm 1) 3250, 2~00, 1690, 1600, 1550, 1340, 1240, 1060, 840, 760, 700 Example 135 Preparation of 1,3-dimethyl-6-~4-(3-methyl-4-nitrobenzylpiperazin-1-yl~-2,4~1H,3H)-pyrimidinedione hydrochloride ~compound 188) HN N~CH3 - ~ N~o N02~CH20H > NO~CHzCl CH3 CH3 CH3(Compound 2) HCl /CH30H
> N02- ~ CH2N ~ - ~NCH3 ~ HCl (Compound 188 ~1) Preparation of 3-methyl-4-nitrobenzyl chloride 3-methyl-4-nitrobenzylalcoho~ (2 g) and 0.2 ml of DMF
were dissolved in 20 ml of toluene. The solution was added with 1 ml of thionyl chloride and stirred under heating with reflux for 3 hours. The reaction mi~ture was concentrated and thus 2.2 g of an oil, 3-methyl-4-nitrobenzyl chloride, 281)1389 was obtained. This compound was used for the following reaction without further purification.
(2~ Preparation of 1,3-dimethyl-6-t4-(3-methyl-4-nitrobenZYl)piperazin-l-yl~-2,4~1H,3H~-pyrimidinedione S chloride (compound 188) 3-methyl-4-nitrobenzyl chloride (2.2 g) obtained in ~1 above, 2.2 g of 1,3-dimethyl-6-(piperazin-1-yl3-2,4(1H,3H)-pyrimidinedione (compound 2) and 4.1 ml of triethylamine were dissolved in 40 ml of isopropanol, and the solution was stirred under heating with reflux for 2.5 hours. After the reaction, the solvent was removed in vacuo, and the residue was dissolved in 50 ml of chloroform. The chloroform solution was washed with water and dried over sodium sulfate anhydrous and then the solvent was removed in vacuo; thereby 2.76 g ~f crystalline 1,3-dimethyl-6- r 4-(3-methyl-4-nitrobenzyl)Piperazin-l-yl]-2~4(lH~3H)-pyrimidinedione was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
Melting point: 162 -164~C
NMR (CDC13~, ~ ppm: 2.5-3.3 (m, 8H). 2.61 (s, 3H), 3.26 ~s, 3H~, 3.36 (s, 3H), 3.61 ~br, 2H), 5.15 (s, lH~, 7.35 (m, 2H), 7.87 (d, LH) This pyrimidinedione derivative (2.4 g) was treated with a hydrochloric acid/methanol solution by the ordinary method; thus 2.34 g of crystalline 1,3-dimethyl-6-[4-(3-- 384 - 2 ~ 0 1 3 8 9 methyl-4-nitrobenzyl)piperazin-l-yl]-2~4(lH~3H)-pyrimidinedione hydrochloride (compound 188) was obtained.
Results of the analysis of the comPound 188 thus obtained:
lR ~ KBr max (cm 1~ 3360, 25~0, 1690, 1640, 1520, 1440, 1340, 1200, 980, 840, 760, 700 Elemental analYsis: C18H23N504 HCI H20 Calculated (X): C, 50.52; H, 6.12: N, 16.36; Cl, 8.28 Analyzed (X): C, 50.87; H, 6.64: N, 16.44; Cl, 7.68 Example 136 Preparation of 1,3-dimethyl-6-{2-~N-(2-hydro~yethyl~-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate ~compound 189) ~N ~CH3 ~ HOCH2CH2NHCH2CH2NH ~ CH3 (Compound 6) ~ >
~ C ~ OH ~ ~ -C ~ OCH2CH2CHzBr ( O 02 0 NOz (COOH)2/CH30H
> CH2CH20H o C, ~ OCH2CHzCH2NCHzCH2NH- ~ CH3 CH3 ~(COOH) 2 (Compound 189) (1) Preparation o~ 1,3-dimethyl-6-{2-(2-hydroxyethylamino) B
.. . .
2~01389 ethylamino~-2,~(1H,3H)-pyrimidinedione 6-(1-aziridinyl)-1,3-dimethyl-2-4(1H,3H~-pyrimidinedione (compound 6) ~0.81 g)~ 1 ml of ethanolamine and 50 mg of p-toluenesulfonic acid monohydrate were dissolved in 200 ml of acetonitrile and then the solvent was removed in vacuo. The resultant oil was allowed to react at 90~C for 3 hours. The reaction mixture was cooled down to room temperature and then dissolved by adding ethanol.
Ether was added to this soiution for crystallization. The crystals formed were collected by filtration and further recrystallized using an ethanol/ether mixed solvent; thereby 1.02 g of crystalline 1,3-dimethyl-6-~2-(2-hydroxyethylamino)ethylamino~-2,4(1~,3H)-pyrimidinedione was obtained.
Results of the analysis of the crystals of pyrimidinedione derivative Melting point: 146-148~C
~2) Preparation of 4-(3-bromopropyloxy)-3-nitrobenzophenone 4-hydroxy-3-nitrobenzophenone (2.5 g) and 7.1 g of potassium carbonate were suspended in 15 ml methylethylketone. The suspension was stirred under heating with reflux for 30 minutes, added with 1,3-dibromopropane and then heated with reflux for 6 hours. The reaction mixture was cooled down to room temperature, and insoluble substances were removed by filtration. The filtrate was then concentrated, and the resultant precipitate was - 2C~01389 subjected to silica ~el column chromatograph (hexane/ethyl acetate =3:1 (v/v)~ for purification; thereby 2.08 g of an oil, 4-(3-bromopropyloxy)-3-nitrobenzophenone, was obtained NMR ~CDC13~, ~ ppm: 2.40(m, 2H), 3.66 ~t, 2H), 4.39 (t, 2H), 7.13-8.34 (m, 8H) (3) Preparation of 1,3-dimethyl-6-~2-[N-(2-hydroxyethyl)-3-(4-benzoyl-2-nitrophenoxy~propylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione oxalate (compound 189) A mixture of 0.67 g of 1,3-dimethyl-6-{2-(2-hydroxyethylamino)ethylamino}-2,4(1H,3H)-pyrimidinedione obtained in (1) above, 1.0 g of 4-(3-bromopropyloxy)-3-nitrobenzophenone obtained in (2) above, 1.5 ml of triethylamine and 3 ml of D~F were stirred under heating at 100~C for 1 hour. The mixture was cooled down to room temperature, added with 50 ml chloroform, washed with water and then dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was crystallized using an ethanol/ether mixed solvent; 0.59 g of crystalline 1,3-dimethyl-6-~2-~N-(2-hydroxyethyl)-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(1H,3H~-pyrimidinedione was thus obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
Melting point: 180 -181~C
NMR ~CDC13/DMSO-d6=1/1, v/v~, ~ ppm: 2.0 (m, 2H), 2.fi-3.1 (m, 8H~, 3.21 (s, 3H), 3.34 (s, 3H?, 3.67 (t, 2H~, 4.39 (t, 38 72~1389 2H), 4~58 (s, lH), 6.25 (br, lH~, 7.31 (d, lH), 7.5-8.1 (m, 6H), 8.26 (d, lH) This pyrimidinedione derivative (0.55 g) was treated with an oxalic acid/methanol solution in the ordinary method; 0.62 g of crystalline 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-benzoyl-2-nitrophenoxy) propylamino~ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 189) was thus obtained.
Results of the analysis of the compound 189 thus obtained:
Melting point: 144 - 147~C (Decomposed~
IR ~> KBr max ~cm 1): 3300, 2590, 1720, 1680, 1630, 1530, 1340, 1280, 1070, 7B0, 7tO
Elemental analysis: C26H31N507 (COOH)~ 2 Calculated (X): C, 53.84; H, 5.49: N, 11.21;
Analyzed ~x): C, 53.~8; H, 5.?6: N, 11.27 Example 1~7 Preparation of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-~3-methoxy-4-nitrophenyl~propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 1~0 N0z ~ CH=CHC02H , N02 ~ CH2CHzCOzH
> N02 ~ CH2CH2CNHCH2CH20H
¦ N- ~ CH3 > N02 ~ CHzCH2CH2NHCHzCHzOII CH3 CH30 / (Compound 6) - 388 - 20 n ~ 3 8 9 !
(COOH)2/CH30H
CH2CHzOH o --~ NOz ~ -CHzCHzCHzNCHzCH2NH- ~ NCH3 N o (COOH) 2 (Compound 190) (1) Preparation of 3-(3-metho~y-4-nitrophenyl)propionic acid 3-methoxy-4-nitrocinna~ic acid (6.2 g) and 12.3 g of hydroxyamine sulfate were dissolved in 250 ml of water. To the solution was added 7.1 g of sodium hydroxide, and further alternately added a solution of 18 g of sodium hydroxide in water (27 ml) and 19.2 g of hydroxyamine-o-sulfonic acid little by little, maintaining the p~ at 9.
The mixture was stirred at 5~C for 6 hours and then insoluble substances were removed by filtration. The resultant filtrate was cooled on ice and was added with 6N
sulfuric acid to adjust the pH to 2. Crystals formed were collected by filtration, washed with water and dried; 1.~7 g of crystalline 3-(3-methoxy-4-nitrophenyl)propionic acid was thus obtained.
Results of the analysis of the crystalline propionic acid derivative thus obtained:
Melting point: 137-139~C
(2) Preparation of N-(2-hydrnxyethyl)-3-~3-methoxy-4-nitrophenyl)propanamide 3-(3-methoxy-4-nitrophenyl~propionic acid obtained in ' , , r- .i 2~01389 (1) above (1 2 g) was suspended in 20 ml of thionyl chloride. The suspension was stirred for 2 hours under heating with reflux and then the solvent was removed. The resultant residue was dissolved in 3 ml of chloroform.
Separately, 0.51 g of ethanolamine and 0.78 g of potassium carbonate were dissolved in 8 ml of water, and the resultant solution was cooled down to 0~C and added drop by drop with the chloroform solutinn which had been obtained previously. The mixture ~as vigorously for 1 hour at the temperature maintained at 0~C. Crystals formed were collected by filtration, washed with water and dried.
Furthermore, the crystals were recrystallized using an ethyl acetate solution and thus l.14 g of crystalline N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl~propanamide was obtained.
Results of the analysis of the crystalline amide thus obtained:
Melting point: 155~C (Decomposed) (3) Preparation of N-t2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamine Sodium borohydride (0.78 g) was suspended in 12 ml ofTHF. To this suspension were added ~.1 g of N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propanamide obtained in (2~ above, and further added little by little 1.2 ml of acetic acid. The mixture was stirred until bubbling stopped and then stirred under heating with reflux 2(~01389 for 10 hours. The mixture was cooled down to room temperature and added with lO ml of methanol little by little. The solvent was removed in vacuo. The residue was added with 20 ml of chloroform and then extracted with a lN-HCI solution. The extracted acidic water phase wasalkalinized by adding sodium hydroxide on ice and extracted with chloroform. The chloroform-layer fraction was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, and chloroform was removed;
thereby V.72 g of an oily compound, N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl~propylamine, was obtained. This compound was used for the following reaction without further purification.
(4) Preparation of 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamino~ethylamino}-2,4(1H,3H~-pyrimidinedione oxalate (compound 190) 6-(1-aziridinyl~-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6~ (0.45 g), 0.7 g of N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamine and 50 mg of p-toluenesulfonic acid monohydrate were dissolved in 25 ml of acetonitrile and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80~C for 3 hours and then subjected to silica gel column chromatograph (chloroform~methanol = 40/1, v/v~ for purification; thereby 0.38 g of an oil, 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamino]ethylamino}-2,4~1H,3H)-200138~
pyrimidinedjone, was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR (CDCl3) ~~ ppm: 1.9 (m, 2H), 2.4-3.8 (m, 12H), 3.20 (s, 3H), 3.33 (s, 3H), 3.83 (s, 3H), 4.63 (s, lH), 6.11 (m, lH), 6.75 (m, 2H), 7.26 (m, lH~
This pyrimidinedione derivative (0.33 g) was treated with an oxalic acid/methanol solution in the ordinary method; 0.22 g of an amorphous powder of 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamino]ethylamino}-2,4(1H,~H)-pyrimidinedione oxalate (compound 1gO~ was thus obtained.
Results of the analysis of the compound 190 thus obtained:
IR ~ KBr max (cm 1): 3300, 2550, 1690, 1640, 1540, 1350, 1280, 760, 700 Elemental analysis: C20H29N5O6 2(COOH)2 2H20 Calculated (x): C, 44.24; H, 5.72: N, 10.75 Analyzed (X): C, 43.93; H, 5.85; N, 11.10 - 392 - 20 ~ ~ 3 89 ~
Example 138 Production of 1,3-dimethyl-6-l2-[N- (2-dieth amino) ethyl-3-(4-nitrophenyl)propylamino]ethylaminoJ-2,4(1H,3H)-pyrimidinedione oxalate (Compound 191) o N~2- ~ -CH2CH2CH2NHCH2CH2NH- ~ -CH3 CH ~
(Compound e) 3 ( ClCH2CH2N(C2H5)2 HCl (COOH)2/CH30H
CH2CH2N(C2H5)2 0 N~2- ~_CH2CH2 CH2N_CH2CH2NH_~N-CH3 (CompOund 191) CH3 ~ (C~2 )2 First, 1.4g of 1,3-dimethyl-6-l2-[3-(4-nitro-phenyl) propylamino]ethylamino~-2,4(1H,3H)-pyrimidine-dione hydrochloride (Compound e) was dissolved with 5 ml of water, followed by the addition of K2C03 to render the solution alkaline.
The resulting solution was then extracted with CHCl3. The combined layers were concentrated in vacuo, followed by the addition of 1.0 g of 2-d;ethylamino ethyl-chloride, 3 ml of triethylamine and 20 ml of isopropanol.
The reaction mixture was refluxed for 10 hours.
Solvent was removed in vacuo, and then the resulting residue was directly purified by a silica gel chromatography (eluent: CHCl3/CH30H=20/1, by volume) thereby obtaining 0.6 g -,~
2g~ 89 of 1,3-dimethyl-6-t2-[N-diethylamino)ethyl-3-(4-nitro-phenyl)propylamino~-2,4(1 H,3H)-pyrimidinedione.
Further, 0.6 g of the pyrimidinedione derivative was treated with an oxalic acid/methanol solution by a method known per se in the art to obtain 0.52 g of 1,3-dimethyl-6-t2-[N-(2-diethylamino)ethyl-3-(4-nitrophenyl)-propylamino] ethylamino~-2,4(1 H,3H)-pyrimidinedione (Compound 191) as pale yellow crystals.
Analytical results of crystals of compound 191 thus obtained:
Melting point: 197 - 199~C
IR vKBr(cm 1 ); 3000, 2950, 1720, 1700, 1600, 1340 max 852, 700
TITLE OF THE INYENTION
PYRIMIDINEDiONE DERIVATIVE COMPOUNDS, METHOD OF PRODUCING
THE SAME AND ANTIARRYTHMIC AGENTS CONTAINING THE SAME
BACKGROUND OF THE IN~ENTiON
1. Field of the Invention This invention relates to novel pyrimidinedione derivatives and acid addition salts thereof, to methods of L' producing the same and to pharmaceutical agents containing the same, which are effective for the treatment of cardiac dysfunctions such as arrhythmia and cardiac insufficiency.
2. Description of the Prior Art The mechanism of the occurrence of arrhythmia is camplicated. Abnormalities in stimulation production and disorders in the conducting system or combinations thereof are considered to be responsible.
As to disorders in excitation conduction, the re-entry theory is representative.
One of the conditions of occurrence of arrhyttlmia is irregularity in thc refractory period in various parts of the heart. In addition, one-directional block, shortened refractory period, delay in conduction, the presence of circus movement are complicatedly involved.
Conventionally, varieties of antiarrythmic agents have been used for the treatment of arrhythmia.
The antiarrythmic agents are classified into four 2~ 389 groups according to their mode of action.
Namely, E. M. Vaughan Williams (Vaughan Williams E. M.;
"Advances in dtulg research, vol. 9"; ed. by Harper N. J., Simmonds A. B., Academic Press, London, 1974; pages 69~
classified the antiarrythmic agents into the following four groups according to their action against the action potential of cardiac muscle or against the ionic current which generates the action potential.
Class 1: Sodium channel depressors These agents are efficacious ;n repressing a sodium current. However, these agents have no or only minute effects on the retention time of the normal action potential and decrease the maximum rising velocity (YmaX) of the sodium current. The antiarrythmic agents which belong to this IS class have a high antiarrythmic activity but at the same time strongly repress cardiac functions. Careful consideration is required in administering to patients with cardiac failure or hypotension.
Class 1l: Beta-blocking agents The agents in this class, represented by propranolol, are efficacious in the beta-blocking action and are useful in treating patients with arrhythmia in which the sympathetic nerve is involved. However, the care must be taken for use since these agents have side-effects caused by the beta-blocking action, such a.s depression of card;ac fllnctions, induction of bronchial asthmatic attach and _ 3 _ 20~''1389 hypoglycemic seizures.
Class III: Pharmaceutical agents for prolonging the retention time of the action current.
These agents are efficacious in remarkably prolonging the retention time of the action current of the cardiac muscle and in prolonging an effective refractory period. Re-entry arrhythmia is considered to be suppressed by the action of the pharmaceutical agents of Class III. The medicaments of this Class III include amiodarone and bretylium. However, all the agents have severe side effects; therefore, careful consideration is required for use.
Class IV: Calcium antagonists These agents control a calcium channel and suppress arrhythmia due to automatic sthenia of sinoatrial nodes and to ventricular tachycardia in which atrial nodes are contained the re-entry cycle.
Among these antiarrythmic agents, pharmaceutical agents of the Class III type are considered to be particularly important and the most efficacious, and known to be effective on ventricular arrhythmia, the most fatal of all symptoms.
SUMMARY OF THE INVENTION
An object of an aspect of the present invention is to provide a novel compound which is useful as a Class III type antiarrythmic agent and to provide a process for producing the same.
Another object of an aspect of the present invention is to provide a novel compound which is effective in improving cardiac dysfunction such as cardiac insufficiency and a process for the preparation of the same.
Another object of an aspect of the present invention is to provide a pharmaceutical agent, which contains the novel compound as an effective component, for the treatment of cardiac dysfunctions such as arrythmic and cardiac insufficiency.
Accordingly, an aspect of the invention provides compounds of the general formula (1) shown below and acid addition salts thereof, along with their pharmacological properties. These compounds have pharmacological characteristics to markedly prolong the retention time of the action potential of cardiomuscular cells and to markedly prolong the ventricular refractory period.
Furthermore, the compounds of this invention have a positive inotropic action and are useful as therapeutic agents for cardiac insufficiency.
According to another aspect of the invention, compounds of the invention are represented by Formula (1):
N0z R' RZ ~ 0 X ~ A-N-(CH2) n - N ~ ~N-R4 (1) X2 R3 ~
in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1 ~ -N3 or -NHCH2CH-CH2-;
OH
B represents an oxygen or a sulfur atom, -N-, -CNH- or -CO-;
O OH O
Il l 11 D represents -NHC-, -CH- or -C-;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group or a lower alkyl group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected from the group consisting of a hydroxy group; a .. ~
_ ~ - 5 ~ 2 ~ ~ ~ 3 8 9 lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom, or a lower alkyl group;
X1 and x2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl group, a carboxy group, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring;
n represents an integral number 2 or 3; m represents an integral number, O, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and l represents an integral number, O, 1, 2, 3 or 4.
2 0 û ~ 3 8 9 -5a-DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Compounds according to the present invention is those of the general formula (1) shown below and acid addition salts thereof. More specifically, the compounds are described in Examples thereinafter as preferred embodiments.
N02 A-N-(CH2) n - N ~ -R~ .. ~1 X2 R3' ~
In the formula. A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-. -N ~ OI -NHCH2CH-CH~-;
OH
~5 O O
11 ll B represents an oxygen or a sulfur atom, -N-, -CNH- or -CO-;
o OH ~
Il l 11 D represents -NHC-, -CH- or -C-;
Rl and R2 each independently represent a hydrogen atom~ a lower alkyloxycarbonyl graup, an unsaturated lower alkyl - group or a lower alky1 group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected from the group consisting of a hydroxy group; a lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group; a benzoylvxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or Rl and R2 may be so linked as to form an alkylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
xl and X~ ea~h independently represent a hydrogen atom, -CO-Rfi, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl, groupacarboxylgroup, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group. a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to form an alkylene 2~ 89 chain and thus form a heterqcyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups independently selected from a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring;
n represents an integral number 2 or 3: m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number. 0, 1, 2, 3 or 4.
In the above formula (1), examples of the unsaturated lower alkyl group include vinyl, allyl and propargyl groups.
Examples of the lower alkyl group include linear- or branched-alkyl groups having 1 - 5 carbon atoms, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary-butyl and secondary-butyl groups.
Examples of the lower alkyl group substituted by a hydroxyl group include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyprqpyl and 4-hydroxy-butyl groups.
Examples of the lower alkyl group substituted by a lower monoalkylamino group include 2-(methylamino)ethyl, 3-(methylamino)propyl and 2-(ethylamino3ethyl groups.
Examples of the lower alkyl group substituted by a lower dialkylamino group include 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl and 3-(dimethylamino)propyl groups.
An example of the lower alkyloxy group is an oxygen - 8 - ~ 0 ~ ~ ~ 8 ~
atom substituted by a lower alkyl group described above.
Examples of the lower alkanoyloxy group include acetyloxy, propionyloxy, ~L~loxy~isobutyryloxY and pivaloyloxy groups.
Examples of the lower alkyl group substituted by a benzoyloxy group include 2-benzoyloxYethyl~ 3-benzoyloxypropyl, ~-benzoyloxypropyl and 2-benzoyloxy-1-methylethyl groups.
Examples of the lower alkyl group substituted by a phenyl group include benzyl, 2-phenylethyl and 3-phenylpropyl groups.
An example of the lower alkyl group in the lower alkyloxycarbonyl group is that identical with the lower alkyl group described above.
Examples of the halogen atom include fluorine, chlorine, bromine and iqdine atoms.
No limitation is required of substitution sites in the halogen-substituted lower alkyl group; the lower alkyl group substituted by a substituting group selected from the group consisting of the lower alkyloxy group. the lower alkanoyloxy group. the benzoyloxy group substituted by a halogen atom or a lower alkyloxy group, the phenyl group substituted by a halogen atom or a lower alkyloxy group and the lower alkyloxycarbonyl group; the benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; and the phenyl group substituted bY a halogen atom or a lower .... .
-2~ 389 alkyloxy group.
Examples of the lower alkylthio group include sulfur atoms substituted by the lower alkyl group mentioned above.
Examples of the lower alkanoylamino group include acetylamino and propionylamino groups.
Examples of the lower alkylsulfonamido group include methanesulfonamido and ethanesulfonamido groups.
Examples of the mono- or di-lower alkylamino group include methylamino, ethylamino, dimethylamino and diethylamino groups.
Examples of the phenyl group-substituted lower alkylamino group include the above-mentioned alkylamino groups which are further substituted by phenyl group. No limitation is required in this substitution.
~xamples of the unsaturated lower alkyloxy group include vinyloxy, allyloxy and propargyloxy groups.
Examples of the alkyl chain to link Rl and R2 or ~1 and R5 include ethylene and propylene chains.
Examples of the lower alkanoyl group include formyl, acetyl, propionyl and butyryl and pivaloyl groups.
Examples of the lower alkylsulfonyl group include methanesulfonyl and ethanesulfonyl g~oups.
Examples of the cycloalkyl group include cyclopentyl and cyclohexyl groups.
Examples of the heterocyclic group as ~6 include pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl Z~89 gI-O UpS .
No limitation is required of the substitution sites in the phenyl grqup substituted by a substituting group in R6.
The expression "pharmaceutically acceptable" as used to describe the pharmaceutically acceptable acid addition salts in the compounds of the general formula (1) described above means not to have remarkable side effects or absence of toxicity and not to reduce the pharmaceutical activities, when administered to man. These acid addition salts can be produced by neutralization of the corresponding free bases.
~ xamples of the acids from which these pharmaceutically acceptalbe salts can be prepared include organic acids or inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, .
methanesulfonic acid, maleic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, lactic acid. and benzenesulfonic acid.
The concrete examples of the compounds of the general formula (1) include the following compounds.
2~1389 1. I,3-dimethyl-6-[2-~4-nitrqanilino~ethylamino]-2,~-(lH,3H)-p~rimidinedione 2. 1,3-dimethyl-6-[3-(~-nitroanilino)propylamino]-2,4(1H,3H)-pyrimidineditne 3. 1,3-dimethyl-6-[4-(4-nitrophenyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione . 1,3-dimethyl-fi-[N-ethyl-2-(4-nitroanilino)ethyl-amino~-2,~(1H,3H')-pyrimidinedione .~. 1,3-dimethyl-6-[2-(N-meth~ nitroanilino~ethyl-amino)]-2.~1H.3H'-pyrimidinedione 6. 1,3-dimethyl-6-~ 4-nltrophenyl!homo~ipera~in-]-yl~-2.4(1H.3HI-pyrimidinedione 7. 1,3-dimethyl-6-~2-(4-nitro~enzylamino~ethyl-amino]-2,4~1H,3H)-pyrimidinedlone 8. 1,3-dimethyl-6-~3-(~-nitrobenzylamino)Dr.)~yl-amino)]-2,~(1H,3H)-p~rimidinedione . 1,3-dimethyl-6-[4-(4-nittlobenzyl)piperazin-1-yl]-2,~(1H,3H)-pyrimidinedione 10. 1,3-dimethyl-6-[N-propyl-2-;1-nitrobenzylamino)-ethYlamino~-2.4(lH~3H~-pyrimidinedione 11. 1,3-dimethyl-6-[2-~N-ethvl-4-nitr-)benzylamino)-ethylamino)~ llH.3H~-pyl-imidinedione 12. 1,3-dimethyl-6-~-[~ 2-hYdro-x~ethy~
nitroben7.ylamino~ethylamino'~-2.~1H.3H!-pyrimidinedione 13. 1.3-dimethyl-fi-~2-~J--.~-nitrophenvl)ethylamino~-Z~1389 ethylamino~-2,~(1H,3H)-pyrimidinedione 14. 1,3-dimethyl-6-~3-t2-14-nitrophenyl)eth~laminn~-propylamino}-2,~(1H,3H)-pyrimidinedione 15. 1,3-dimethy]-6-{N-(2-hydroxyethyl)-2-t2-~4-nitrophenyl)ethylamino]ethylamino~-2,~(1H,3H)-pyrimidinedione 16. 1,3-dimethyl-6-~2-tN-ethyl-2-(4-nitrophenYl)-ethylamino]ethylamino~-2~4(1H.3H!-pyrimidinedione, 17. 1.3-dimethyl-Ç-~2-~N-(2-hydroxyethyl)-2-(~-nitro-phenyl)ethylamino]ethylamino~-2,4~1H.3H)-pyrimidinedione 18. 1.3-dimethyl-6-{~-[2-~4-nitl-ophenyl'~ethyl]-piperazin-l-yl~-2.~(IH.3H)-~yrimidinedione 19 . 1, 3-d i methyl -6- ~4- t2- ( 4-ni tl-ophenyl !ethyl ] -hnmopiperazin-l-yl~-2?4(1H,~H)-pyrimidinedinne 20. 1,3-dimethyl-6-~2-[N-~'2-acetoxyethyl)-5-l~-nitl(,-phenyl~ethylamino]ethylamino~-2,~(IH,3H)-pyrimidinedione 21. 1,3-dimethyl-6-{2-~N-1'3-hydroxypropyl)-2-~nitrophenyl)ethY]amino]ethylamino'~-2.~(]H.3H!-pyrimidinedione 22. 1.~-dimethyl-6-~2-~N-~'3-benzoyloxypropyl!-2-(~-nitrophenyl~ethylamino~ethylamino~-2.~(1H.3H)-pyrimidinedlone 23. 1.3-dimethyl-6-~-[2-~3-nitro~henvl~eth piperazin-l-yl ~-2.4~1H.3H!-pYr~ idinedione 2~1389 2~. 1,3-dimethyl-6-{~-~2-~2-nitrophenyl)ethY
piperazin-1-yll-2,1(1H,~H~-pylimidinedione 25. 3-methyl-6-~-t2-(4-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedinne 26. 1-methyl-6-~-t2-(~-nitrophenyl)ethyl~piperazin-I-yl3-2,4(1H,3H~-pyrimidinedione 27. 1,3-diethyl-6-~2-[N-~'2-hydroxvethvl)-2-~4-nitrophenyl!ethylaminc~ethylaminc,'~ 'lH.3H~-pyrimidinedione 28. 1.3-diisopropyl-G-~2-rN-~'2-hYdrc,xyethYl!-2-~-nitrophenyl)ethylaminn]ethylamin~ IH.3H~-pyrimidinedione 29. 1,3-dimethyl-fi-{2-t3-(4-nitr-)phenyl~propylamino~-ethylamino~-2~4(1H.3H)-pyrimidinedione 30. 1,3-dimethyl-6-~3-~3-(~-nitroDhenyl)proipylamino]-propylamino~-2.4(1H.3H)-pyrimidlnedione 31. 1,3-dimethyl-6-{N-methyl-2-t3-(~-nitrophenyl)-propylamino~ethylamino'~ ('lH.3H)-pyrimidinedione 3~. l,3-dimethyl-~-{~-ethyl-~-~3-~-nitro~henYl)-propy]amino~ethylamino~ (1H.3H!-pyrimidinedione 33. I,3-dimethyl-fi-i~'-pro~yl-~-t3-~-nitriphenvl)-propylamino~ethylamin-,~ ]H.3H!-pyrimidinedi-Jne 3~. I.3-dimethyl-fi-~N-~3-hYdro-x~ethVl~-'-t3-~-nitrophenyl?propylamln~ ethylamincl~ (lH~3H?-pyrlmidinedion~
3~. I,3-dimethyl-6-~N-~ hYdroxypl~-3py~ - t3- ( ~-2~1~1389 nitr~iphenyl)propylamino]ethylamino~-7,~IH.3H~-pylimidinedione 36. I~3-dimethyl-6-{N-(~2-hydroxy-I-methylethyl~-2-t3-(4-nitrophenyl)prnpylamino~ethylamino~-~7,4-(IHs3H)-pyrimidinedione 3~. 1,3-dimethyl-6-~N-~2-acetoxyethyl)-2-[3-(~- -nitrnr3henyl)r3ropylamino~ethylamino'~-2.~-~IH.3H~-pyrimidinedione 38. 1.3-dimethyl-6-{~-methoxycarbonylmethyl-2-t3-~l-nitrophenyl~proDylamino~eth~lamln~-2.1~lH.3H!-pyrimidinedione 39. I,3-dimethyl-6-{~-''2-phenylethyl)-2-~3-'~-nitro-phenyl)pl~opylamino]ethylamino~-2,4-(1H,3H)-pyrimidinedi~ne 40. 3,3-dimethyl-6-~2-~N-methy]-3-~-nitrophenyl)-propylamino]ethylamino~-2,~1H,3H~-pyrimidinedi(lne ~1. 1,3-dimethyl-6-{2-<N'-ethyl-N-t3-~-nitror3henyl!-propyl]amino>ethylamino~-2,~('IH.3H)-pyrimidinedi-3ne ~'7. 113-dimethyl-6-~2-[N-propyl-3-~4-nitl~oDhenyl~-propylaminr33ethylamin-3~-2.~1H.3H)--7yrimidinedil~ne ~3. 1.3-dimethyl-6-~- r~- (l-meth~]ethyl!-3-(~-nitrophenyl)propylamlnolethylamino'~ lHt3H)-pyrimidinedi-ne . 1,3-dimethyl-~ -tN-butyl-3-'4-nitrophenyl)-propylamino~ethvlamin()l-~ '2.~(1H.3H)-pyrimidinedi-~ne 20~1389 , 5 15. 1,3-dimethyl-fi-~2-t~ tert-butyl~-3(~-nitrnphenyl)-propylamino]ethylamino~ ,1(1H,3H~-pyrimidinedione ~6. 1,3-dimethyl-6-{2-<N-(2-hydroxyethyl)-N-[3-~nitrophenyl)pl-cpyl~amino>ethy1amina~-2.4(~H~3H~-pyrimidinedione 4~ . 1 ,3-dimethyl-6-~ ~-rN-~3-hydl-oxypr~pyl !-3-(~-nitrophen~l)propylamino]ethylaminll~-2~/1H.3H)-pyrimidinedione . 1.3-dimethyl-6-~'2-[N-.~-hv~roxy-l-meth~lethyl)-3-('4-nitrophenyllplopylamina~ethyl~mino'~
~~1H,3H)-~yrimidinedione ~9. 1.3-dimethyl-6-~-[~-(2-hydroxypropyl--3-('4-nitrophenyl)pro~ylamino]ethylamino}-2.~(1H.3H'-pyrimidinedione 5~. 1,3-dimethyl-6-~2-~ -hydroxybutyl)-3-(~-nitrophenyl)propylamincl~ethylamino'~ lH.3h' -pyrimidinedione 51. 1,3-dimethyl-6-~ -acetoxyethylj-3-~.l-nitl-o-pheny]!~ropylamino]ethylamin-J'~-2~1H.3H~-pyrimidinedi.-,n~
. 1.3-dimethYl-6-~ N-(2-f~llmylc!x'~ t~lyl !-;~-~4-nitronhenyl~ranylamino]ethylamino~-~J.~(lH.3H)-pyrimidinedione ~3. 1.~-dimethyl-6-~-[N-(2-~ropionylaxyethyl)-3-'~-nitrophenvl )pr(pylamina~ethylamincl~-J.~IH,3H!-pyrimidinedinne 2~1389 .~4. 1 3-dimethyl-6-~-[N-(2-isobutyryldxyethyl3-3 ~-nitrophenyl~propylamino~ethylamino~-2.4(IH 3H'-pyrimidinedione ~5. I 3-dimethyl-6-~2-[N-(2-pival~yloxyethyl~ (4-nitrophenyl)propylaminn]ethylamino~-2 ~(lH.3H~-pyrimidinedione 56. 1.3-dimethyl-6-~2-~N-~2-acetoxypr~pyl)-3-(4-nitrophenyl)propylamino3ethylaminc~ .4(lH~3H!
pyrimidinedi-ne 57. 1 3-dimethyl-6-~2-tN-.2-acetoxy-1-methylethyl)-3-(4-nitrophenyl~propylamino~ethylamino~-2.~(IH.3H)-pyrimidinedione 58. ] 3-dimethyl-6-~-tN-~2-benzoyloxyethyl)-3-(4-nitrophenyl)propy1amino]ethylamino~-2 1(1H.~H~-pyrimidinedione ~9. l,3-d.imethyl-t~-{2-<~ -('4-fluo~ benzovlnxY~-ethyl]-3-(~-nitrophenyl-pro~ylamincl>ethylamirlol-~.4'1H,3H)-pvrimidinedion-?
fiO. I~3-dimethYl-fi-~-<N-[2(4-methoxybenzoylf!xy!eth~l3 3- 4-nitl-oDhen~ propylaminl)~ethvlamino~-2.~(IH.3H~-pylimi~inedi-1ne 61. l.3-dimethyl-fi-~2-<N-~ hlorobenzoyloxv)ethyl ]-3-(~-nitroDhenyl~pl~cpylamino>ethylamino~-2.4-~1H 3H)-pyrimid.inedione G2. I 3-dimethyl-6-~2-<N-[2-(3~-dimethoxybenzoyloxY!-ethyl~-3-(~-nitrophenyl)prnpylamino>ethylamin-~-Xg~13~39 2,4(1H,3H)-pyrimidinedione 63. 1,3-dimethYl-6-~2-<N-[2-~3~4-dibromobenzoyloxy)-ethyl~-3-(4-nitrophenyl)propylamino>ethylamino~- -2,1(1H,3H)-pyrimidinedione 6~. 1,3-dimethyl-6-{2-tN-(2-methoxyethyl)-3-(~-nitrophenyl)propylamino]ethylamino~-2.4(1H.3Hl-pyrimidinedione 63 . 1,3-dimethyl-6-~ '-(2-propyloxyethyli-3-~-nitrophenyl~propylamino]ethylamino'~-2,4~'1H.3H~-pyrimidinedidne 66. 1,3-dimethyl-6-~-[h~-benzYl-3-(~4-nitJophenYl' propylamino~ethylamino~-~,4~1H~3H~-pyrimidinedione 67. 1,3-dimethyl-6-~2-~-(4-methoxybenzyl)-3-(~-nitro-phenyl~propylamino~ethylamino~-2,4tlH,3H)-pyrimidinedione fi8. 1,3-dimethyl-6-~2-[N-(3.1.~-trimethoxybenzyli-3-(4-nitrophenyl)prflpylamino~ethylamino~-2.4~lH.3H~-pyrimidined.inne 69. l.3-dimethyl-6-{,-rN-( r -chloroben,vl ! -;i- ~ ~-nitrophenyl)proDylamindlethylamino'~ lH.3H~-pyl~imidined~one 7(). 1.3-dimethyl-6-~2-~ henylethyl)-3-/l-nitrf.~phenyl )prnpylamino]ethylaminn~-2.~(1H.3H)-pyrimidinedione 71 1,3-dimethyl-6-~2-rN-vinyl-3-~'l-nitl-nphenyl)-propylamino]ethylamino~-2,~(1H.3H)-pyrimidinedione 72. 1~3-dimethyl-6-~2-rN-allYl-3-~4-nitrophenyl !-propylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione 73. l,3-dimethyl-6-{2-t~-propar~Yl-3-(4-nitrophenyl ! -propylamino]ethylamino~-2.~1H.3H~-pyrimidinedi~ne 7~ 3-dimethyl-6-~2-[N-etho~ycarb~n~lmethyl-~-(l- -nitrophenyl)propylamino]ethylamino~-2.~IH.3H)-p~rimidinedione 5. l,3-dimethYl-~-t2-~N-tert-but~xycal-bonylmethyl-3-(4-nitrophenyl)propylamino~ethylamino~-~.4(lH.3H~-pyrinidinedinne 76. 1,3-dimethyl-6-t2-[N-~2-methoxycarbonylethyl)-3-(~-nitrophenyl~propylamino~ethylamino~-2,411Hl3H)-.. .
pyrimidinedione 7I. ],3-dimethyl-6-tN-methy]-2-tN-methyl-3-(~-nitrophenyl~propylamino]ethylaminn~-2,i(1H.3H~-pyrimidinedione 78. 1,3-dimethyl-6-tN-ethyl-2~N-''2-hydr~xYethyli-3-(~-nitl-ophenyl3prc~pylamin~1~ethylamino}
~IH,3H3-Dyrimidinedi~-)ne 7~. l.3-dimethyl-6-t2-<~-ethy~ 3-(;~-nitrophenvl)-pr~lpyl]aminn>ethylamin-!~-2.~;H.3Hl-pyrimidinedione 80. 1,3-dimethYI-~-~'2-~N-methnxycatbnnvl-3--~-nitl-ophenYl)Dl-opylamino~ethylamino~-2 (IH,3H)-pylimidinedione 81. 1,3-dimethyl-6-i2-[N-~tert-butoxycarbonyl)-3-(4-nitrophenyl)propylamino]ethylamino~-~.1-(IH.3H)-pyrimidinedione 82. l,3-dimethyl-6-~2-<N-~2-('N-methylamino?ethyl]-3-(4-nitrophenyl)propylamino>ethylaminQ~-2.~-(lH,3H)-py~imidinedione 83. 1~3-dimethyl-6-~2-~r~-t2-(N.N-dimethyl~mino)ethvl]
3-(4-nitrophenyl')propylamino~ethylamino'~-7.~-~IH.3H)-pyrimidinedione 8~. 1,3-dimethyl-6-{~-<N-t2-(N.N-diethylamino)-ethyl3-3-(2-nitrophenyl'~propylamino>ethyl-amino~-2,4(1H,~H)-pyrimidinedinne 85. 1,3-dimethyl-6-{-7-rN-(2-hydroxyethyl~-3-s7-nitrophenyl)propylamino~ethylamino'~-2,~1H.3H)-pyrimidinedione 86. 1,3-dimethyl-6-{~-[3-(~-nitrophenyl)pl-opyl~-piperazin-l-yl'~-2.~slH.3H)-pyrimidinedinne 8~. l,3-dimeth~rl-6-~-t3-(1-nitroDheny]~pl-op~
homopiperazin-l-yl~-2.~1lH.3H)-pyrimidlnedione 88. 3-methyl-6-~-r~ -nitl-ophenyl~pl-opyll-~ipera7in-l-vl'~-2.~(1H.3H)-pvrlmidinedlone 89. 1-propyl-6-{2-tN-~2-hydroxyethyl?-3-(~-nitrophenyl)propylamino]ethylamino~-2.~-(lH,3H)-pyrimidinedione 9~. 6-~2-tN-ethyl-3-(~-nitrophenyl)propylamino]-ethylamino~-].3,3-tl-imethyl-'~ ~lH,3H'~-2~2~-89 pynimidinedione 91. 6-{2-[N-(2-hydroxYethy~ nitrophenyl~-- proprlamino3eth~1amino~-].3.~-trimethyl-~.4-(lH.3H)-pyrimidinedione 92. 1.3-dimethy]-6-~?-[~'-(ethyl-3-('4-nitrophenyl!-proDylamino3ethylamino~-5-nltro-2.~(lH.3H)-pyrimidinedione 93. 1.3-dimethYl-6-{2-~-(Z-hYdroxyethyl)-3-~4-nitrophenyl~propylamino]ethylamino~-5-nitro-2,4(1H,3H~-pyrimidinedione 9~. 1,3-dimethyl-6-{2-~N-~methoxycal-bonylmethyl ! -3- ( 4-nitrophenyl)propylamino]ethylamino3-5-cyano-2,~(1H,3H)-pyrimid.inedione ' 95. 1,3-dimethyl-6-f2-~N-~2-hydroxyethyl)-3-(~-nitrophenyl)propylamino3ethylamino~-v-cyano-2.~(lH.3H)-pyrimidinedi~ne 96. 1.3-dimethyl-6-~2-~ -nitlophenyl!hutylamin~
ethylamino~-2.~1H.3H)-pyrimidin~dione g~. 6-(~i-ethyl-~i<~-[~-(4-nitrophenyl)butylam~no3-ethyl>amino3-1.3-dimethvl-2.~1H.3H,-pyrimidinedione 98. l.3-dimethyl-6-s~'-(2-hydroxyethYl)-2 ~-nitrophen~l)butylamino3ethYlamino~-2.
IlH,3H)-pyrimidinedione 99. l,3-dimethyl-6-~'-methoxycarbonylmethyl-2-~ -nitrophenyl)~utylamino]ethylamino~-2.~'1H.3H!-pyrimidinedione 100. 1.3-dim~thvl-~-~2-[N-ethY~ -nitrophen~
butylamino]ethylamino)-~2.i(~1H~3H!-pyl-imidinedione 101. l,3-dimethyl-6-(2-[N-(tert-butyl)-4-(4-nitrQphenyl)-butylamino~ethylamino~-2~4(lH.3H!-pyl-imidinedinne 102. 1,3-dimethyl-6-~2-[N-i2-hydroxyethyl)-4-(4-nitrophenyl)butylamino~ethylamino'~-2~4(1H,3H)-pyrimidinedione 103. 1,3-dimethyl-6-{2-tN-('3-hrdroxypropyl~-4-~4-nitrophenyl)butylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione 104. 1,3-dimethyl-6-{2-CN-~'2-acetnxyethyl')-4-(4-nitrophenyhl'~butylamino]ethylamino~-2.~(1H.3H!-pyrimidinedione 10~. 1.3-dimethyl-6-~2-[r3-~2-methoxyethy]~-4-(4-nitrnDhenvl)hutylamino~ethylamino'~-7.4tlH.:~H)-pyrimidinedione 106. 1~3-dimethyl-6-~2-tN-benzyl-4-(4-nitr-~)phen-il~-butylamino]ethylamino~-2~4~1H~3H!-pyrimidinedione 107. 1,3-dimethyl-6-~2-rl~-allyl-4-('4-nitrophenyl)-butylamino]ethylamino~-2,4<'IH,3H)-pyrimidinedione 108. 1,3-dimethyl-6-~2-[N-ethoxycarbonylmethyl-4-(4-nitrophenyl)blltylamino]ethylamino~-2.4-(IH,3H)-pyrimidinedi-~ne 109 . I .3-dimethYl-6-~i-methyl-2-tN-methy~
nitr~phenyl!butylamino~ethyl~mino~ .4-slH~3H)-pyrimidinedione 1l~). 1,3-dimethyl-6-{2-CN-t~-('N.~-d iethylamino~ethyl~-4-(4-nitrophenyl)butylamino>ethylamino~-2.4(IH~3H)-pyrimidinedione 111. 1,3-dimethyl-6-{4-t4-(4-nitrophenyl')butyl]-piperazin-l-yl~-2,4(1H,3H)-pyrimidinedione 112. 6-{2-tN-ethyl-4-14-nitrophenyl)butylamino]-ethylamino~-1,3,5-tlimethyl-2,4(1H,3H~-pyrimidinedione 113. 1,3-dimethyl-6-(2-t2-('4-nitrophenoxy!-ethylamino]ethylamino-~.~(IH.3H)-pyrimidinedione . l,3-dimethyl-6-~-ethyl-~-t2-(~-nitroiphenoxy~-ethylamino~ethylamino'~-2.4t;H~3H~-pvl-imidinedinne 11~. 1.3-dimethy]-6-t4-t2-(4-nitl-ophenoxy!ethyl3-piperazin-1-vl'~-7~/lH.;lHj-pvrimidinedlone l16. 1.3-dimethyl-6-{2-[3-(~-nltroDhenox~!propYl-amino]ethylamino~-2~/lH,3H~-pyrimidinedione 11/. 1,3-dimethyl-6-~ thyl- -t3-~4-nitroPhen~xv ! -propylamino]ethylamino~-2,~l1H,3H~-pyrimidinedione 118. 1,3-dimethyl-6-{2-tN-ethyl-3-(~-nitrophenoxy)-propylamino]ethylamino~ (lH,3H)-pyrimidinedione 119. 1,3-dimethyl-6-{2-[.N-(2-hydroxyethyl)-3-(4-nitrophenoxy)~ropYlamino]ethylaminh~-2~ H~3H) pyrimidinedione -Z~1389 -?(~ dimethvl-6-~ J-~c~t~ xY~thyl ~
nitrophen(xy~propylamino~thYlamin("-J ~;IH.1H!-pyrimidinedione 121. 1.3-dimethyl-6-~N-methyl-2-[N-methyl-3-~-nitrophenoxy~propylamino]ethylamino~-2.~(IH,3H)-pyrimidinedione 122. I,3-dimethyl-6-~-t3-~4-nitrophenboxy)proeyl]-piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione 123. 3-methyl-6-{~-[3-(4-nitrophenoxy)propyl]-piperazin-1-yl~-2,~(1H.-3H)-pyrimidinedjone 12~. 1,3-dimethyl-6-~4-[3-('3-nitrophenoxy)propyl~-piperazin-l-yl~-,.4~1H.3H!-~yrimidinedione 125. 1.3-dimethyl-6-~4-~3-~2-nitrophenoxY~propyl]-piperazin-l-~ -2.~(1H,~ -pyrimldlnedione I26. 1.3-dimethyl-6-~2-~t-~-nitrophennxy)bllt l~mino3 ethylalr,ino~-c.~(~]H~3H!-pyrilr,idine(iione 127. 1.3-dimethyl-~-~N'-methyl-2~N-methvl-~-(~-nitrophenoxy!buty]aminc!~ethvlaminc~ 5~(1H.3H~-pyrimidinedione 128. 1,3-dimethyl-6-{~-~4-(4-nitrophenoxv~butyl~-piperazin-I-yl~-2,~(IH,3H)-pyrimidinedione 129. ~,3-dimethyl-6-~2-[N-ethyl-2-(4-nitr-)phenylthic~-ethylamino]ethylamino'~-2,~(IH,3H)-pyrimidinedione 130. 1,3-dimethyl-6-~2-~N-(2-hYdrox~ethyl)-3-l~-nitrophenylthio)proDylamino]ethylamino~-2.~-~H..~H~-pyrimidinedione Z~ 89 131. 1,~-dimethyl-6-i4-[3-~4-nitl-o~henYlthio)DIop~l]-piperazin-l-yl~-2,~1H.3H'-pyrimidinedinne 132. 1.3-dimethyl-6-{N-methyl-'~-t~i-methvl-~-(4-nitrophenylthioibutylamino]ethYl~min 2,~( 1H.3H~-pyrimid.inedinne 133. 1,3-dimethy]-6-t~-(4-nitrophenacyl)piperazin-1-y1~- -2,~(1H,3H)-pyrimidinedi d ne 134. 1,3-dimethyl-6-~-r5-~4-nitrobenzoyl~ethyl]-Diperazin-1-yl~ (lH,3H)-pYrimidinedione 135. 1,3-dimethyl-6-{N-methyl-5- tN-methYl-4-(4-nitrophenylthio~butylamino]ethvlaminn~-2.4-(lH,3H)-pyrimidinedione 136. 1,3-dimethyl-6-{4-t.5-hydroxy-2-(~-nitrophenyl)-ethyl]piperazin-l-yl~-2,~1H.3H~-pyrimidinedione 13~. 1,3-dimethyl-6-{1-t2--~-nitrnbenzoyl.~xy~ethvl3-piperazin-l-yl3-2.~(1H~3H~-p~l~imidinedione 138. 1,3-dimethyl-fi-~2-[N-ethvl-~ -nitrQbenzoylnxy)-propylamino~ethylamin~ .4(~H~3H?-pyl-in,idinedinne 139. 1.3-dimethyl-6-t2-~-ni t ioben~o~laminn)-ethylaminn~-2.4~1H.;~H ! -p~rimidinedione 140. 1,3-dimethyl-6-{4-[~-~4-nitrobenzoylaminoi-ethy]~piperazin-1-yl~-2.4('1H.3H)-pyrimidinedione 1~1. 1,3-dimethyl-6-~4-tN-~4-nitroDhenyl)carbamoyl-methyl~piperazin-1-yl}-2 4(1H,3H)-pyrimidinedione 142. 1,3-dimethyl-fi-{4-t~-(4-nitrophenyl~-carhamoylethyl~homopipel-azin-1-yl~ (lH.3H!-ZCli~)~3~9 pvrimidinedione 1~3. 1,3-dimethyl-~ -[3-~-nitroanilino~-2-hydroxypropyl~piperazin-1-yl~-2.4(1H.3H!-pyrimidinedione ]44. ~,3-dimethyl-6-~4-<4-tN-(~-nitrophenyl)-carbamoyl]butyl>piperazin-l-yl~-2,~(lH.3H)- -pyrimidinedione 145. 1,3-dimethyl-6-~N-methyl-2-[N-methyl-2-(4-nitroanilino)ethylamino~ethylamino~-2.~(1H,3H)-pyrimidinedione 146. 1 ,-.~-dimethyl-6-~ lethyl-'~-rN-~2-hyd~ xyet~yl !-2-~-nitroanillno~ethvlamino]ethylamin 2.4~1H.3H)-pyrimidinedic~ne -; li7. 1.3-dimethyl-6-~-[~-eth 1-2-~-nitroanilino)-ethylaminc~ethylamin-,i-2.4~1H.3H!-p.vrimidinedi-,ne l~x. 1,3-dimethyl-6-~.3-[N-propyl-2-1~-nitroanilino'j-ethylamino~propylamincl}-2.4~1H.3H~-pyrimidinediclne 1~9. 1,3-dimethyl-6-~-methvl-2-[~'-methyl-2-(N-methyl-4-nitroanilino)ethy]aminc]ethylamino'~-- 2,~11H,3H)-pyrimidinedione 15~ 3-dimethyl-6-~N-methYl-3-tN-methyl-2-(4-nitroanilino')ethylamino~propylamino~-2,~-(1H,3H)-pyrimidinedione 151. 1,3-dimethyl-6-~2-t.N-ethYl-3-~-nitroanilino)-propylamino]ethYlamino~-2~ H.;:;Hl-ovl imidinedi-~ne 1.-,2. 1.3-dimethyl-fi-~2-[.N-~2-hdvrox-~ethyl~-;3~
2~3~1389 nitroanilino)propylamino]propylamino~-2.4(1H.3H)-pyl-imidinedione 1.~3. 1,3-dimethyl-6-{2-tN-methoxycarbonylmethyl-3-(4-nitroanilino)propylamino~ethYlamino~-2~4(lH~3H!
pyrimidinedione 154. '1,3-dimethyl-6-~4-[3-(4-nitroanilino')propyl]- --piperazin-l-yl~-2,4('1H,3H)-pyrimidinedione 15~. 1,3-dimethyl-6-{4-t3-(N-methyl-4-nitroanilino~-propyl]piperazin-1-yl~-2,4(1H,3H~-pyrimidinedione 156. 1,3-dimethyl-6-{4-t3-(N-propyl-4-nitroanilinc~-propyl]piperazin-l-yl)-~s4(IH,3H)-pyrimid.inedione 1~. 1,3-dimethyl-6-{4-[3-('N-methanesulfonyl-4-nitro-anilino~propyl]piperazin-l-Yl~-2~4(lH~3H) pyrimidinedione 1~8. 1.3-dimethyl-6-~4-[3-iN-ethaneslllfonYl-4-nitroanilinn'.~Dropyl]piperazin-1-vl-~-2.~(1H.3H!-pyrimidinedione 1~. l,3-dim~thyl-6-~-t3-(N-acetyl-~-nitroanilino!-propyl]piperazin-1-yl~-~.4~1H.3H)-pyl-imidinedione 160. I,3-d.imethyl-6-~4-[3-lN-propionyl-~-nitroanilino)-propyl~piperazin-l-yl~-2,4('1Ht3H3-pyrimidinedic)ne Ifil. 1,3-dimethyl-6-~2-<[1-(4-nitrophenyl)piperidine-~-yl ]amino>ethylamino~-2,4('1H,~H)-pyl-imidinedione 162 1,3-dimethyl-6-~.2-t4-(~-nitrophenylJpiperazin-]-yl ]eth,vlamino~-2,~(1H.3H!-Dyrimidinedione - 2~13~39 163. 1,3-dimethYl-6-{3-[~ -nitr()Dhenyl)piperazin yl ]propylamino~-2,4(1H,3H3-pYrimidinedione 164. 1,3-dimethyl-6-~N-(2-hydroxyethyl)-~(4-nitrophenyl)piperazin-1-yl~-ethylamino~-2,4(1H,3H)-pyrimidinedione 165. 1,3-dimethyl-6-~N-methyl-2-[4-(~-nitroDhenyl)-piperazin-l-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione 166. 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrnphenyl)-propyl]piperazin-1-yl~-2.~]H.3H)-~Yrimidinedic!ne I67. 1~3-dlmethyl-6-~-tN-eth~ -benz~vl-i-nitrnphenyl!ethylamino~ethylaminoJ-2~4(1H,3H!-pyrimidinedione 168. 1,3-dimethyl-6-t4-(3-acetyl-1-nitroiDhenyl~-piperazin-l-yl]-~2,J~lH,3H~-pyrimidinedione 169. 1,3-dimethyl-6-{4-t1-~-acetyl-~-nitrophenoxy)-butyl]piperazin-l-yl~-2,i~lH,3H)-~yrimidinedione 170. 1-methyl-6-~4-[3-(2-acetyl-4-nitrophenoxy~-propyl]piperazin-l-yl~-2,~(1H,3H~-pyrimidinedione 1~1. 1,3-dimethyl-6-{~-<3-t2-nitro-4-( -pyridinecarbonyl)phennxy]propyl>piperazin-l-yl~-2.~1H.3H!-pyrimidinedi~ne 172. 1.3-dimethyl-6-(~-[N-~2-hdvrnxyethyl)-3-~4-benzoyl-2-nitl-~phenoxy~pl(lpyl~min(~
ethylamin~-2.~1H.3H)-Dvrimidinedlnne 173. 1 3-dimethyl-6-~-[3-~ cetYi-~-nitroanilin 2~13~39 propyl]piperazin-l-yl}-2,~(1H.3H)-pyrimidinedione 174. 1,3-dimethyl-6-{~-~3-('2-cyclopentanecarbonyl-4-nitroanilino)propyl]piperazin-l-yl~-2.~(1H,3H)-pyrimidinedione 175~ 1,3-dimethyl-6-~4-<3-~2-~2-chlorobenzoyl)-4-nitroanilino]propyl>piperazin-1-yl~-~.4- -(IH,3H)-pyrimidinedione 176. 1.3-dimethyl-6-~4-<3-[2-(~-~yridinecarbonyl !-4-nitroanilino~propyl>piperazin-l-yl~-2~ H.3H) pyrimidinedione 1~7. 1.3-dimethyl-6-~4-<3-~2-'~-pvridinecarb~nyl)-4-nitroanilino3propyl>pipel-azin-1-vl~-2,~1H,3H)-pyrimidinedione 1~8~ 1,3-dimethyl-6-~4-[3-14-acetyl-~-nitroanilino3-propyl]piperazin-l-yl~-2,~lH.3H)-pYrimidinedione 179. 1,3-dimethyl-6-~4-t3-(4-propanoyl-~-nitroanilino~propyl]piperazin-l-yl'~-2~-(1H,3H)-pyrimidinedione 18~. 1,3-dimethyl-6-~1-t3-~4-benzoyl-2-nitroanilino)-propyl~piperazin-1-yl~-~.1(1H.3H'I-nyl-imidinedione 181. 1,3-dimethyl-6-i~-~3-~'3-acetyl-~-nitroanilino~-propyl]piperazin-l-yl~ (1H.3H~-~yt~imidinedione 182. 1.3-dimethyl-6-~-[3-~-acetyl-~-nitroanilinoj-propylamino~ethylaminc~-2.~(1H.3H;-pvrimidinedione 183. l~3-dimethyl-6-~3-~N-'''-h-~dr-lxvethyl)-3-~-propanoyl-~-nitl-nanilino!nl-nDylamln(~-2~C)1;~89 pro~ylamino~-2.~1H.3H)-Dyrimidinedione l84. l.3-dimethyl-6-~4-t3-(2-ben,oyl-~-nitro~nilino~-propyl]piDerazin-l-yl~-~,4~1H.-3H~-~yrimidinedione 18~. 3-methyl-6-~4-t3-(2-benzoyl-~-ni troani ] ino!-propyl~piperazin-1-yl~-~,451H.3Hl-pyrimidinedione J86. 1t3-dimethyl-6-{N-ethy]-2-t3-(~-fol-myl-~-nitroanilino~propylamino]ethylamino~-2.~1H,3H)-pyrimidinedicne 187. 1,3-dimethyl-6-{~-[3-~3-fluoro-~-nitrophenoxy~-propyl~piperazin-l-yl~-2.~(lH~3H!-pyl-imidinedione 188 . I, 3-dimethyl-~-{~-[3-(3-fluoro-~-nitroanilino)-propy]~piperazin-1-yl~-2,1(1H.3H~-pyrimidinedione 189. 1,3-dimethyl-6-~4-t3-(3,5-difluoro-~-nitroDhenoxy)-; propyl]piperazin-l-yl~-2,~1H.3H)-pyrimidinedione 190. It3-dimethyl-6-~4-[3-~3.5-difluol-(?-~-nitr-lanilino)-propyl~niperazin-]-yli-2.~1H.3H~-D~.t~ ]dinedione 191. 1.3-dimethyl-6-~-t3~ -fluorn-~-nltroanilino~-propyl~piperazin-l-yl~-2.~(lH.~H!-Dyl-imidinedione 19~. 1,3-dimethyl-6-1~-[3-~2-methl-1xy-~-ni troDhenoxy~-propylamino~ethylamino~-2.~1H.3H.-Dyl-imidinedione 193. 1.3-dimethyl-6-~3-[~-ethyl-3-(3-tl-ifluoromethyl-~-nitroanilino)propylamino~pl-opylamino~-2~4(lH.3H) pyrimidinedione 194. ~,3-dimethyl-6-~2-t4-(2-acetyloxy-4-nitro-phenoxy)butylamino]ethylamino~ (IH,3H)-pyrimidinedione 2~)1389 195. 1,3-dimethyl-6-{4-~3-(2-dimethylamino-~-nitroanilino)propyl~homopiperazin-1-yl}-2,~(1H,3H)-pyrimidinedione 196. ],3-dimethyl-6-~2-[2-(2-diethylamino-4-nit anilino)ethylamino]ethylamino~-2,4(lH,3H)-pyrimidinedione 197. 3-methyl-6-~2-[3-~'2-hydroxy-4-nitrophenoxy)-propylamino~ethylamino~-2~4~1H,3H?-pyrimidinedione 1~8. l-ethYl-6-i4-[3-(2-brtmo-~-nitroanilino !-propyl~piperazin-1-yl~ 1H.3H)-pyrimidinedione I99. 6-{4-[2-{2-ethyl-~-nitroanilino)ethylamino]-piperazin-1-yl~-5,~1H,3H)-pyrimidinedione 200. 1,3-dimethyl-6-{~-[N-t3-fllloro-4-nitroiphenyl)-carbamoylmelthyl~piperazin-l-yl'~-2,4(1H,3H)--pyrimidinedione 1. I,3-dimethyl-6-{2-[3-t~-ethoxy-~-nitroDhenylthio~-propylamino~ethylamino}-2,~(1H.~H ! -pyl- i diminediorle . I,3-dimethyl-6-i~-t3-'2-ethaneslllfonamldo-4-nitrophenox~)propyl3piperazin-~-yl'~ -(1H.3H?-~yrimidinedione 203. 1,3-dimethyl-6-i4-[2-~'3-fluolc!-~-nitrophenYl~-ethyl]piperazin-l-yI'~ tlH.3H)-pyrimidinedione 20~. 1,3-dimethyl-6-~2-[N-ethyl-3-(3-fluoro-~-nitrophenyl)propYlamino]ethylamino}-~
2~8~389 ('lH.3H!-pyrimidinedione 205. 1.3-dimethYl-~-f3-~N-~?-hvdr-~xyethyl3-~-~3..~-dif]uaro-~-nitronhenyl!pl-opylamino~-propylamino~-2.~lH.3H)-pvrimidinedione 206. l.3-dimethyl-6-~2-rN-(~?-acetoxyethrl~-3-(2-dimethylamino-~-nitrophenyl)propylamino]-ethylamino~-2,4(1H,3H)-oyrimidinedione 207. 1,3-dimethyl-6-{2-[N-ethyl-3-~2-ethoxy-~-nitrnphenyl)propylamino]ethylamino}-2,4-(lH,3H)-pyrimidinedione 208. 1,3-dimethyl-6-~3- rN- (2-acetyloxrethyl !-3-(2-ethanesulfonamido-~-nitrophenyl)-proDylamino]proDylamino~-2.~(lH.3H~-pyrimidinedione .~
2~9. l,3-dimethyl-6-~ 3-methyl-~-nitrnbenzyl)-piperazin-1-y]]-2.~(1H.3H~-Dyl-imidinedione 210. 1,3-dimethyl-6-~J-[~ -hy~roxyethv~ /3-methoxy-~-nitrophen~ pl-oDYl~min~]ethylamino~-2,4-(lH,3H)-pyrimidinedione 21~. 1.3-dimethyl-6-~2-t.~-(3-ben~oyloxypl-opyl~-3-(2-ethoxycarbonyl-~-nitrophenyl;propylamino]-ethylamino~-2,~(~H ! 3H)-pyrimidinedione 212. 1,3-dimethyl-6-~-[3-(2-acetyl-~-nitrophenoxy)-propyl]piperazin-l-yl~-2,i~H.3H)-prrimidinedione 213. 1,3-dimethyl-6-~-[3-(~-acetyl-2-nitrophenoxy)-propyl~pipera7jn-1-yl}-2,~(1H,3H~-pyl-imidinedi~ne 21~. 1,3-dimethy~ -[3-~-benzoYl-?-nitrdphenoxyj-2(~ 9 pl'ODyl ]pipel-azin-l-YI~-2.~' lH.;3H~-plrrimi-linedillne 21~. 1.3-dimethyl-6-i~-[3-13-acetyl-4-nitl-ophen-xy~-propyl]piperazin-1-vl)-2.4(1H.3H)-pyrimidinedione 216. 1,3-dimethyl-6-~4-[3-~2-benzoy]-4-nitrophenoxy!-propyl]piperazin-l-yl~-2.~(1H,3H~-pyrimidinedione 217. 1,3-dimethyl-6-~4-<3-[2-(4-bromobenzoyl~-4-nitrophenoxy]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione 218. 1,3-dimethyl-6-{4-<3-t2-(3-pyrazolylcarbonyl)-4-nitrophenoxy]propyl>piperazin-l-yl~-2,4(1H.3H)-pyrimidinedione 2~9. 1,3-dimethy]-6-~-<3-[2-(;!-pyridineCalbonyl !-1-nitrophenboxy]propyl>piperazin-l-yl~ i lH.3H)-pyrimidinedione 220. 1,3-dimethyl-fi-~-<3-t2-t3-pvridinecalbon~ -4-nitrophenoxy~propyl>piperazin-l-yl~-2.~(1H 3H)-pyrimidinedione 221. l,3-dimethyl-6-~4-<3-tJ-(4-Dyridinecal-bonYli-4-nitrophenoxy]propyl>piperazin-1-yl~- ,4-(1H,3H~-pyrimidinedione 222. 1,3-dimethyl-6-~-<3-t2-(2-pyrimidinylcarhnnyl)-4-nitrophenoxy~propyl>piperazin-1-ylt-2.~ ,3H)-pyrimidinedione 223. 1,3-dimethyl-6-~-[2-(2-acetyl-4-nitrovhenoxy!-ethyl]piperazin-1-yl~-2,411H,3H)-pyrimidinedione 22~. 1,3-dimethyl-6-~-t -(2-benzoyl-4-nitloph~noxy~-26~11389 ethyl]piDel-azine-l.-vl'~-2.~1,H.3H)-pvl-imi(linedione 22~ . 1 . 3-d i me thyl -fi- ~ ~-< 2- [2- ( 4-bl ~lm~)henzoyl ! -~-nitrophenoxy~ethyl>piperazin-l-yl~ lH.3H)-pyrimidinedione 226. 1,3-dimethyl-6-~-[2-(3-acetyl-~-nitrophenyl)-ethyl~piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione 227. 1,3-dimethyl-6-{4-~2-~2-nitro-4-acetyl)ethyl]-piperazin-]-yl3-2,4('~H,3H)-pyrimidinedi~ne 228. 1,3-dimethyl-fi-14-t2-('2-nitro-4-benzoyl)-ethyl~piperazin-1-yl~-2,i(1 Hl 3H3-pyrimidinedione 229. 1,3-dimethyl-6~ 3-~2-(2-hydroxybenzoyl)-4-nitrophenox~propyl>r3ipe3-azin-l-yl~-2.4( IH. 3H'-pyrimidinedione 230. 1.3-dimethyl-6-~'4-<3-C2-(2-chlorobenzoyl)-4-nitrophenoxy]prop~l>piperazin-l-yl~
(lH.3H~-pvrimldinedlone 231. 1,3-dimethYl-b-~ i-[~-nitro-~pyridinecarbonyl!phenylthic~propyl>plpel-azin-1-yl}-2,1~1H,3H~-pyrimidinedione 23~. 3-methyl-6-~4-t3-~-nitro-2-benz~ylphen~,xy!-propyl]piperazin-l-yl~-2.4~1H,3H)-pyrimidinedione 233. 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitr~phenoxY~-propylamino~ethylamino~-2,1(1H,3H)-pyrimidinedione 234. 1,3-dimethYI-G-(2-[N-ethYI-~-14-benzc)YI-2-nitr~phenoxy)propylamino]ethYlamino-2 1 IH.3H)-pvl~lmidinedione 2~389 23.~. 1.3-dimethyl-6-f4-~ -benzovl-4-nitll-,phenylthi~
ethyl~ipel-azin-l-yl~-2.~1H.3H!-pyrimidinedi~ne 236. 1,3-dimethyl-6-~4-('2-benzoyl-4-nitrophenyl~-piperazin-]-yl]-2,4(1H,3H)-pyrimidinedione 237. l~3-dimethyl-6-~3-~-nitro-2-(3-pyridinecarbonyl)-phenylamino]propylamino~-2,4(1H,3H)-pyrimidinedi~ne 238. 1,3-dimethyl-6-[3-(2-benzoyl-4-nitrophenylamino)-propylamino~-2,4(1H,3H)-pyrimidinedione 239. 1,3-dimethyl-6-t2-~2-benzoyl-4-nitrophenylamino'~-ethylamino]-5,4(1H,3H!-~yrimidinedione 2~0. 1.3-dimethyl-6-~'2-[1-nitro-2-~3-pyridinecarbonyl)-phenylamino]ethylamino~-2.4(1H.3H!-pyrilrlidinedione 241. 1.3-dimethyl-6-~ 2-benzoYI-4-nitro~henyl!-ethyl3piperazin-1-yl~-2.4(1H.3H!-pyrimidinedirne 242. 1,~.j-dimethyl-6-s~-[r'2-ben~oyl-4-nitrophenyl)-methyl]piperazin-l-yl~-2,4(1H.3H~-pyl~imidinedione 243. 1,3-dimethyl-6-{2-~5'2-benzoyl-4-nitrnphenyl)-methylamino]ethylamino~-2,~(lH,3H)-pyrimidinedione 24~ -dimethyl-6-{4-~3-('~-benzoyl-~-nitrophenyl;-propyl]piperazin-1-yl~-2,4(1H.3H)-pyrimidinedione 245. 1,3-dimethyl-6-{4-t2-~'4-benzoyl-2-nitrophenyl)-ethyl]piperazin-l-yl~-2,4~'1H.3H)-pvlimidinedione 246. 1,3-dimethyl-6-{4-~3-(3-methyl-4-nitro~henyloxYl-propyl]piperazin-l-yl~-2.4(lH.3H~-pyl-imidinedione 247. 1.3-dimethyl-6-s'~-~3-(~-chloro-~-nitrsJphenvloxv)-propyl ~piperazin-l-Yl ~-2.4~1H.3H!-D~;rimidlne~ione -X(~
?~8. 1,3-dimethyl-6-~4-t3-t:2-chlor~ -nitro-phenyloxy)propyl]piperazin-l-~l}-2,4~1H.3H~-pyrimidinedione 249. 1,3-dimethyl-6-~4-t3-(4-methanesulfonamido-~-nitrophenyloxy)propyl~piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione 250. 1,3-dimethyl-6-~4-t3-(4-acetamido-2-nitro-phenyloxy)propyl]piperazin-l-yl~-~.4(1H.3H)-pyrimidinedione 251. 1,3-dimethyl-6-{4-[3-(2-hYdroxY-~-nitro-phenyloxy)propyl]piperazin- 1-YI ~ -2 . ~ ( I H. 3H) -pyrimidinedione 252. 1~3-dimethyl-6-~-[3-(2-allyloxy-5-nitro- ,--phenyloxy~pl-opyl]piperazin-1-yl3 -? . ~ lH.3H!-pyrimidinedione 253. 1,3-d.imethyl-6-~4-t3-(~-methylthio- -nitrophenyloxy:3propyl]piperazin-l-yl~-2,4(1H.3H)-pyrimidinedione 2~. I,3-dimethyl-6- {~-<3- t2-(~-hYdroxYbenzyl)-4-nitrophenyloxy]propyl>pipel-azin-1-~2,4(1H,~H)-pyrimidinedione 25~. ],3-dimethyl-6-~-t3-~3-trifluoromethyl-~-nitrophenyloxy)propyl]pipera7in-l-yl~
(1H.3H~-pyrimidinedione ?56. 1,3-dimethyl-6-~-[3-/~-m*thoxyearb/ln~JI-~-nitrophenylxoy!pl-opyl]pipel-aLin-1-yl~-2~11389 -~ lH.3H)-pyrimidinedione 257. 1,3-dimethyl-6-~4-~3-(2-carboxy-~-nitrophenyloxy~propyl~piperazin-I-yl~ IH,3H)-pyrimidinedione 258. 1,3-dimethyl-6-{4-t3-(2-amino-~-nitrophenylxoy~-propyl]piperadin-1-yl3-2,~(1H.3H)-pyrimidinedione 259. 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-~-nitrophenyloxy)propyl]piperazin-1-yl~-2.~(1H,3H~-pyrimidinedione 260. 1.3-dimethyl-6-~4-[3-(2-~yano-~-nitrophenvl--,xyi-prnpyl]piperazin-l-yl}-2,4(1H,3H)-py,imidinedione 261. 1.3-dimethyl-6-i4-t3-(2-cyano-1-nitrophenyiaminol-prr1pyl~pioel-azin-l-yl~-2.4(lH.3H!-pyrlmidinedione 2fi2. 1.3-dimethyl-6-{~-[3-52-chloro-~-nitrophenYl-amino)pl-opyl~piperazin-l-yl~-2.~(1H.3Hi-pyrimidinedione 263. 1,3-dimethyl-6-~ 3-(2-methoxy-5-nitrophenyloxy)-propyl]piperazin-l-yl~ 1H,3H3-pyrimidinedione 264. 1,3-dimethyl-6-~-[3-(2-allyloxy-4-nitro-phenyloxy)propyl~piperazin-]-yl~ IH.3H~-pyrimidinedione ~265. 1,3-dimethyl-6-~4-{3-(2-hydroxy-4-nitrophenyloxY
propyl ~pipel-azin-l-yl ~ (lH. ~1H3-pyrimidinedione 266. 1,3-dimethYl-6-~4-[3-l2-benzylamino-~-nitro~henyloxy~pl-oipyl3pipel~azin-l-~ lH.3H~-D y 1- imidinedione 2~a~1389 267. I,3-dimethyl-6-~ 3-lj-melthoxy-4-nitr-,phenyldxy~-propyl~piperazin-1-yl~-~,4(1H,~H)-pyrimidinedione 268. 1,3-dimethyl-6-~.~-[3-~2,6-dichloro-~-nitrophe-nyloxy)propyl]piperazin-]-yl}-2.~(1H,3H~-pyrimidinedione 2~389 As shown in the general formula (I) above, compounds of the present invention have a basic backbone in which the phenyl and pyrimidinedione parts are linked by a structure comprising mainly an alkyl chain containing at least two nitrogen atoms. This basic back bone structure is believed to be responsible for the pha~maceutical effects.
When the compounds shown by the general formula (1) above were applied to the fol~owing arrhythmia pathological models, all the compounds demonstrated efficacy.
I0 Atrial f ibrillation model Atrial fibrillation model animals were made according to the method of A. L. Goldberger et al. (lnternational lournal of Cardiology, 13, 47-55, 1986) by anesthetizing adult mongrel dogs with pentobarbital sodium (30 mg/kg, intravenously). Using these atrial fibrillation model animals, the effects of the compound5 of the present invention on the a~rial fibrillation model were investigated by administering the compounds intravenously at a dose of 0.1 -10 mg/kg. As a result, all Of the compounds according to the present invention were confirmed to have therapeutic effects on atrial f ibrillation.
Ventricular tachYcardia model Adult mongrel dogs were anesthetized with pentobarbital sodium (30 mg/kg, intravenously). A left thoracotomy was performed in the fourth intercostal space under artificial respiration, and the left anterior descending coronary 28~)1389 artery was ligated at the border of the atrial appendage.
The blood was recirculated for 1~0 minutes after the ligation so that an cardiac infarction lesion was formed to readily induce tachycardia in each animal.
Thereafter, the ventricular tachycardia model animals were made by inducing ventricular tachycardia according to the method of Lynch (~ournal of Cardiovascular Pharmacology, ~, 1132-1141, 1984).
Using these model animals, the compounds of the present invention were confirmed to have therapeutic effects on ventricular tachycardia when administered intravenously at a dose of 0.1 - 3 mg/kg.
The compounds according to the present invention have marked therapeutic effects on the arrhythmia pathology model, i.e. atrial fibrillation model and ventricular tachycardia model; thus they are useful for the treatment and prevention of arrhythmia.
Furthermore~ the effects of the compounds of the present invention on cardiac functions were experimentally investigated and the following results were obtained.
Mongrel dogs (body weights: 8 - 15 kg~ were anesthetized with pentobarbital sodium (30 mg~kg, intravenously~. A microsensor catheter was inserted through the common carotid artery into the left ventricle of each animal so that primary differential values (dp/dt~ of the inner pressure of the left ventricle and electrocardiograms Z~389 were recorded. The compounds of the present invention were administered intravenously to the dogs ~lmg/kg) and changes in the dp/dt and electrocardiograms were investigated.
As a result, it was revealed that the compounds of the present invention significantly increased the values of dp/dt max and significantly extended QTc on the electrocardiograms.
Consequently, the compounds according to the present invention were confirmed to have an antiarrythmic action and particularly to be useful as Class 111 type antiarrythmic agents. Furthermore, the significant increase in dp~dt max demonstrated that the compounds according to the present invention have a positive inotropic action and accordingly they are useful as therapeutic agents for cardiac insufficiency.
As mentioned above, in general, most of patients with arrhythmia have deficiency in cardiac functions. In the case where, for example, antiarrythmic agents classified in Class I or 1l are given to such patients, the greatest care has to be taken for use because these agents exert more or less antiarrythmic action as well as a negative inotropic action ~action to further repress cardiac functions3 (Eivind S. Platous, Journal of Cardiovascular Pharmacology, 8~3), 459, 1986).
On the contrary, as mentioned above~ the compounds according to the present invention t-ave a positive inotropic 2Q~1389 action to significantly increase the dp/dt max, as well as an antiarrythmic action. Accordingly, they are expected to provide satisfactory results to the patients with arrhythmia, whose cardiac functions are depressed.
Representative examples of processes for the production of the compounds of the general formula (1) according to the present invention will be demonstrated hereinafter; however, these examples are not to be construed to limit the scope of the invention Among the compounds of the general formula (1) described above, a compound of the following general formula (2) can be produced according to a method containing the following step (a).
15NO 2 R ' " X; o ~0- (CH2) K-N- (CH2) n N~' N-R4 x2 R3~ ~
...(2) [rn the formula (2), ~1 and R2 each independently represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower 2al~1389 alkyloxy g-;oup; a phenyl graup; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or Rl and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure; and Xl, X2, R2, R3, R4, k and n are defined as in the formula (1) .
Step (a~:
A compound of the following general formula (9) NOz ~ -OH (~) xi ~
XZ
~in which Xl and x2 are defined as in the general formula (1) above]
and a compound of the following general formula (10 X3 o H0- (CH2) k-N- (CHz) n--N ~N-R~ (lo N~
R3! o rin which R1 is defined as in the general formula (2) above and R2, R3, R4, X3, n and k are defined as in the general formula (1) above]
are allowed to react in the presence of a dehydratecondensing agent in a solution using an appropriate solvent or in a suspension usin~ an appropriate dispersing 2(~1389 agent (Application of Mitunobu reaction; 0. Mitunabu, Synthesis, 1-~8, ]981), thereby the compound of the general formula (2) above being obtained.
The reaction is carried out at or below the reflux temperature of the solvent or dispersing agent used for the reaction. For example, the temperature in the range -10 to 80~C is selected.
Examples of the dehydratecondensing agent to be used in this reaction include various dehydratecondensing agents used ordinarily for ether bond formation. Among them, mixed condensing agents of diethylazodicarboxylate and triphenylphosphine are preferably used.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to the reaction.
For example, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane or dioxane can be used.
Next, among the compounds of the general formula (1) above, a compound of the following general formula (4) can be produced according to a method containing the following step (b).
N0z Rl RzX O
~ A''-N-(CHz) n - N ~
rln the formula (4), A" repre.sents -B"-(C~2)k- or -N ~ , in which B" represents an oxygen or sulfur atom or Z0~13~9 -N- ;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or Rl and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
k represents an integral number, 2, 3 or 4; and Xl, X2, R1, R2, R3, R4, X3 and n are defined as in the formula ~I) above3.
Step (b):
A compound of the following general formula (11 NOz ~Y ~11) - X Z
[in which y2 represents a halogen atom and X1 and x2 are defined as in the general formula (I) above]
and a compound of the following general formula (12) Rl X3 0 201 1 ~ (12) HA~-N-(CH2) n - N ~ N-R4 N~
R3~ ~
[in which A is defined as in the general formula (4) above and Rl, R2, R3, R4, X3 and n are defined as in the general formula (1) above3 are allowed to react by mixing without a solvent, dissolving Z~1389 - ~5 -using an appropriate solvent or suspending using an appropriate dispersing agent, thereby the compound of the general formula (4) above being obtained.
The reaction is carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. ~or example, a temperature in the range between 20 - 150~C is preferably selected.
The reaction can be more preferably conducted in the presence of a base in the reaction mixture.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to this reaction. For example, alcohols such as methanol and ethanol, tetrahydrofuran, dimethylformamide, chloroform, dichloromethane, dioxane, benzene and dimethylsufonoxide can be used.
~ urthermore, examples of the base effective to facilitate this reaction include triethylamine, pyridine, potassium carbonate, sodium carbonate and sodium hydroxide.
Next, among the compounds of the general formula (1) above, a compound of the following general formula (3~ can be produced according to a method containing the following - step (c).
2a~ 389 NOz A -N- (CHz) n--N ~ON-R (3, X l x2 R3' ~
[In the formula (3), A' represents -(CH2)m-, -B'-(CH2)~- or ~ , in which B' represents an oxygen or sulfur atom IR
or -N-;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group (but does not form a heterocyclic structure with Rl );
m represents an integral number, 0, 1, 2, 3 or 4;
k represents an integral number~ 2, 3 or 4;
1~ R1 is defined as in the general formula (2) above; and R2, R3, R4, X1, X2. X3 and n are defined as in the general formula (1) above.
Step (c):
A compound of the following general formula (13) ~A -Y ' (13 X ' ~
x2 [in which y1 represents a halogen atom or a substituting groue that can be an eliminating group in the reaction with a compound of the general formula (14) helow, Xl and x2 are 2~01~89 defined as in the general f~rmula (I) above, and A' is defined as in the general formula (3) above]
and a compound of the following general formula ~14) HN - ( C H 2 ~ n--N ~1~ - R ~ ( 14 N~
R3' ~
[in which Rl is defined as in the general formula ~2~ above and R2, R3, R4, X3 and n are as defined in the general formula (1) above]
are allowed to react by mixing without a solvent, dissolving using an appropriate solvent or suspending using an appropriate dispersing agent, thereby the compound of the general formula {3) above being obtained.
The reaction is carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. For example. a temperature in the range between 20 and 170~C is preferably selected.
The reaction can be more preferably conducted in the presence of a base in the reaction mixture.
Any solvent or dispersing agent can be unlimitedly used for the reaction provided it is inactive to this reaction.
For example, any of those exemplified in the step (b) above can be used.
Furthermore, examples of the base effective to facilitate this reaction include those exemplified in the - 2(~)1389 - ~8 -step (b) above.
The compounds of the general formula (1) above can also be produced according to a method containing the fallowing step (d):
5A compound of the following general formula (15) NO2 Rl R2 ~A-N- (CH2) n~N~{ (15) Xl x2 [in which A, Xl, X2, R1, R2 and n are defined as in the general formula (1) above~
and a compound of the following general formula (16) X o Y3 ~ N-R~ (163 15N~
[in which Y3 is a halogen atom or a substituting group that t can be an eliminating group in the reaction with the compound of the general formula (15) above and R3, R4 and X3 are defined as in the general formula (1) above]
are allowed to react by mixing without a solvent, dissolving using an appropriate solvent or suspending using an appropriate dispersing agent, thereby the compound of the general formula (1) above being obtained The reaction can be earried out at a temperature in the range from room temperature to the reflux temperature of the z~al~ss reaction mixture. For example, a temperature in the range between 20 and 150~C is preferably selected.
The reaction can be more preferably conducted in the presence of a base in the reaction mixture.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to this reaction. For example, any of those exemplified in the step (b) above can be used.
Furthermore, examples of the base useful to facilitate this reaction include those exemplified in the step (b~
above.
Next, among the compounds of the general formula (1) above, a compound of the following general formula (5) can be produced according to a method containing the following step (e~.
~ A-N- (C ~ 2 ) Z- g ~ - Y ~
~In the formula (S), A represents -(CH2)m-, -B-(CH2)k-, -D-~CH2)1 ~ -N ~ or -NHCH2CH-CH2 , OH
F~S
wherein B represents an oxygen or sulfur atom, -N-, - Z~ 89 - so -o o o OH ~
Il 11 11 l 11 -CNH- or -CO- and ~ represents -NHC-, -CH- or -C-;
R represents a hydrogen atom, a lower alkyloxycarbonyl.
unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino. lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or may be so linked with R5 as to make an alkylene chain and thus . form a heterocyclic structure but not linked with any of other sites to form heterocyclic structure;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl grou~; and X1, X2, X3, R3 and R4 are defined as in the formula (1) above Step ~e):
A compound of the following general formula (17) N0z Rl' ~ A-NH
X' Xz [in which Xl and x2 are defined as in the general formula Z0~31389 (1~ above and A and Rl are defined as in the general formula (5) above]
and a compound of the folIowing general formula (18) ~N ~ N-R~ (18) N~
R3/ ~
~in which R3, ~4 and X3 are defined as in the general formula (1~ above]
are allowed to react hy mixing without a solvent, dissolving using an appropriate solvent or suseending using an appropriate dispersing agent, thereby the compound of the general formula (5) above being obtained.
The reaction is carried out at a temperature in the range from room temperature to the reflux temperature of the reaction mixture. For example, a temperature in the range between 20~C and 180~C is preferably selected.
Furthermore, the reaction can be more preferably conducted in the presence of an acid catalyst in the reaction mixture.
Any solvent or dispersing agent can be used for the reaction provided it is inactive to this reaction. For example, any of those exemplified in the step (b) above can he used.
Furthermore, examples of the above-mentioned acid catalyst include p-toluenesulfonic acid and an acidic ion ~Cl 01389 exchange resin (for example, AmberlistR (Rhome and Haas, USA.
e.g., Amberlist 15R)).
Among the compounds of the general formula (I) above, a compound of the following general formula (7) can also be produced according to a method containing the following step ~f). I
N0z R'- R2,X 0 X~A-N- (CH2) n--N ~N-R4 X2 R3 ~
tln the formula (7), A represents -(CH2)m-, -B-(CH2)k-, -1~- (CH2 ) I -, - N~, or -NHCH2C~l-G~2-, OH
wherein B represents an oxygen or sulfur atom, -N-, O O O OH O
Il 11 1~ 1 ~I
-CNH- or -CO- and D represents -NHC-, -CH- or -C-;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated. Iower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl gro~lps may be substituted by a substituti-ng group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by ~ halogen atom or a lower alkyloxy group; a 2~1)1389 phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group; or Rl and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure; and Xl, X2, X3, R~, R4, m, k, I and n are defined as in the general formula ~1) above].
Step (f):
A compound of the general formula (17) above and a compound of the following general formula (19) RZ' ~~
Y~- (CHz) n--N ~ N-R~ (lg lS N~
R3' ~
[in the formula (19), R2 represents a hydrogen atom, a lower alkyloxycarbonyl, unsatnrated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkrloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl 2 ~ Q 1 ~ 8 9 . _ group~ and is not so linked with Rl' to form any heterocyclic ring;
R3, R4, X3 and n are defined as in the general formula ~1) above; and Y4 represents a halogen atom or a substituting group that can be an eliminating group in the reaction with a compound of the general formula (17) above]
are treated in the same manner as in the step (c) above, thereby the compound of the general formula ~7~ above being obtained.
Among the compounds of the general formula (1) above~ a compound of the following general formula (8) can also be produced according to a method containing the follo~ing step (g).
NO2 R"-- R2.X o ~A----N- ~CH2) n - N ~ -R4 (8) ( tin the formula (8), A"' represents -(CH2~m-, -B'-'-(CH2)k-, -D-(CH2)1-. - ~ or -NHCH2CH-CH2 ;
OH
5 ' O
B"' represents an oxygen or sulfur atom, -N-, -CNH- or -CO-;
~ Il 1 11 D represents -NHC-, -CH- or -C-;
~ .... .
2~)1389 R~ and R2 each independently reprosent a hydrogen atom. a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be replaced by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower 1"' alkyloxy group and a lower alkyloxycarbonyl group~, R
does not link to other sites including R2 or R5 ;
R is defined as in the general formula (3) above; and X1, X2, X3, A, R3, R4 and n are defined as in the formula (1) above].
Step (g):
A compound of the following general formula (20 20~A;" N- (CH z ) n--N ~ R- ~20 ) ~in w~ich A"' and R2 are defined as in the general formula (8) above; and X1, X2, X3, R3, R4 and n are defined as in the general formula (I) above]
and a compound of the following general formula (21) 251''' 4 (21) [in which Y4 represents a halogen atom or a substituting 2~1389 grollp that can be elîminated in the rea tion with a compound of the general formula (20) above and R is defined as in the general formula (8) above]
are treated in the same manner as in the step (c~ above;
thereby the compound of the general formula (8) above being obtained.
Further, for yl~ y3 and Y4 in the compounds to be used in the production steps above, examples of the substituting group that can be an eliminating group include arylsulfonyloxy group such as p-toluenesulfonyloxy group and alkylsulfonyloxy group such as methanesulfonyloxy group.
The relationships among Rl, Rl , Rl , Rl , R2, R- , R5 and R5 can be summarized as foLlows:
R may link to R2 or R5 as to form a heterocyclic structure. R
may link only to R5. Rl may link only to R2. R1 , R2 and R5 form no linkage, i.e., no heterocyclic structure with other sites.
R , R1 , R1 & R1 R2 & R2 and R5 & R5 are synonymously defined except their above relationshipS.
A compound of the general for~ula (18) above can be produced according to a method containing the following step (h).
Step (h):
A compound of the general formula (16) above and 2-aminoethanol are treated in the same manner as in the step (d) above so that a comPound of the following general formula (22) can be prePared.
Z(~ 389 .
Xj~J~N R~
HocH2-cH2-NH~N~o (2-~ ) [In the formula (21), X3, ~3 and R~ are defined as in the general formula (I) above].
The resultant compound is either sulfonated using methanesulfonyl chloride, p-toluenesulfonyl chloride or the like, or halogenized using thionyl chloride or phosphorus tribromide. The compound thus obtained is mixed in the presence of a base such as sodium hydroxide or sodium hydride and in a solvent such as acetonitrile, chloroform, benzene dimethylsulfonoxide and methanol at room temperature 15 or under heating, thereby a compound of the general formula ~18) above being obtained.
A pharmaceutically acceptable acid addition salt of a compound of the general formula (1) above can be produced by allowing the compound of the general formula (1) above to react in w~ter or an organic solvent or the mixture thereof, for example, with an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid, oxalic acid or methanesulfonic acid.
~hen the compounds of the general formula (1) above according to the present invention and the acid addition Z~1389 salts thereof are used as a theraPeUtiC agent to treat patients with cardiac malfunctions such as arrhythmia and cardiac insufficiency, the amount and form of doses are different depending on the properties of the compound of the present invention to be used as an active ingredient and on the symptoms of the patients to be treated. ~or example, the amount in the range from 10 to 1,000 mg/day, preferably lO -500 mg/day for an adult can be orally administered in forms such as tablets, granules, powders, suspensions and capsules, or parenterally in forms of depositories, injections, fluids for infusion, inhalations or plasters. Daily doses by injection for adults, in particular phleboclysis, may range from 1 - 1,000 mg, preferably 1 - 300 mg.
General processes for producing pharmaceutical compositions of the present invention include a method in which the compound o~ the present invention is dissolved in an appropriate amount in an oil selected from the group consisting of cotton seed oil, corn oil, peanut oil, olive oil and the like so as to prepare non-aqueous injections; a method in which the compound of the present invention is either suspended or emulsified in water in the presence of an appropriate surfactant so as to prepare aqueous injections; or a method in which the compound of the present invention is prepared in a tablet form ~y adding lactose, crystallized cellulose~ corn starch or the like and finally adding magnesium stearate. However, the pharmaceutical preparations of the present invention can be prepared by any ordinary method in ~ddition to the methods exemplified above.
2C~1389 Useful antiarrythmic agents, therapeutic agents for cardiac insufficiency can be provided by the compounds of the present invention.
The following Examples demanstrate the present invention more in detail; however, it should be understood that they are not intended to limit the invention.
X~1389 Example 1 Preparation of 1,3-dimethyl-6-[4-(4-nitrophenyl)pipera-zin-1-yl3-2,4(1H,3H)-pyrimidinedione (compound 1):
O
02N~F + HNJI~N-CH3 ~ 0 (compound 2)-CH~
> o2N-~-~I4~N-CH3 (compound 1) CH3 In the first place, 0.36 ml of 4-fluoronitrobenzene, 1 g of sodium bicarbonate and 0.5 g of 1,3-dimethyl-6-(piperazin-1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) were added to 5 ml of dimethyl sulfoxide, and reaction was then performed at 100~C for 3 hours. Afterward, the reaction mixture was poured into 50 ml of water and was then extracted with chloroform.
Next, the chloroform extract was washed with water and was then dried over anhydrous magnesium sulfate, and the used solvent was distilled off under reduced pressure. The resulting residue was then purified with a silica gel column chromatograph (chloroform/methanol = 40:1 in terms of volume ~1389 - 61 _ ratio) in order to obtain 0.44 g of 1,3-dimethyl-6-[4-(4-nitrophenyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 1).
Analytical results of the resulting crystalline compound 1:
Melting point: 249-250~C
IR V KBrmax (cm~1): 1700, 1660, 1610, 1530 1340, 840 NMR (d6-DMSO), ~ppm: 8.13, 6.98 (dx2, 2Hx2), 5.23 (s, 1H), 3.23, 3.36 (Sx2, 3Hx2), 3.0 (m, 8H) Values of elemental analysis (as C16H19NsO4) Calcd. (%): C 55.65; H 5.55; N 20.28 Found (%): C 55.34; H 5.76; N 20.46 Example 2 Preparation of 1,3-dimethyl-6-[4-(4-nitrobenzyl)pipera-zine-1-yl]-2,4(1H,3H)-pyrimidinedione oxalate (compound 3):
H ~-~~ C H 3 ( compound 2) ,N O
02 N~CH 2 Br (COOH) 2 /CH 3 OH
02 N~CH 2 N, N4~N-CH 3 (COOH) 2 (compound 3) C H 3 First, 0.48 g of 4-nitrobenzyl bromide, 0.5 g of 1,3-dimethyl-6-(piperazin -1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) and 0.5 ml of triethylamine were suspended in 5 ml of isopropanol, and the resulting suspension was then heated under reflux for 8 hours. Afterward, the used solvent was removed from the resulting reaction mixture by distillation under reduced pressure, and the residue was dissolved in chloroform and was then washed with water. The washed organic layer was dried over anhydrous sodium sulfate. Furthermore, the dried organic layer was subjected to distillation under reduced pressure so as to remove the solvent therefrom, and the residue was then purified through a silica gel column chromatograph (chloroformtmethanol =
50/1 to 20/1 in terms of volume ratio) in order to obtain 0.88 g of 1,3-dimethyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.6 (m, 2H), 3,0 (m, 2H), 3.22, 3.34 (Sx2, 3Hx2), 3.36 (S, 2H), 5.14 (S, 1H) ;~01389 7.55, 8.17 (dx2, 2Hx2) Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in an ordinary manner, thereby preparing 1,3-dimethyl-6-[4-(4-nitrobenzyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione oxalate (compound 3).
Analytical results of the crystalline compound 3 thus obtained:
Melting point: 211-212~C (decomposed) IR y KBrmax (cm~1): 2950, 1720, 1670, 1650 1620, 1520, 1360, 760 Values of elemental analysis [as C17H21N5~4-(C~~H)2]
Calcd. (%): C 50.78; H 5.16; N 15.58 Found (%): C 50.70; H 5.44; N 15.77 Example 3 Preparation of 1,3-dimethyl-6-{2-<N-ethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino~-2,4(1H,3H)-pyrimidine-dione hydrochloride (compound 4):
~ N-CH3 Cl ~ ~0 Cl-13 HOCH2CH2NH2 CH3~SO2Cl > >
- 64 _ -~ CHa ~ SOa~CH2CH2NH ~ ~ N-CH3 >
(compound 5) CH 3 NaH/DMSO N ~ ~~CHa > / N~o >
(Compound 6) CH3 02N ~ CH2CH2CH2NH HCl/CH30H
(compound 7) CH2CH3 ~
02N ~ CH2CH2CH2-N-CH2CH2NH y ~ -CH3 (compound 4) CH~
(1) Preparation of 1,3-dimethyl-6-[2-(p-toluenesulfo-nyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 5):
First, 35.0 g of 2-aminoethanol was heated up to 90~C
and then taken out from the oil bath, and 50.0 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione was added thereto, so that reaction was performed therebetween. In ~0~1389 this case, the addition was carried out at such a velocity that the reaction temperature was maintained in the range of 90 to 110~C. After completion of the addition, the reaction mixture was stirred for 10 minutes, and 300 ml of dioxane/-methanol (which was 10/1 in terms of volume ratio) was thenadded thereto. Afterward, the mixture was allowed to stand overnight. The resulting crystals were then washed with a small amount of dioxane, followed by drying to obtain 49.0 g of white crystals of 1,3-dimethyl-6-(2-hydroxyethylamino)-2,4(1H,3H)-pyrimidinedione.
Next, 200 ml of a pyridine suspension containing 49.0 g of the above-mentioned white crystals was cooled to -5~C, and 40.0 g of p-toluenesulfonyl chloride ~as then added thereto at such a velocity that the reaction temperature does not rise up to 5~C or more. In order for the suspen-sion of the reaction mixture to disappear completely, 51.0 g of p-toluenesulfonyl chloride was further used.
Moreover, the reaction mixture was then poured into 1.5 liters of ice water containing 70 g of potassium carbonate and was then allowed to stand overnight. The resulting crystals were collected by filtration, then washed with water, and dried under reduced pressure, thereby preparing 50.5 g of light yellow crystals of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 5).
Analytical results of the crystalline compound 5 thus obtained:
Melting point: 146.0-149.0~C
IR ~ KBrmax (cm~1): 3270, 1682, 1615, 1550, 1480, 1435, 1360, 1190, 1178, 1010, 903, 780 (2) Preparation of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6):
To 150 ml of an anhydrous dimethyl sulfoxide solution containing 47.2 g of the above prepared compound 5 was slowly added 6.24 g of sodium hydride (60% dispersion in mineral oil) at room temperature. The resulting liquid mixture was then stirred vigorously at ~oom temperature for 5 hours and was cooled, and a small amount of water was then added thereto in order to bring the reaction to an end.
Afterward, this mixture was poured into 1 liter of water containing 70 g of potassium carbonate and was then extracted with 200 ml of chloroform three times. The combined organic layers were then dried over anhydrous sodium sulfate and was concentrated, and 300 ml of ether was added to the resulting concentrate. Afterward, the mixture was allowed to stand overnight.
Light yellow crystals which had been deposited by the overnight standing were collected by filtration and were then washed with ether, followed by drying under reduced _ 67 -pressure to obtain 15.2 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6).
Analytical results of the crystalline compound 6 thus obtained:
Melting point: 126.0-126.5~C
IR ~ KBrmax (cm~1): 1705, 1650, 1612, 1470, 1440, 1305, 1160, 783, 490 H-NMR (CDCl3), ~ppm: 2.34 (s, 4H), 3.35 (s, 3H), 3.56 (s, 3H), 5.25 (s, 1H) (3) Preparation of 1,3-dimethyl-6-~2-<N-ethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)pyrimidine-dione hydrochloride (compound 4):
In 5 ml of chloroform were dissolved 1.28 g of N-ethyl-N-[3-(4-nitrophenyl)propyl]amine (compound 7) and 1.11 g of the above prepared 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6), and the resulting mixture was then concentrated under reduced pressure.
Afterward, 10 mg of Amberlist 15 (made by Rohm & Haas Co.) was added to the residue (concentrate), and the mixture was then heated at 80~C for 1 hour.
Next, the resulting reaction mixture was dissolved in 20 ml of ethyl acetate, and the Amberlist was removed therefrom by filtration. Afterward, 30 ml of n-hexane was added to the filtrate.
The solution was allowed to stand overnight, and the 20~1389 - 68 _ deposited light yellow crystals were then collected by filtration. After washing with ether, the crystals were dried under reduced pressure to obtain 2.20 g of 1,3-dimethyl-6- 2- N-ethyl-N-[3-(4-nitrophenyl)propyl]amino -ethylamino -2,4(1H,3H)-pyrimidinedione.
This product was further recrystallized from ethyl acetate and n-hexane, followed by filtering, washing and drying in order to obtain 1.85 g of light yellow crystals.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
IR ~ KBrmax (cm-1): 3310, 2940, 1692, 1620, 1600, 1545, 1515, 1345, 1205, 770, 755 1H-NMR (CDCl3), ~ppm: 1.07 (t, 3H, J=7.5 Hz), 1.90 (m, 2H), 2.17-3.27 (m, 10H), 3.37 (s, 3H), 3.44 (s, 3H), 4.90 (s, 1H), 5.64 (brs, 1H), 7.47 (m, 2H), 8.30 (m, 2H) Values of elemental analysis (as C1gH27NsO4) Calcd. (%): C 58.60; H 6.99; N 17.98 Found (%): C 58.61; H 7.41; N 17.57 Moreover, the light yellow crystals which had been recrystallized from ethyl acetate and n-hexane were treated with hydrochloric acid/methanol in a usual manner in order to obtain an amorphous powder of 1,3-dimethyl-6-{2-~N-ethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 4).
Analytical results of the amorphous powder of the compound 4:
IR V KBrmax (cm~1): 3450, 1705, 1608, 1513, 1345 Values of elemental analysis (as C1gH27NsO4 HCl) Calcd. (%): C 53.58; H 6.63; N 16.44; Cl 8.33 Found (%): C 53.11; H 6.81; N 16.12; Cl 7.95 Example 4 Preparation of 1,3-dimethyl-6-~2-~N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione fumarate (compound 8):
02N ~ CH2CH2CH20SO2 ~ CH3 ' CH2CH20H
> NO2 ~ CH2CH2CH2NH
(compound 9) ~
CH3 ~ S03CH2CH2NH ~ ~ N-CH3 (compound 5) C H3 >
~n ~ ~ ~ 8 9 _ 70 -(=CHCOOH)2 CH2CH20H ~
02N ~ CH2CH2CH2NCH2CH2NH ~ N-CH~
N~o (=CHCOOH)2 (compound 8) C H~ -(1) Preparation of N-(2-hydroxyethyl)-N-l3-(4-nitro-phenyl)propyl]amine (compound 9):
A mixture of 37.5 g of 3-(4-nitrophenyl)propyl p-toluene sulfonate, 125 g of aminoethanol and 65 ml of dioxane was heated with stirring at a temperature of 90 to 100~C for 3 hours. Thereafter, the used solvent was distilled off from the mixture under reduced pressure, and the residue was dissolved in 800 ml of chloroform and the solution was then washed with 1 liter of water. The washed ( organic layer was further washed with a 0.5 N sodium hydroxide solution and then with water, followed by drying over anhydrous sodium sulfate. The dried organic layer was then treated under reduced pressure to distill off the solvent therefrom, and the residue was recrystallized from benzene/hexane (which was 2/1 in terms of volume ratio).
The obtained crystals were collected by filtration, washed and dried, thereby preparing 21 g of N-(2-hydroxyethyl)-N-.~
~, ~,. -~ ~ Q 11 ~ 8 ~
[3-(4-nitrophenyl)propyl]amine (compound 9).
Analytical results of the crystalline compound 9 thus obtained:
Melting point: 80.5-81~C
(2) Preparation of 1,3-dimethyl-6-~2-<N-(2-hydroxy-ethyl)-N-[3-(4-nitrophenyl)propyl]amino)ethylamino}-2,4-(1H,3H)-pyrimidinedione fumarate (compound 8):
In 350 ml of methanol was dissolved 23.2 g of 1,3-dimethyl-6-[2-(p-tolllen~r~11fonyloxy)ethylamino]-2,4(lH,3H)-pyrimidinedione (compound 5) synthesized in Example 3-(1), and 2.76 g of sodium hydroxide was further added thereto slowly. The resulting mixture was stirred at a temperature of S0 to 60~C for 1 hour, and the solvent was then distilled off from the reaction mixture. Afterward, 120 ml of chloroform was added to the residue, and insoluble materials were removed by filtration therefrom. To the filtrate were added 17 g of N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]-( amine (compound 9) and 0.66 g of p-toluene-sulfonic acid, and the reaction mixture was then treated under reduced pressure to distill off the solvent therefrom. The solvent-free residue was heated and stirred at 80~C for 1 hour and was then dissolved in 480 ml of chloroform, and the reaction mixture was extracted twice with 300 ml of O.S N
hydrochloric acid. Afterward, potassium carbonate was added to the extract (hydrochloric acid solution) with the ,,~ .
ZO~)1389 - 72 _ intention of making the latter alkaline, and the liquid mixture was then stirred at room temperature for 1 hour.
The resulting crystals were then collected by filtration.
The crystals were dried, recrystallized from ethanol, collected by filtration, washed and dried in order to obtain 22.1 g of 1,3-dimethyl-6-~2-<N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amino>ethylamino~-2,4(1H,3H)-pyrimidine-dione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 117.5-118.5~C
H-NMR (CDCl3), ~ppm: 1.86 (m, 2H), 2.48-3.00 (m, 11H), 3.00-3.26 (m, 2H), 3.27 (s, 3H), 3.39 (s, 3H), 3.71 (m, 2H), 4.78 (s, 1H), 6.06 (m, 1H), 7.38 (d, 2H), 8.18 (d, 2H) This pyrimidinedione derivative was treated with a fumaric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)-propyl]amino)ethylamino}-2,4(1H,3H)-pyrimidinedione fumarate (compound 8).
Analytical results of the prepared crystalline compound 8:
Melting point: 152.5-153.5~C
IR ~ KBrmax (cm-1): 3400, 2960, 1700, 1630, 2001:~39 1600, 1555, 1520, 1450, 1355, 1250, 1070, 990, 780 3) Preparation of 1,3-dimethyl-6-~2-(N-(2-hydroxy-ethyl)-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4-(1H,3H)-pyrimidinedione hydrochloride (compund 8'):
1,3-Dimethyl-6-{2-<N-(2-hydroxyethyl)-N-[3-(4-nitro-phenyl)propyl]amino~ethylamino32,4(1H,3H)-pyrimidinedione (free from of compound 8) (2.6 g ) was dissolved in 26 ml methanol under heating and to the resulting solution was added 2.7 ml 13% (w/w) of HCl/methanol solution drop by drop, while the temperature of the mixture was maintained at 40~C.
The resulting mixture was cooled on ice and was left overnight. Crystals thus formed were collected by filtra-tion and dried in vacuum; thus, 1,3-dimethyl-6-{2-<N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amino~ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 8') was obtained.
Analytical results of the crystalline 8' thus obtained:
Melting point: 172-174~C
IR V KBrmax (cm-1): 3230, 1640, 1605, 1540, 1340, 1240 Example 5 Preparation of 1,3-dimethyl-6-{4-[2-(2-nitrophenyl)-2 ~ Q ~ 3 8 9 - 74 _ ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 10):
~ CH2CH20H ~ ~ cH2cH2Br ~2 . 02 (compound 11) ( HN ~ ~ ~ N-CH~
(compound 2) C H~ (COOH) 2 /CH~ON
O
~ CH2CH2 ~ ~ N-CH~
? '-~NO2 N ~ (COOH)2 (compound 10) CH~
(1) Preparation of 2-(2-nitrophenyl)ethyl bromide (compound 11):
( First, 2.5 ml of 2-(2-nitrophenyl)ethanol and 5.4 ml of PBr3 were mixed and stirred at 0~C for 30 minutes to perform reaction therebetween, and the resulting reaction mixture was diluted with 30 ml of benzene and was then poured into 30 ml of water. Afterward, the separated organic layer~was collected, dried over anhydrous sodium sulfate, and then treated under reduced pressure to distill off the solvent therefrom, thereby preparing 3 g of a crude product, ~ ' ;~
Z~1~1389 _ 75 -2-(2-nitrophenyl)ethyl bromide (compound 11).
(2) Preparation of 1,3-dimethyl-6-{4-[2-(2-nitro-phenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 10):
To 15 ml of isopropanol were added 3.0 g of the above prepared compound 11, 3.2 g of 1,3-dimethyl-6-(piperazine-1-yl)-2,4(1H,3H)-pyrimidinedione (compound 2) and 4.2 ml of triethylamine, and the resulting mixture was then treated by the same procedure as in Example 2 in order to obtain 2.2 g of 1,3-dimethyl-6-{4-[2-(2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.7-3.0 (m, 12H), 3.39 (s, 3H), 3.41 (s, 3H), 5.11 (s, 1H), 7.53 (m, 3H), 7.96 (m, 1H) Furthermore, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner, thereby preparing 1,3-dimethyl-6-{4-[2-(2-nitro-phenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 10).
Analytical results of the prepared crystalline compound 10:
Melting point: 212-214~C
Z~1389 Values of elemental analysis (as C18H23N5o4-(cOOH)2-2H2o) Calcd. (%): C 50.85; H 5.55; N 14.82 Found (~): C 50.57; H 5.54; N 14.44 IR ~ KBrmax (cm-1): 3050, 2940, 1720, 1680, 1630, 1550, 1380, 770 Example 6 Preparation of 1,3-dimethyl-6-[2-(4-nitroanilino)ethyl-amino]-2,4(1H,3H)-pyrimidinedione (compound 12):
02N ~ F + H2NCH2CH2NH ~ oN-CH3 (Compound 13) C H3 > 02N ~ -NHCH2CH2NH ~ ~ -CH3 (compound 12) C H3N
The same procedure as in Example 1 was repeated with the exception that 1,3-dimethyl-6-(piperazin-1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) was replaced with 0.45 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), in order to obtain 0.5 g of 1,3-dimethyl-6-[2-(4-nitroanilino)ethylamino]-2,4(1H,3H)-2~389 pyrimidinedione (compound 12).
Analytical results of the crystalline compound 12 thus obtained:
Melting point: 308~C (decomposed) IR ~ KBrmax (cm-1): 1690, 1660, 1600, 1550, 1320, 850 NMR (DMSO-d6), ~ppm: 2.9 (m, 2H), 3.1 (m, 2H), 3.29 (s, 3H), 3.38 (s, 3H), 5.09 (s, 1H), 7.04 (d, 2H), 8.09 (d, 2H) Values of elemental analysis (as C14H17NsO4) Calcd. (%): C 52.66; H 5.37; N 21.93 Found (%): C 52.55; H 5.34; N 21.82 Example 7 Preparation of 1,3-dimethyl-6-~4-[2-(4-nitrophenyl)-ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 14):
, ~ ~ 021~CH2CH2Br H ~ N ~ N-CH3 >
/~ 0 (compound 2) HCl/CH30H
>
- 78 _ -CH2CH2N ~ ~ -CH3 (compound 14) CH3 The same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide was replaced with 0.51 g of 4-nitrophenethyl bromide, in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrophenyl)ethyl]piperazin -1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.8 (m, 12H), 3.22 (s, 3H), 3.36 (s, 3H), 5.19 (s, 1H), 7.36 (d, 2H), 8.12 (d, 2H) Moreover, this pyrimidinedione derivative was treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[2-(4-nitrophenyl)ethyl]pipera-zin-1-yl~-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 14).
Analytical results of the crystalline compound 14 thus obtained:
Melting point: 263-266~C (decomposed) Values of elemental analysis tas C1gH23NsO4-HCl-0.5H2O) Calcd. (%): C 51.61; H 6.02; N 16.72; Cl 8.46 Found (%): C 51.78; H 6.28; N 16.93; Cl 8.60 IR V KBrmax (cm~1): 2950, 2500, 1700, 1690, 1630, 1520, 1350, 805 Example 8 Preparation of 1,3-dimethyl-6-[2-(4-nitrobenzylamino)-ethylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 15):
02N ~ -CH2Br + H2N-CH2CH2NH ~ N-CH3 (compound 13) CH3 (COOH)2/CH30H
> >
02N ~ CH2NHCH2CH2NH ~ N-CH3 N ~ n .(COOH)2 (compound 15) C H3 u The same procedure as in Example 2 was repeated with the exception that 1,3-dimethyl-6-(piperazin-1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) was replaced with - X~ 389 - 80 _ 0.45 g of 6-t2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), in order to obtain 1,3-dimethyl-6-[2-(4-nitrobenzylamino)ethylamino]-2,4(1H,3H)-pyrimidinedione.
Analytical results of the prepared pyrimidinedione derivative:
NMR (CDCl3:DMSO-d6=1:1), ~ppm: 2.9 (m, 2H), 3.2 (m, 2H), 3.30 (s, 3H), 3.38 (s, 3H), 3.60 (m, 2H), 5.07 (s, 1H), 7.42 (d, 2H), 8.06 (d, 2H) Moreover, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain crystals of 1,3-dimethyl-6-[2-(4-nitrobenzylamino)-ethylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 15).
Analytical results of the crystalline compound 15 thus obtained:
Melting point: 203-205~C (decomposed) IR V KBrmax (cm-1): 3150, 2900, 1710, 1650, 1640, 1630, 870 Values of elemental analysis [as C1sH19NsO4 (COoH)2~o 5H2o]
Calcd. (%): C 47.22; H 5.13; N 16.20 Found (%): C 47.04; H 4.40; N 16.61 Example 9 Preparation of 1,3-dimethyl-6-{2-[2-(4-nitrophenyl)-ethylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 16):
02N ~ CH2CH2Br_t H2NCH2CH2NH ~ N-CH~
(compound 13)C H~
(COOH)2/CH 3 OH
> >
02N ~ CH2CH2NHCH2CH2NH ~ \N-CH~ -(COmpound 16) ~N ~ ~ ~(COOH~2 The same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide and 1,3-dimethyl-6-piperazin -1-yl)-2,4-(1H,3H)-pyrimidinedione (compound 2) were replaced with 0.51 g of 2-(4-nitrophenyl)ethyl bromide and 0.45 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 13), respectively, in order to obtain 1,3-dimethyl-6-{2-[2-(4-nitrophenyl)ethylamino]-ethylamino3-2,4(1H,3H)-pyrimidinedione.
-- 2~)13~9 Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ppm: 2.7-3.2 (m, 6H), 3.29 (s, 3H), 3.37 (s, 3H), 3.51 (t, 2H), 5.01 (s, 1H), 8.13 (d, 2H), 8.43 (d, 2H) Furthermore, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner, thereby preparing crystals of 1,3-dimethyl-6- 2-[2-(4-nitrophenyl)ethylamino]ethylamino -2,4(1H,3H)-pyrimidine-dione oxalate (compound 16).
Analytical results of the crystalline compound 16 thus obtained:
Melting point: 200-202~C (decomposed) Values of elemental analysis (as C16H21NsO4-(cOoH)2o2H2o) Calcd. (%): C 48.43; H 5.42; N 15.69 Found (%): C 48.52; H 5.16; N 16.25 IR KBrmax (cm-1): 3100, 2900, 1710, 1640, 1620, 1560, 1360, 850 Example 10 Preparation of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 17):
_ 83 -O CHaNHCH2CH2NHCH~
C1 ~ _~N-CH~
3 o CH~
CH~ ~
CH~NHCH2CH2N ~ N-CH~
( N ~ o (compound 18)C H~
O2N ~ CH2CH2CH2B r (COOH)2/CH~OH
CH3 CH3 ~
02N ~ CH2CH2CH2NCH2CH2N ~ N-CH3 ~ N ~ o (COOH)2 (compound 17) C H3 (1) Preparation of 1,3-dimethyl-6-{N-methyl-N-~2-(methylamino)ethyl]amino}-2,4(1H,3H)-pyrimidinedione (compound 18):
In 200 ml of chloroform were dissolved 50 g of N,N'-dimethylethylenediamine and 19.8 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione, and the reaction mixture was then heated with stirring under reflux for B
~ . . ..
--- 2~1389 - 84 _ 5 hours.
The reaction mixture was washed with water, and a separated organic layer was then dried over anhydrous sodium sulfate. Furthermore, the dried organic layer was treated under reduced pressure to distill off the solvent, and ether was then added to the resulting residue so as to deposit crystals. The latter were then collected by filtration, washed and dried in order to obtain 10 g of 1,3-dimethyl-6-{N-methyl-N-[2-(methylamino)ethyl]amino}-2,4(1H,3H)-pyridine-dione (compound 18).
Analytical results of the crystalline compound 18 thus obtained:
'! NMR (CDCl3), ~ppm: 2.7 (s, 3H), 2.5-3.3 (m, 4H), 3.25 (s, 3H), 3.3 (s, 3H), 3.33 (s, 3H), 5.25 (s, 1H) (2) Preparation of 1,3-dimethyl-6-~N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 17):
To 60 ml of isopropanol were added 5.0 g of the above compound 18, 5.5 g of 3-(4-nitrophenyl)propyl bromide and 6 ml of triethylamine, and the resuting mixture was then treated by the same procedure as in Example 2 in order to obtain 8.1 g of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione.
~1389 Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ,~ppm: 1.5-2.2 (m, 2H), 2.25 (s, 3H), 2.25-3.2 (m, 8H), 3.3 (s, 3H), 3.35 (s, 3H), 5.25 (s, 1H), 7.3 (d, 2H), 8.15 (d, 2H) Moreover, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain crystals of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1 H,3H)-pyrimidine-10 dione oxalate (compound 17).
Analytical results of the prepared crystalline compound 17:
Values of elemental analysis [as C1gH27NsO4-(cOoH)2]
Calcd. (%): C 52.60; H 6.10; N 14.61 Found (%): C 52.41; H 6.33; N 14.21 Example 11 The same procedure as in Example 3-(3) was repeated with the exception that N-ethyl-N-[3-(4-nitrophenyl)propyl]-20 amine (compound 7) was replaced with each amino compound in which the ethyl group portion (R1 ) and the number (m) of carbon atoms in an alkyl chain of the compound 7 were as shown in Table 1, in order to obtain compounds 19 to 24.
Physical properties of these compounds are set forth in ~5 Table 1.
-2~0~89 ~ _ _ ~
C~ ~D U~ O
~ ~ ~ O O ~
_z .. .. .. ..
~ _ _ _ _ ~ o <s~ U~ ~ ~ ~ ~
:~ ~C .. .. .. ..
_ _ o .. .. .. ..
O O ~ ~~ CJ', o , o o ~C
~ ~ In 0 0-1~ 0-1~ 00 ~ O
o~ ~ ~ ~ ~Z ~Z ~ Z ~ Z ~Z ~ Z
,Z =~ ~ ~ ~ ~~ ~ ~ I
1~ 0 ~ 0 0 00 0~ 0 C O~ C~
Z ~ ~,C~ _ C,,~ _C~ _C,) _ C~ _ O _ ---- ~~ t-- ~ o oIn ou~ 0 ~ a~
U
-- X' ' '~ ~o oIn o ~ ~ o ~ ~ o O ~ ~ ~ ~ ~ ~ 0 --.- --~
~ ~~ ~ ~ ~ ~ Q ~ Q
11 ~ _ _ o oo o ~ o ~ o o oo U~
O H~ ~ f'~
~n o o o U
~ ~n o o o C ~O ~
I
o In u~If) . . .
~ l ~
o z -N
U
S~ -~ O ~ O
C~ Z
g Example 12 Preparation of 1,3-dimethyl-6-{2-<N-ethyl-N-[3-(3-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidine-dione hydrochloride (compound 25):
C2HsNH2 ~ CH2CH2CH20SO2 ~ CH3 >
NOz CH3 ~ 03CHzCH2NH ~ N-CHs ~N ~ o (compound 5) C H3 HCl/CH 3 OH
>
~ CH2CH2CH2NCH2CH2NH ~ N-CH3 NO2 /N ~ o HCl (compound 25) C H3 The same procedure as in Example 4 was repeated with the exception that 37.5 g of 3-(3-nitrophenyl)propyl p-toluene sulfonate, 120 g of ethylamine and 188 g of 1,3-dimethyl-6-l2-(p-toluenesulfonyloxy)ethylamino-2,4-(1H,3H)-pyrimidinedione (compound 5) were used as starting ~0~1389 .
- 88 _ materials, in order to obtain crystals of 1,3-dimethyl-6-{2-<N-ethyl-N-[3-(3-nitrophenyl)propyl]amino> ethylamino3-2,4(1 H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
NMR (CDC13), ,~ppm: 1.00 (t, 3H), 1.6-2.0 (m, 2H),-2.4-2.8 (m, 8H), 2.9-3.1 (m, 2H), 3.2 (s, 3H), 3.3 (s, 3H), 4.75 (s, 1H), 5.5 (br, 1H), 7.3-7.4 (m, 2H), 7.8-8.0 (m, 2H) The thus obtained crystals were treated with a hydrochloric acid/methanol solution in an ordinary manner to obtain crystals of 1,3-dimethyl-6-{2-(N-ethyl-N-[3-(3-nitrophenyl)propyl]amino>ethylamino} -2,4(1 H,3H)-pyrimidine-dione hydrochloride (compound 25).
Analytical results of the crystalline compound 25 thus obtained:
Values of elemental analysis (as C1gH27NsO4-HCl) Calcd. (%): C 53.58; H 6.63; N 16.44; Cl 8.33 Found (%): C 53.02; H 6.79; N 16.01; Cl 7.98 Example 13 Preparation of 1,3-dimethyl-6-~N-ethyl-N-~2-[4-(4-nitro-phenyl)butylamino]ethyl>amino~ -2,4(1 H,3H)-pyrimidinedione oxalate (compound 26):
20~ 89 _ 89 -~ HOCH2CH2NHC2Hs Cl ~ N-CH3 >
/N
C,2 H s ~' HOCH 2 CH 2 N ~ N-CH 3 /N~o (compound 27)CH3 ~ H
>
1 s ~ N C H 2 G H ~ N ~ON- G H a ~ ~ o (compound 29) ~ CH3 >
C~2Hs ~
NH2CH2CH2N ~ /N-CH 3 /N~o (compound 28) CH 3 - Z6)~ 89 02N ~ -(CH2)3CH0 NaBH4 (COOH)2/CH3OH
> > . >
C2H5 ~
02N ~ (CH2)4-NHCH2CH2~ ~ N-CH3 (compound 26) C~ ~ ~ ~(CO2H)2 (1) Preparation of 1,3-dimethyl -6-[ N-ethyl-N-( 2-hydroxyethyl)amino]-2,4(1H,3H)-pyrimidinedione (compound 27):
Up to 100~C, 11 g of N-ethylaminoethanol was heated, and while the above temperature was maintained, 10 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione was added thereto little by little.
The reaction mixture was heated at the same temperature for 1 hour, and 100 ml of dioxane was then added thereto, ~ollowed by stirring under ice cooling for 1 hour.
The crystals deposited by the above stirring were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Afterward, the residue (concentrate) was purified through a silica gel column chromatograph (ethyl acetate/methanol = 20/1 in terms of volume ratio) to obtain 7.2 g of 1,3-dimethyl-6-[N-ethyl-N-( 2 -hydroxyethyl)amino]-2,4(1H,3H)-pyrimidinedione -2~)1389 (compound 27).
Analytical results of the compound 27 thus obtained:
NMR (CDCl3), ,~ppm: 1.15 (t, 3H), 3.0-3.3 (m, 4H), 3.3 (s, 3H), 3.4 (s, 3H), 3.6-3.9 (m, 2H), 5.35 (s, 1H) (2) Preparation of 1,3-dimethyl-6-[N-ethyl-N-(2-amino-ethyl)amino]-2,4(1 H,3H)-pyrimidinedione (compound 28):
In 200 ml of tetrahydrofurane were suspended 16.8 g of the above compound 27, 8.6 g of triphenylphosphine and 11.96 g of phthalimide, and 14.81 g of diethyl azodicarboxy-late was further added dropwise to the resulting suspension under ice cooling.
Next, after completion of the addition, the used solvent was distilled off from the reaction mixture under reduced pressure, and the residue was then purified through a silica gel column chromatograph (ethyl acetate) in order to obtain 22.5 g of 6-[N-ethyl-N-(2-phthaloylaminoethyl)-amino]-1,3-dimethyl-2,4(1 H,3H)-pyrimidinedione (compound 29). The latter compound was then treated with hydrazine monohydrate in ethanol in a usual method to remove the phthaloyl group therefrom, thereby preparing crystals of 1,3-dimethyl-6-[N-ethyl-N-(2-aminoethyl)amino]_2,4(1 H,3H)-pyrimidinedione (compound 28).
Analytical results of the crystalline compound 28 thus obtained:
25~0~389 NMR (CDCl3:DMSO-d6 = 1:1, v/v), 5ppm: 1.15 (t, 3H), 2.65 (q, 2H), 2.6-3.3 (m, 4H), 3.3 (s, 3H), 3.4 (s, 3H), 4.8 (s, 1H) (3) Preparation of 1,3-dimethyl-6-{N-ethyl-N-~2-[4-(4-nitrophenyl)butylamino]ethyl>amino3-2,4(1H,3H)-pyrimidine-dione oxalate (compound 26):
In 25 ml of ethanol were dissolved 1.58 g of 1,3-dimethyl-6-[N-ethyl-N-(2-aminoethyl)amino]-2,4(1H,3H)-pyrimidinedione (compound 28) and 1.35 g of 4-(4-nitro-phenyl)butanal, and 0.5 g of molecular shieves (3A) (made byJunsei Kagaku Co., Ltd.) was then added to the solution, followed by stirring at room temperature for 3 hours.
To the resulting reaction mixture was added 0.8 g of sodium borohydride, and the mixture was then stirred for 2 hours. A small amount of water was added to the mixture, and the solvent was then distilled off from the mixture under reduced pressure. Afterward, the resulting residue was dissolved in chloroform. The chloroform solution was washed with water, and a separated organic layer was then dried over anhydous sodium sulfate. The solution was treated under reduced pressure so as to distill off the solvent. The resulting residue was purified through a silica gel column chromatograph (chloroform/methanol = 30/1 in terms of volume), then recrystallized from ethyl acetate, collected by filtration, washed, and dried in order to - 236~389 obtain 0.78 g of 1,3-dimethyl-6-{N-ethyl-N- (2-[4-(4-nitro-phenyl)butylamino]ethyl) amino~ -2,4(1H,3H)-pyrimidinedione.
Analytical results of the obtained crystalline pyrimidinedione derivative:
NMR (CDCl3), ~ppm: 1.05 (t, 3H), 1.4-1.8 (m, 4H), 2.2-2.8 (m, 8H), 2.9-3.1 (m, 2H), 3.3 (s, 6H), 4.8 (s, 1H), 5.6 (m, 1H), 7.35 (d, 2H), 8.15 (d, 2H) The thus obtained crystals were treated with an oxalic 10 acid/methanol solution in a usual manner in order to prepare 1,3-dimethyl-6-~N-ethyl-N- (2-[4-(4-nitrophenyl)butylamino]-ethyl) amino}-2,4(1 H,3H)-pyrimidinedione oxalate (compound 26).
Analytical results of the crystalline compound 26 thus obtained:
Melting point: 164-166~C
Values of elemental analysis [as C20H2gNsO4~(COOH)2]
Calcd. (%): C 53.54; H 6.33; N 14.19 Found (%): C 53.21; H 6.32; N 13.98 Example 14 Preparation of 1,3-dimethyl-6-[3-(4-nitroanilino)-propylamino]-2,4(1 H,3H)-pyrimidinedione oxalate (compound 30):
-Z~1389 - 94 _ p NH 2 -(CH 2 ) 3 -NH 2 Cl ~ ~N-CH3 >
~ N o ~ NO2 ~ F
NH2-(CH2~3-NH ~ ~N-CH3 (compound 31) CH3 (COOH)2/CH30H-NO2 ~ NH-(CH2~3-NH ~ N-CH 3 (compound 30) C ~ ~ ~(COOH)2 (1) Preparation of 1,3-dimethyl-6-(3-aminopropyl-amino)-2, 4(1 H,3H)-pyrimidinedione (compound 31):
The same procedure as in Example 10-(1) was repeated with the exception that N,N'-dimethylethylenediamine was replaced with 50 g of 1,3-diaminopropane, in order to obtain 9.5 g of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione (compound 31).
Analytical results of the compound 31 thus obtained:
2~389 NMR (CDCl3), ,~ppm: 1.75-2.10 (m, 2H), 2.75-3.48 (m, 4H), 3.12 (s, 3H), 3.35 (s, 3H), 4.75 (s, 1H) (2) Preparation of 1,3-dimethyl-6-[3-(4-nitroanilino)-5 propylamino]-2,4(1 H,3H)-pyrimidinedione oxalate (compound 30):
The same procedure as in Example 1 was repeated with the exception that the compound 2 was replaced with 0.5 g of the above compound 31, in order to obtain 1,3-dimethyl-6-[3-(4-nitroanilino)propylamino]-2,4(1H,3H)-pyrimidinedione.
The latter compound was further treated with an oxalic acid/methanol solution in a usual manner, thereby preparing 0.45 g of crystalline 1,3-dimethyl-6-[3-(4-nitroanilino)-propylamino]-2,4(1 H,3H)-pyrimidinedione oxalate 15 (compound 30).
Analytical results of the crystalline compound 30 thus obtained:
Melting point: 213-21 4~C (decomposed) IR 1~ KBrmax (cm-1): 2600, 1700, 1640, 1600 1560, 1320, 840 Values of elemental analysis [as C1sH1gNsO4-2(COOH)2]
Calcd. (%): C 50.79; H 5.33; N 18.51 Found (%): C 50.95; H 5.38; N 18.82 Example 15 Preparation of 1,3-dimethyl-6-[3-(4-nitrobenzylamino)-2(~)1389 _ 96 -propylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 32):
NH2-(CH2) 3 -NH ~ N-CH 3 (compound 31) /N 0 NO2 ~ -CH2Br (COOH) 2 /CH 3 OH
> >
NO2 ~ CH2NH-(CH2)3-NH ~ N-CH3 (compound 32) CH (COOH)2 To 20 ml of isopropanol were added 1.45 g of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione (compound 31) obtained in Example 14-(1), 1.44 g of p-nitrobenzyl bromide and 1.5 ml of triethylamine, and the resulting mixture was then treated in the same manner as in Example 2 in order to obtain crystals of 1,3-dimethyl-6-[3-(4-nitrobenzylamino)propylamino]-2,4(1H,3H)-pyrimidinedione oxalate (compound 32).
Analytical results of the crystalline compound 32 thus obtained:
Melting point: 175-178~C
IR y KBrmax (cm-1): 2600, 1690, 1620, 1610 1550, 1350, 850 Values of elemental analysis [as C16H21N5o4-(cooH)2~3H2o]
Calcd. (%): C 43.99; H 5.95; N 14.25 Found (%): C 43.52; H 6.05; N 14.33 Example 16 The same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide was replaced with 0.51 g of 3-(4-nitrophenyl)propyl bromide, in order to obtain 1,3-dimethyl-6-{4-[3-(4-nitrophenyl)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 33).
Furthermore, the same procedure as in Example 2 was repeated with the exception that 4-nitrobenzyl bromide was replaced with 0.55 g of 4-(4-nitrophenyl)butyl bromide and that the oxalic acid/methanol solution was replaced with hydrochloric acid/methanol, in order to obtain 1,3-dimethyl-6-{4-[4-(4-nitrophenyl)butyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 34).
Physical properties of these compounds were as follows:
(1) 1,3-dimethyl-6-~4-[3-(4-nitrophenyl)propyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 33) 20~1389 NO2- ~ -CH2CH2CH2Br + HN N ~ N-CH3 (compound 2) (CO2H)2/CH3OH A n ~
> NO2- ~ Nl~o (compound 33) Melting point: 153-156~C (decomposed) IR V KBrmax (cm~1): 2550, 1680, 1630, 1600 1590, 1510, 1340, 850 Values of elemental analysis [as C1 gH25N5O4-(cOOH)2-1~5H2O]
Calcd. (%): C 50.00; H 5.99; N 13.88 Found (%): C 50.24; H 5.64; N 13.23 (2) 1,3 -dimethyl -6-{4-[4-(4 -nitrophenyl)butyl]pipera-zine-1-yl} -2,4(1H,3H)-pyrimidinedione hydrochloride (compound 3 4) NO2- ~ CH2cH2cH2cH2Br + HN N- ~ -CH3 >
(compound 2) 2~1389 HCl/CH30H n ~4 > N02-~-CH2CH2CH2CH2NL~Ny N-CH3 HCl (compound 34) Melting point: 202-205.5~C
IR V KBrmax (cm-1): 2920, 2450, 1700, 1650 1615, 1440, 1345, 791, 762, 740' Values of elemental analysis tas C20H27NsO4 HCl]
Calcd. (%): C 54.85; H 6.44; N 15.99; Cl 8.10 Found (~): C 54.20; H 6.67; N 15.56; Cl 8.95 Example 17 Preparation of tablets containing, as an effective component, 1,3-dimethyl-6-[4-(4-nitrobenzyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione oxalate (compound 3) which can be obtained by the process of Example 2:
With 20 g of corn starch were mixed 1 g of the above pyrimidinedione derivative oxalate (compound 3) and 123 g of lactose, and the mixture was further mixed with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in 100 ml of water, so as to form grains, followed by drying the grains at 50~C for 4 hours. Afterward, 1 g of magnesium stearate was added to the dried grains and was then mixed sufficiently. The mixture was then formed into tablets by the use of a tableting machine, the weight of each tablet -being 150 mg.
Example 18 Preparation of capsules containing, as an effective component, 1,3-dimethyl-6-~2-<N-ethyl-N-[3-(4-nitrophenyl)-propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 4) which can be obtained by the process of Example 3:
With 25 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (com-pound 4) and 120 g of lactose, and hard capsules were filled with the resulting mixture by the use of a capsule filling machine to prepare capsules, the content of the mixture in each capsule being 150 mg.
Example 19 1) Preparation of an injection containing, as an effective component, 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl-N-[3-(4-nitrophenyl)propyl]amino>ethylamino}-2,4(1H,3H)-pyrimidinedione fumarate (compound 8) which can be obtained by the process of Example 4:
In distilled water for injection were dissolved 20 mg of the above pyrimidinedione derivative fumarate (compound 8) and 0.85 g of sodium chloride, and the total volume of the liquid was regulated to be 100 ml, thereby preparing an injection.
2) Preparation of capsules containing, as an effective Z(~13~9 component, 1,3-dimethyl-6-{2-(N-(2-hydroxyethyl-N-[3-(4-nitrophenyl)propyl]amino~ethylamino}-2,4(1H,3H)-pyrimidine-dione hydrochloride (compound 8') which can be otained by process of Example 4:
With 24 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (compound 8') and 120 g of lactose and the resulting mixture and 1 g of magnesium stearate were mixed to prepare the final mixture.
Hard capsules were filled with the resulting final mixture by the use of a capsule filling machine to prepare capsules, the content of the mixture in each capsule being 150 mg.
Pharmacological Test 1 (1) Influence on myocardial action potential duration time (APD7s) To a hybrid adult dog, 30 mg/kg of pentobarbital was administered through a vein, and after being anesthetized, the heart was removed. Afterward, the right ventricular free- wall of the heart was cut out in a Tyrode solution.
The right ventricular free wall was fixed in an incubator at 37~C, and a nutritional solution (20 ml of the Tyrode solution) was refluxed.
In this isolated condition, myocardial action potential duration times (APD7s) were measured before and after the 26~ 389 administration of the respective compounds prepared in the above examples in Table 2 and d-sotalol as a control medicine, and APD75(%) was calculated from the measured results in accordance with the formula:
APD7s(%) = (B - A)/A x 100 A: APD7s before administration B: APD7s after administration Here, APD7s was measured as follows: A field stimula-- tion of 1 Hz was given to the right ventricular free wall, and any variation ~fan action potential was depicted on an oscilloscope via a glass microelectrode (10 to 20 MQ) thrust into a Purkinje fiber of the free wall and via an amplifier.
Afterward, a waveform on the oscilloscope was analyzed by the use of a computer, and the ti~c of from a point of the action potential generation to a point of 75% repolarization was measured. This measured time was regarded as the myocardial action potential duration time (APD7s).
Each of the compounds and d-sotalol shown in Table 2 was separately added to the refluxing nutritional solution (20 ml), and after 20 minutes' incubation, APD7s after the administration was calculated from the variation of the myocardial action potential duration time.
Incidentally, this test was carried out in accordance with a Sato et al's method [H. Sato, K. Hashimoto, Arzneimit-tel Forschung, 34 (1), 3a, 376-380 (1984)].
2~389 - 103 _ The results are set forth in Table 2.
(2) Influence on ventricular muscle refractory period Refractory periods were measured in the following manner before and after each of the compounds and d-sotalol shown in Table 2 was separately administered to a vein or a duodenum, and ERP (%; extensibility of refractory period) was calculated from the measured values:
ERP (~) = (W - Y)/Y x 100 W: Refractory period after administration Y: Refractory period before administration To a mongrel adult dog, 30 mgtkg of pentobarbital was administered intravenously, and afterbeinganesthetized, apair of silver-silver chloride electrodes separated by 3 mm was sewn on an opened right ventricule, and electrical stimula-tion was given at an interval of 400 msec at a duration timeof 4 msec under a current twice as much as the threshold.
Afterward, a small amount of alcohol was injected into a sinus artery in order toextinguishapacemaker activity, and the ventricular refractory period (ERP) was measured under 20 ventricule pacing.
That is,each ltraincomprisedlOstimulationshaving intervals of 400 msec, and an interval between the trains was usually 400 msec. However, this interval was shortened 10 msec by 10 msec at the time of the refractory period measurement, and an interval between the trains at the time 2~1389 when reaction to the first stimulation of the traindisappeared was regarded as the refractory period.
In this case, the electrical stimulation was fed in accordance with a program by a heart stimulation device (Diamedical Co., Ltd.; DHM-226-3).
The results are set forth in Table 2.
Table 2 (results of pharmacological test) Com- APD75 (%) ER;' (%) pound Dose (~g~ml) Dose mg/kg,i.v.) No. 0.3 1.0 3.0 10.0 0.10.: 1.0 3.0 1 - - - - 3.63.6 10.3 4 - 11 16 - 5.611.1 16.7 16.7 8 16 22 38 - 010.7 21.4 14.2 - - 2 11 6.76.7 13.3 20 14 18 43 - - 1433.5 - - 6 16 6.312.5 12.5 18.8 16 - - 22 - 6.713.3 13.3 26 - 20 30 35 6.56.5 6.5 6.5 33 - 17 22 31 14.314.3 17.9 21.4 d-sota- 0 3 7.4 15.8 1.76.7 8.7 15.5 lol - 2~ 389 Toxicity Test 1 Each of the compounds prepared in the above-mentioned examples was administered into a mouse (ddY strain, male).
In each case, oral administration (p.o.) and intra perito-neal administration (i.p.) were separately carried out in adose of 300 mg/kg and 250 mg/kg, respectively.
A mortality rate (number of specimens: one group = 2 to 4 mice) of the mice 24 hours after the administration was calculated, and the results are set forth in Table 3.
Table 3 (results of toxicity test) CompoundMortality Rate (%) Number300 mg/kg (p.o.)250 mg/kg (i.p.) Example 20 Preparation of 1,3-dimethyl-6-~4-[3-(4-nitrophenoxy)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 35):
HocH2cH2cH2Br + HN N ~ N-CH3 N
(compound 37) HOCH2CH2CH2N~__,N ~ N-CH3 ,N
(compound 36) 02N ~ OH j HCl/CH30H
2002N ~ OCH2CH2CH2N N ~ N-CH3 (compound 35) CH3 (1) Preparation of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-1-yl]-2, 4(1H,3H)-pyrimidinedione (compound 36):
25To 250 ml of ethanol were added 14.1 g of 1,3-dimethyl-28~389 -- 107 _ 6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37), 11.7 g of 3-bromo-1-propanol and 13 g of triethylamine, and the mixture was then heated under reflux for 20 hours to perform reaction. After completion of the reaction, the reaction mixture was concentrated to dryness, and the residue was then dissolved in 300 ml of chloroform. The resulting solution was washed with 100 ml of water twice, and the washed orgnaic layer was then dried over anhydrous magnesium sulfate. This organic layer was treated under reduced pressure to distill off the solvent, thereby obtaining 20.5 g of a composition. Afterward, ether was added to this composition, followed by crystallizing, recovering, washing and drying in order to obtain 12.4 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4-(lH,3H)-pyrimidinedione (compound 36) (yield 69.8%).
Analytical results of the crystalline compound 36 thus obtained:
Melting point: 119-121~C
NMR (CDCl3), ~ppm: 1.8 (dt, 2H), 2.7 (m, 6H), 3.02 (m, 4H), 3.36 (s, 3H), 3.43 (s, 3H), 3.82 (t, 2H), 4.34 (br, 1H), 5.26 (s, 1H) IR v KBrmax (cm~1): 3380, 3180, 2830, 1695, 1650, 1605, 1440, 1213, 1068, 1000, 921, 760 (2) Preparation of 1,3-dimethyl-6-~4-[3-(4-nitro-phenoxy)propyl]piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione _ 108 --hydrochloride (compound 35):
In 15 ml of anhydrous tetrahydrofuran were suspended 1.0 g of the above compound 36, 1.1 g of triphenylphosphine and 0.57 g of 4-nitrophenol, and 15 ml of an anhydrous tetrahydrofuran solution containing 0.71 g of diethyl azodicarboxylate was further added to the resulting suspension at room temperature.
Next, the resulting reaction mixture was stirred for 10 minutes and then concentrated to dryness, and the residue was purified through a silica gel column chromatograph (methanol/ethyl acetate = 1/15 to 1/7 in the terms of volume ratio) to obtain 1.3 g of 1,3-dimethyl-6-{4-[3-(4-nitro-phenoxy)propyl]piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione (yield 80%).
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 167-170~C
Values of elemental analysis (as C1gH2sN3Os) Calcd. (%): C 56.57; H 6.25; N 17.36 Found (96): C 56.29; H 6.17; N 17.17 Furthermore, the thus obtained 1,3-dimethyl-6-{4-[3-(4-nitrophenoxy)propyl]piperazin-1-yl} -2,4(1H,3H)-pyrimidine-dione was treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-~4-[3-(4-nitro-phenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione 2~ 89 hydrochloride (compound 35).
Analytical results of the crystalline compound 35 thus obtained:
Melting point: 244-246~C (decomposed) Example 21 Preparation of 1,3-dimethyl-6-{4-[3-(3-nitrophenoxy)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 38):
~OH + BrcH2cH2cH2Br ' > ~OCH2CH2CH2Br 0 2 N - (compound 39) HNN~N-CH3 HCl/CH30H
~Nff (compound 37) - 2~0~389 ~OCH2CH2CH2N N~;~N-CH~
(compound 38) CH 3 (1) Preparation of 3-(3-nitrophenoxy)propyl bromide (compound 39):
To 100 ml of methyl ethyl ketone were added 13.9 g of 3-nitrophenol, 101 g of 1,3-dibromopropane and 15.2 g of anhydrous potassium carbonate, and the mixture was then heated under reflux for 2 hours to perform reaction. After completion of the reaction, insoluble matters were removed from the reaction mixture by filtration, and the filtrate was then concentrated. Next, the resulting concentrate was dissolved in 300 ml of chloroform, and this chloroform solution was washed with water. Afterward, the washed organic layer was then dried over anhydrous magnesium sulfate. This organic layer was then treated under reduced pressure to distill off the solvent, thereby obtaining 24.6 g of 3-(3-nitrophenoxy)propyl bromide (compound 39) as an oily product. This product could be used in the subsequent reaction without purifying particularly.
(2) Preparation of 1,3-dimethyl-6-~4-[3-(3-nitro-phenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 38):
- 2~01389 In 20 ml of dioxane were dissolved 1.69 g of the above oily compound 39, 1.12 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37) and 1 ml of triethylamine, and the solution was then heated under reflux for 4 hours to perform reaction. After completion of the reaction, insoluble matters were removed from the reaction mixture by filtration, the resulting filtrate was then concentrated. The residue (concentrate) was dissolved in chloroform, and the resulting chloroform solution was then washed with water. Afterward, the water-washed organic layer was dried over anhydrous magnesium sulfate and then treated under reduced pressure to distill off the solvent.
Furthermore, the residue was purified through a silica gel column chromatograph (chloroform/methanol = 100/1 to 25/1 in terms of volume ratio), and the purified material was then recrystallized from methanol. Afterward, the crystals were collected by filtration, washed and dried in order to obtain 1.35 g of 1,3-dimethyl-6-~4-[3-(3-nitrophenoxy)propyl]-piperazin -1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 164-165~C
NMR(CDC13), ~ppm: 1.8-2.2 (m, 2H), 2.4-2.8 (m, 6H), 2.8-3.8 (m, 4H), 3.34 (s, 3H), 3.42 (s, 3H), 4.15 (t, 2H), 5.25 (s, 1H), 7.1-8.0 (m, 4H) -- ZC~389 Values of elemental analysis (as C1gH2sNsOs) Calcd. (~): C 56.57; H 6.25; N 17.36 Found (%): C 56.27; H 6.69; N 17.21 Next, the thus obtained 1,3-dimethyl-6- 4-[3-(3-nitro-phenoxy)propyl]piperazin-1-yl -2,4(1H,3H)-pyrimidinedione was treated with a hydrochloric acid/methanol solution to obtain 1,3-dimethyl-6-~4-[3-(3-nitrophenoxy)propyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 38).
10Analytical results of the crystalline compound 38 thus obtained:
IR V KBrmax (cm~1): 1690, 1650, 1525, 1345, 1240, 1200, 1025, 980, 790, 760, 740, 670 Values of elemental analysis (as C1gH2sNsOs HCl MeOH) 15Calcd. (%): C 51.00; H 6.21; N 14.87; Cl 7.53 Found (%): C 50.60; H 6.71; N 14.81; Cl 7.74 Example 22 Preparation of 1,3-dimethyl-6-~4-[2-(4-nitrobenzoyl-oxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40):
HOCH2CH2N~ N~N-CH3 O
(compound 41) CH~
2(~)1389 - 113 _ 02N ~ COCl (COOH)2/CH~OH
02N ~ COOCH2CH2N N ~ N-CH3 N ~ . ( COOH)2 (compound 40) / u To 5 ml of tetrahydrofuran were added 0. 5 g of 4-nitrobenzoyl chloride, 0.47 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) and 1.5 ml of triethylamine, and the resulting mixture was stirred at room temperature overnight.
Afterward, the used solvent was distilled off under reduced pressure, and the residue was then dissolved in chloroform.
The resulting chloroform solution was washed with water, then dried over anhydrous sodium sulfate, and concentrated to dryness, thereby obtaining a crude product. The latter was then purified through a silica gel column chromatograph (chloroform/methanol = 4û/1 in terms of volume ratio) in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)-ethyl]piperazin-1 -yl3 -2,4(1H,3H)-pyrimidinedione. Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.84 g 2 5 of 1,3-dimethyl-6-~4-[2-(4-nitrobenzoyloxy)ethyl]piperazine-_ 114 -1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40).
Analytical results of the crystalline compound 40 thus obtained:
Melting point: 171-173~C (decomposed) S IR ~ KBrmax (cm 1): 3100, 2550, 1740, 1700, 1660, 1640, 1540, 1360, 850 Values of elemental analysis ~as C1gH25NsO6-(cOoH)2-2H2o]
Calcd. (%): C 46.24; H 5.73; N 12.84 Found (%): C 46.64; H 5.38; N 12.83 Example 23 Preparation of 1,3-dimethyl-6-[4-(4-nitrophenacyl)-piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 42):
HN N~N~CHa N~
CHa ~_~ Br (compound 37) 02N~COCH~ 2 ~ -r~
2~1389 - 115 _ 02N ~ COCH2N N ~ ~ N-CH3 (compound 43) C H3 HCI/CH30H A ~
- 02N ~ COCH2N N ~ N-CH3 N ~ HCl (compound 42) C H 3 In 200 ml of chloroform was dissolved 8.25 g of 4-nitroacetophenone, and 20 ml of a chloroform solution containing 8 g of bromine was added dropwise thereto under cooling. The resulting reaction mixture was concentrated, and the residue (concentrate) was recrystallized from chloroform/ether, collected by filtration, washed, and dried to obtain 8.03 g of p-nitrophenacyl bromide.
Next, to 150 ml of dioxane were added 4.88 g of the above prepared p-nitrophenacyl bromide, 4.48 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37) and 4.2 ml of triethylamine, and the solution was heated under reflux for 1 hour. Afterward, the reaction mixture was cooled to deposit crystals, and the latter were 26:~C)1389 collected by filtration, dissolved in chloroform, washed with water, and dried (over anhydrous sodium sulfate).
Afterward, the used solvent was distilled off, and methanol was then added to the residue so as to crystallize it. The resulting crystals were then collected by filtration, washed, and dried to obtain 4.02 g of 1,3-dimethyl-6-[4-(4-nitrophenacyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 43).
Analytical results of the crystalline compound 43 thus obtained:
Melting point: 189-192~C
Values of elemental analysis (as C18H21N5~5 2CH30H) Calcd. (%): C 55.08; H 5.75; N 17.36 Found (%): C 54.86; H 5.44; N 17.62 NMR (CF3COOH), ~ppm: 3.63 (s, 3H), 3.73 (s, 3H), 3.7-4.3 (m, 8H), 5.21 (s, 2H), 6.12 (s, 1H), 8.28 (s, 2H), 8.52 (d, 2H) Furthermore, 0.9 g of the compound 43 was treated with a hydrochloric acid/methanol solution in a usual manner to obtain 0.91 g of 1,3-dimethyl-6-[4-(4-nitrophenacyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 42).
Analytical results of the crystalline compound 42 thus obtained:
Melting point: 257-262~C
-_ 117 -IR V KBrmax (cm~1): 1685, 1630, 1520, 1340, 1190, 960, 845, 790, 740 Values of elemental analysis (as C1gH21NsOs-HCl-~CH30H) Calcd. (%): C 50.52; H 5.50; N 15.92; Cl 8.06 Found (%): C 50.77; H 5.29; N 15.82; Cl 7.61 Example 24 Preparation of 1,3-dimethyl-6-{4-l2-hydroxy-2-(4-nitrophenyl)ethyl]piperazin-1-yl~-2,4-(1H,3H)-pyrimidine-dione hydrochloride (compound 44):
O 2 N ~ C O C H 2 N~_JN ~ N-CH 3 >
(compound 43) C/H
LiAlH4 HCl/CH30H
> >
OH O
02N~CHCH2-N, N~N-CH~ ~HCl (compound 44) CH 3 Under ice cooling, 3.46 g of lithium aluminum hydride ; .. , 2~ 89 -was added to 700 ml of a dried tetrahydrofuran suspension containing 8.12 g of 1,3-dimethyl-6-[4-(4-nitrophenacyl)-piperazin-1-yl~-2,4-(1H,3H)-pyrimidinedione (compound 43), and the mixture was then stirred at the same temperature for 30 minutes, followed by stirring at room temperature for 2 hours.
After completion of the stirring operation, 50 ml of water was added to the reaction mixture under cooling in order to bring the reaction to an end, and insoluble matters were removed therefrom by filtration and the filtrate was then concentrated.
The residue (concentrate) was dissolved in chloroform, washed with water and dried (over anhydrous sodium sulfate), and the resulting organic layer was concentrated to a small amount. Afterward, the concentrate was purified through a silica gel column chromatograph (chloroform/methanol = 100:1 to 100:2 in terms of volume ratio), thereby preparing 3.7 g of 1,3-dimethyl-6-{4-[2-hydroxy-2-(4-nitrophenyl)ethyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 205-207~C
NMR (DMSO-d6), ~ppm: 2.5-2.7 (m, 6H), 2.7-2.95 (m, 4H), 3.06 (s, 3H), 3.20 (s, 3H), 4.79 (t, lH), 7.47 (d, 2H), 8.04 (d, 2H) ~31389 Next, 0.55 g of this pyrimidinedione derivative was treated with a hydrochloric acid/methanol solution in a usual manner in order to obtain 0.53 g of 1,3-dimethyl-6-~4-[2-hydroxy-2-(4-nitrophenyl)ethyl]piperazin-1 -yl3 -2,4-(1H,3H)-pyrimidinedione hydrochloride (compound 44).
Analytical results of the crystalline compound 44 thus obtained:
Melting point: 250-265~C (gradually colored and decomposed) Values of elemental analysis (as C18H22NsOs-Hcl-4H2O):
Calcd. (%): C 50.23; H 5.74; N 16.27; Cl 8.24 Found (%): C 50.22; H 6.07; N 16.04; Cl 8.20 IR V KBrmax (cm~1): 1700, 1620, 1430, 1340, 1190, 1165, 850, 785 Example 25 Preparation of 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyl-amino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45):
NH2CH2CH2Br HBr NO2 ~COC 1 X~1389 H-N N ~ N-CH3 N
(compound 37) ~ 02N ~ CONHCHzCH2Br (compound 46) HCl/CH30H
>
o2N~CoNHCH2CH2-N~J~4~,N-CH3 (compund 45) / 0 CH~ 2HCl (1) Preparation of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46):
In 30 ml of chloroform were added 3 g of 4-nitrobenzoyl chloride, 3.3 g of 2-aminoethyl bromide hydrobromide and 3.9 ml of pyridine under ice cooling, and they were stirred at the same temperature for 1 hour. The reaction mixture was then washed with water, and the resulting organic layer was concentrated to obtain a crude product of 2-(4-nitro-benzoylamino)ethyl bromide. Afterward, the latter was 2~389 recrystallized from hexane/ethanol, the resulting crystals were collected by filtration, washed and dried to prepare 2.9 g of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46).
Analytical results of the crystalline compound 46 thus obtained:
Melting point: 104-108~C
(2) Preparation of 1,3-dimethyl-6-{4-[2-(4-nitroben-zoylamino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45):
A mixture of 1.3 g of the compound 46 obtained in the paragraph (1), 1.8 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)pyrimidinedione (compound 37), 1.3 ml of triethyl-amine and 10 ml of isopropanol was heated under reflux for 3 hours.
Next, the used solvent was distilled off from the resulting reaction mixture, and water was added to the reaction mixture, followed by extracting with chloroform.
Furthermore, a chloroform extract was washed with water, dried over anhydrous sodium sulfate, and concentrated in order to obtain a crude product. Afterward, the latter was recrystallized from hexane/ethanol, and the resulting crystals were collected by filtration, washed and dried in order to obtain 1.77 g of 1,3-dimethyl-6-{4-[2-(4-nitro-benzoylamino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 169-171~C
IR V KBrmax (cm~1): 3000, 2900, 1700, 1640, 1530, 1340, 850, 700 Next, the thus obtained pyrimidinedione derivative crystals were treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-~4-[2-(4-nitrobenzoylamino)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45).
Analytical results of the crystalline compound 45 thus obtained:
Melting point: 283-285~C (decomposed) Values of elemental analysis (as C1gH24N6O5 2HCl):
Calcd. (~): C 46.62; H 5.66; N 17.20; Cl 14.49 Found (~): C 46.45; H 5.79; N 17.01; Cl 14.67 Example 26 Preparation of 1,3-dimethyl-6-{4-[N-(4-nitrophenyl)-carbamoylmethyl]piperazin-1-yl}-2,4(1H,3H)pyrimidinedione oxalate (compound 47):
BrCH2COBr 02N~NH2 Z~389 HN N ~ N-CH3 N
(compound 37) 02N { ~ NHCOCH2Br (compound 48) (COOH) 2/CH 3 OH
~
0 2N~NHCOCH 2N~JN~ ~ (COOH)- 2 (compound 47) C H 3 A mixture of 0.8 g of 4-nitroaniline, 0.6 ml of bromoacetyl bromide, 1.5 g of anhydrous potassium carbonate and 10 ml of dimethyl sulfoxide was stirred at 100~C for 4 hours, and insoluble matters were removed from the mixture by filtration while the latter was hot. The filtrate was cooled to deposit 4-(bromoacetamide)nitrobenzene (compound 48) crystals, and the latter were collected by filtration and then heated under reflux for 16 hours together with 1.3 g of 1,3-dimethyl-6~ piperazinyl)-2,4(1H,3H)-pyrimi-dinedione (compound 37), 1.6 g of triethylamine and 15 ml 2~)1389 of isopropanol.
After cooling, the used solvent was distilled off, and the residue was then dissolved in chloroform. Afterward, the resulting solution was washed with water and dried over 5 anhydrous sodium sulfate.
Afterward, the solvent was distilled off from the dried chloroform solution under reduced pressure, and the residue was purified through a silica gel chromatograph (chloro-form/methanol = 100/1 to 25/1 in terms of volume ratio) to obtain 0.85 g of 1,3-dimethyl-6-~4-[N-(4-nitrophenyl)car-bamoylmethyl]piperazin-1-yl} -2,4(1H,3H)pyrimidinedione.
Analytical results of the crystalline pyrimidine derivative thus obtained:
NMR (DMSO-d6), ,~ppm: 2.5-2.9 (m, 10H), 3.28 (s, 3H), 3.37 (s, 3H), 5.00 (s, 1H), 7.29 (d, 2H), 8.01 (d, 2H) Next, this pyrimidine derivative was treated with an oxalic acid/methanol solution in a usual manner, thereby preparing 0.81 g of 1,3-dimethyl-6-~4-[N-(4-nitrophenyl)-carbamoylmethyl]piperazin-1-yl~-2,4(1H,3H)pyrimidinedione 20 oxalate (compound 47).
Analytical results of the crystalline compound 47 thus obtained:
Melting point: 281-283~C (decomposed) Values of elemental analysis (as C18H22N6Os (cOoH)2-H2o) Calcd. (%): C 47.06; H 5.13; N 16.46 Found (%): C 46.90; H 5.34; N 16.37 Example 27 Preparation of 1,3-dimethyl-6-~4-[3-(4-nitroanilino)-2-hydroxypropyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 49):
o ClCH2CH-CH2N N ~ -CH~
b H ~N~o (Compound 50) CH~
NH3/CH~OH 02N ~ F (COOH)2/CH30H
1s ~ >
02N ~ NHCH2CH-CH2N N ~ N-CH3 OH jN-~o (COOH)2 (compound 49) CH3 In the first place, 20 ml (0.1 g/ml) of an ammonic methanol solution containing 2.0 g of 1,3-dimethyl-6-~4-(3-chloro-2-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidine-dione (compound 50) was heated at 90~C for 8 hours. The B
~ . .
Z~1389 reaction mixture was concentrated under reduced pressure, and the residue (concentrate) was mixed with 0.9 g of 4-nitrofluorobenzene and 1 ml of triethylamine and then heated at 90~C for 2 hours. The resulting reaction mixture was poured into 100 ml of water, and the deposited crystals were then collected by filtration, washed with methanol/-ether, and dried in order to obtain 2.15 g of yellow crystalline 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-2-hydroxy-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Furthermore, the yellow crystals were treated with an oxalic acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-2-hydroxypropyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 49).
Analytical results of the crystalline compound 49 thus obtained:
IR ~ KBrmax tcm~1): 3375 (br), 1693, 1640, 1600, 1470 (br), 1308, 1113 Values of elemental analysis [as C19H26N6~5-(C~2H)2]:
Calcd. (~): C 49.60; H 5.55; N 16.53 Found (%): C 50.10; H 5.98; N 16.79 Example 28 Preparation of 1,3-dimethyl-6-{4-[3-(4-nitrophenylthio)-propyl]piperazin-1-yl 3 -2,4(1H,3H)-pyrimidinedione oxalate (compound 51):
!20n~389 ' ~ BrCH2CH2CH2Br 02N ~ SH
s o2N~scH2cH2cH2Br ?
(compound 52) 0 HN N ~ N-CH~
N ~ . .
CHa (compound 37) ~ (COOH~2/CH30H~
02N ~ SCH2CH2CH2N N ~ N-CHs N ~ -1.5(COOH)2 (compound 51) ~ u CHa (1) Preparation of 3-(4-nitrophenylthio)propyl bromide (compound 52):
To 50 ml of a 2-butanone solution containing 5.5 g of 4-nitrothiophenol and 28.3 g of 1,3-dibromopropane was added 9.0 g of anhydrous potassium carbonate, and the solution was then stirred for 30 minutes at room temperature.
Afterward, insoluble matters were removed from the ~' ~ .
26~1389 resulting reaction mixture by filtration, and the filtrate was then concentrated. The concentrate was dissolved in chloroform, and the resulting chloroform solution was then washed with water. Furthermore, the water-washed orgnaic layer was dried over anhydrous magnesium sulfate and then treated under reduced pressure to distill off the solvent, thereby preparing 8.0 g of crystalline 3-(4-nitrophenylthio)-propyl bromide (compound 52). This product could be used in the subsequent reaction without purifying particularly.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(4-nitrophenyl thio)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 51):
To 30 ml of ethanol were added 2.0 g of the above compound 52, 1.68 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound 37) and 3 ml of triethylamine, and the solution was then heated with stirring under reflux for 3 hours.
The resulting reaction mixture was concentrated to dryness and then mixed with 100 ml of water. Afterward, the deposited material was collected by filtration and then washed with ethanol.
Furthermore, the thus washed deposit was recrystallized from methanol, collected by filtration, washed and dried to obtain 2.4 g of 1,3-dimethyl-6-{4-[3-(4-nitrophenylthio)-propyl]piperazin-1 -yl3 -2,4(1H,3H)-pyrimidinedione.
2C~1389 - 129 _ Analytical results of the resulting crystalline pyrimidinedione derivative:
Melting point: 145-147~C
In 20 ml of methanol was suspended 2.2 g of the thus obtained crystals, and 2.0 g of oxalic acid dihydrate was added thereto, followed by stirring. After complete dissolution, stirring was further continued for a while.
Afterward, 30 ml of ether was added thereto so as to deposit crystals, and the latter was collected by filtration, washed, and dried to obtain 2.0 g of 1,3-dimethyl-6-{4-[3-(4-nitrophenylthio)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 51).
Analytical results of the crystalline compound 51 thus obtained:
Melting point: 164-168~C (decomposed) Values of elemental analysis [as C1gH2sNso4s~1.5(cooH)2-H2o]
Calcd. (%): C 46.15; H 5.28; N 12.23; S 5.60 Found (%): C 45.89; H 5.25; N 12.16; S 6.12 IR V KBrmax (cm-1): 3450, 1700, 1641, 1340, 1222, 978, 851, 745, 722 Example 29 Preparation of 1,3-dimethyl-6-{4-[2-(4-nitrophenoxy)-ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 53):
NO2 ~ 0H + HOCH2CH2N N ~ ~ N-CH, (compound 41 ) C/H
HCl/CH~OH
NO2 ~ OCH2CH2N~_,N ~ N-CH~
~N ~ HCl (compound 53) C H
To 100 ml of anhydrous tetrahydrofuran were added 5.37 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1 -yl]-2,4(1H,3H)-pyrimidinedione (compound 41 ), 3.20 g of 4-nitrophenol and 6.03 g of triphenylphosphine, and the resulting mixture was treated in the same manner as in Example 20-(2) to obtain 5.40 g of crystalline 1 ,3-dimethyl-6-{4-[2-(4-nitrophenoxy)ethyl]piperazin-1 -yl3 -2,4(1 H,3H)-20 pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
IR V KBrmax (cm~1 ): 1705, 1663, 1595, 1505, 1340, 1275, 1213, 1180, 1115, 1010, 862, 805, 750 Furthermore, the thus obtained crystals were treated 2G~1389 with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6- {4-[2-(4-nitrophenoxy)ethyl]pipera-zin-1-yl~ -2,4(1 H,3H)-pyrimidinedione hydrochloride (compound 53).
Analytical results of the crystalline compound 53 thus obtained:
IR lz KBrmax (cm-1 ) 1705, 1655, 1595, 1435, 1342, 1267, 1112, 860, 755 Values of elemental analysis (as C1gH23NsOs-HCl-0.5H2O):
Calcd. (%): C 49.71; H 5.79; N 16.10; Cl 8.15 Found (%): C 49.17; H 6.05; N 16.20; Cl 8.40 Example 30 Preparation of 1,3-dimethyl-6-{4-[4-(4-nitrophenoxy)-butyl]piperazin-1-yl} -2,4(1 H,3H)-pyrimidinedione hydro-chloride (compound 54):
HOCH2CH2CH2-CH2Br + HN~N~ _~N-CH3 (compound 37) C/H
02N{~OH HCl/CH30H
~1389 C2N ~ OCH2CH2CH2CH2N N ~ N-CH3 N ~ HCl (compound 54) C H
The same procedure as in Example 20-(1) was repeated with the exception that 3-bromo-1-propanol was replaced with 12.9 g of 4-bromo-1-butanol, in order to obtain 13.1 g of 1,3-dimethyl-6-[4-(4-hydroxybutyl)piperazin-1-yl]-2,4-10 (1H,3H)-pyrimidinedione.
Furthermore, the same procedure as in Example 20-(2) was repeated with the exception that 1.05 g of this pyrimidinedione derivative was substituted for 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidine-15 dione (compound 36), in order to prepare 1.2 g of crystalsof 1,3-dimethyl-6-{4-[4-(4-nitrophenoxy)butyl]piperazine-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 54).
Analytical results of the crystalline compound 54 thus obtained:
Values of elemental analysis (as C20H27NsOs-HCl-0.5H2O) Calcd. (%): C 51.89; H 6.31; N 15.13; Cl 7.66 Found (%): C 52.01; H 6.24; N 15.41; Cl 7.56 Example 31 Preparation of 1,3-dimethyl-6-{4-[3-(2-nitrophenoxy)-propyl]piperazin-1-yl} -2.4(1H,3H)-pyrimidinedione hydro-~ ~ ~L~89 chloride (compound 55):
BrCH2CH2CH2Br (~OH ' o HN N ~ N~CHa N ~
(compound 37) CH3 HCl/CH30H
O .
OCH2CH2CH2N N~N-CH3 NO2 ~N ~ HCl (compound 55) C H 3 The same procedure as in Example 21-(1) and 21-(2) was repeated with the exception that 3-nitrophenol was replaced with 13.9 g of 2-nitrophenol, in order to obtain crystals of 1,3-dimethyl-6-{4-[3-(2-nitrophenoxy)propyl]piperazin-1-yl}-2.4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
Melting point: 123.5-125~C
Values of elemental analysis (as C1gH2sNsOs) Calcd. (%): C 56.57; H 6.25; N 17.36 Found (%): C 56.74; H 5.85; N 17.46 -2~9~1389 NMR (CDC13), S ppm: 2.03 (m, 2H), 2.66 (m, 6H), 2.98 (m, 4H), 3.32 (s, 3H), 3.40 (s, 3H), 4.11 (t, 2H), 5.22 (s, 1H), 6.9-7.9 (m, 4H) The thus obtained crystals were treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6- {4-[3-(2-nitrophenoxy)propyl]pipera-zin-1-yl} -2,4(1H,3H)-pyrimidinedione hydrochloride (compound 55).
Analytical results of the crystalline compound 55 thus obtained:
Melting point: 251-252~C (decomposed) Values of elemental analysis (as C1gH2sNsOs-HCl) Calcd. (%): C 51.88; H 5.96; N 15.92; Cl 8.06 Found (%): C 51.29; H 5.84; N 16.06; Cl 7.58 Example 32 Preparation of 1,3-dimethyl-6-[2-(4-nitrobenzoylamino)-ethylamino]-2,4(1 H,3H)-pyrimidinedione (compound 56):
02N ~ COCl + H2NCH2CH2NH ~ N~CHg (compound 57) CH 9 2~ 9 _ 135 --> 02N~CONHCH2CH2NH~ -CH3 (compound 56) C H
The same procedure as in Example 22 was repeated with the exception that 1,3-dimethyl-6-[4-(2-hydroxyethyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) was replaced with 0.35 g of 1,3-dimethyl-6-(2-aminoethylamino)-2,4(1H,3H)-pyrimidinedione (compound 57), in order to obtain crystals of 0.49 g of 1,3-dimethyl-6-[2-(4-nitrobenzoyl-amino)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 56).
Analytical results of the crystalline compound 56 thus obtained:
Melting point: 284-285~C (decomposed) IR V KBrmax (cm~1): 1690, 1660, 1640, 1610, 1550, 1360, 860 NMR (DMSO-d6), ~ppm: 3.3 (m, 4H), 3.36 (s, 3H), 3.28 (s, 3H), 4.98 (s, 1H), 8.18 (d, 2H), 8.41 (d, 2H) Values of elemental analysis (as C1sH17NsOs) Calcd. (%): C 51.87; H 4.93; N 20.16 Found (%): C 51.89; H 5.19; N 19.73 Example 33 Preparation of tablets containing, as an effective component, 1,3-dimethyl-6-{4-[3-(4-nitrophenoxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidine hydrochloride (compound 35) which can be obtained by the process of Example 20:
With 20 g of corn starch were mixed 1 g of the above pyrimidinedione derivative hydrochloride (compound 35) and 123 g of lactose, and the mixture was further mixed with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in 100 ml of water, so as to form grains, followed by drying the grains at 50~C for 4 hours. Afterward, 1 g of magnesium stearate was added to the dried grains and then mixed sufficiently. The mixture was then formed into tablets by the use of a tableting machine, the weight of each tablet being 150 mg.
Example 34 Preparation of capsules containing, as an effective component, 1,3-dimethyl-6-{4-[2-(4-nitrobenzoylamino)ethyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 45) which can be obtained by the process of Example 25:
With 25 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (compound 45) and 120 g of lactose, and hard capsules were filled with the resulting mixture by the use of a capsule filling machine to obtain capsules, the content of the mixture in 2~0~389 each capsule being 150 mg.
Example 35 Preparation of an injection containing, as an effective component, 1,3-dimethyl-6-{4-[3-(4-nitrophenyl)-2-hydroxy-propyl]piperazin-1-yl~-2,4(1H,3H)-pyrimidinedione oxalate (compound 49) which can be obtained by the process of Example 27:
In distilled water for injection were dissolved 20 mg of the above pyrimidinedione derivative oxalate (compound 49) and 0.85 g of sodium chloride, and the total volume of the liquid was regulated to be 100 ml, thereby preparing an n~ ectlon .
Pharmacological Test 2 Following the same procedure as in Pharmacological Test 1, APD7s and ERP of the respective compounds prepared in the above examples in Table 4 were calculated. The resluts are set forth in Table 4.
Toxicity Test 2 Following the same procedure as in Toxicity Test 1, toxicity of the respective compounds prepared in the above examples in Table 5 was tested to calculate a mortality rate of mice.
Administration was made by oral administration (p.o.) in an amount of 300 mg/kg of each compound for one mouse.
2()01389 Table 4 (results of pharmacological test) Com- APD75 (%) ER' (%) pound Dose (llg/ml)Dose mg/kg,i.v.) 5 No. 0.3 1.0 3.0 10.0 0.10. 1.0 3.0 - 17 22 30 6 12 15.8 25.3 42 - 2 10 17 4.69.411.7 18.4 10 44 - 5 13 21 0 7.719.9 27.8 51 - - 33 - 12.612.619.0 53 - 8 22 43 8.82330.1 15 55 - - 18 39 0 0 6.8 13.6 56 - - - - 6.76.76.7 Table 5 (results of toxicity test) 20Compound Number Mortality Rate (%) -~ 139 ~ 2~1389 Example 36 Preparation of 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 58):
O O
NH BrCH2CH2CH2Br ~ N-CH2CH2CH2Br o ( o H ~ ~ N-CH3 N
CHs (compound 60) hydrazine H2O
H2NCH2CH2CH2N N ~ N-CH~
f (compound 59) /N 0 02N ~ F (compound 58') Hcl/cHsoH~
~ . , .
2~389 02N ~ NHCH2CH2CH2N N ~ N-CH3 (compound 58) / 0 HCl (1) Preparation of 1,3-dimethyl-6-[4-(3-aminopropyl)-piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 59):
In 100 ml of dimethylformamide were suspended 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane, and then this suspension was heated with stirring at 120~C
for 6 hours so as to perform reaction. Next, insoluble matters were removed from the resulting reaction mixture by filtration, and the filtrate was then concentrated to dryness under reduced pressure. The residue was washed with hexane and then recrystallized from ethanol/water, and the resulting crystals were collected by filtration, washed, and dried to obtain 13.8 g of N-(3-bromopropyl)phthalimide.
Afterward, 13.0 g of this N-(3-bromopropyl)phthalimide, 10.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimi-dinedione (compound 60) and 20 g of triethylamine were suspended in 200 ml of dioxane, and the resulting suspension was refluxed for 6 hours.
Furthermore, insoluble matters were removed from the reaction mixture by filtration, and the filtrate was then concentrated to dryness under reduced pressure. The residue (concentrate) was recrystallized from ethyl 2~)01389 - 141 _ acetate/n-hexane, and the resulting crystals were collected by filtration, washed, and dried to obtain 12.5 g of 1,3-dimethyl-6-[4-(3-phthaloylaminopropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Next, 12.5 g of the thus obtained crystals and 6.0 g of hydrazine nomohydrate were suspensed in 200 ml of ethanol, and the suspension was then refluxed for 4 hours. After cooling, the resulting insoluble matters were removed therefrom by filtration, and the filtrate was then concen-trated to dryness under reduced pressure. Furthermore, the residue (concentrate) was dissolved in water, and dilute hydrochloric acid was added thereto to adjust a pH to about 3. Insoluble matters which had been formed at this time were then removed therefrom by filtration, and a great deal of potassium carbonate was added to the filtrate, followed by extracting with chloroform. After completion of the extraction, the resulting organic layer was dried over anhydrous sodium sulfate and then subjected to a treatment under reduced pressure so as to distill off the solvent, thereby obtaining 1,3-dimethyl-6-[4-(3-aminopropyl)pipera-zin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 59) as a colorless syrupy. This product was then allowed to stand, whereby it crystallized.
(2) Preparation of 1,3-dimethyl-6-~4-[3-(4-nitro-anilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 58):
To 20 ml of dimethyl sulfoxide were added 2.50 g of the above obtained compound (compound 59) and 1.90 g of 4-nitrofluorobenzene, and the resulting mixture solution was heated at 80~C for 3 hours. After cooling, the deposited crystals were collected by filteration, washed, and dried to obtain 2.75 g of 1,3-dimethyl-6-{4-[3-(4-nitroanilino)-propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (compound 58').
Analytical results of the crystalline compound 58' thus obtained:
IR ~ KBrmax (cm-1): 3280, 1635, 1592, 1450, 1425, 1295, 1105, 990, 840 Values of elemental analysis (as C1gH26N6O4):
Calcd. (%): C 56.70; H 6.51; N 20.88 Found (%): C 56.19; H 6.88; N 20.50 Next, the thus prepared compound 58' was treated with a hydrochloric acid/methanol solution in a usual manner to prepare 1,3-dimethyl-6-~4-[3-(4-nitroanilino)propyl]pipera-zin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 58).
Analytical results of the crystalline compound 58 thus obtained:
Melting point: 270~C or more IR V KBrmax (cm-1): 3230, 1645, 1595, 1432, -2 ~ 8 9 1315, 1105, 837, 745 Values of elemental analysis (as C1gH26N6O4-HCl):
Calcd. ~%): C 51.99; H 6.20; N 19.15; Cl 8.08 Found (%): C 52.30; H 6.56; N 18.91; Cl 8.56 Example 37 Preparation of 1,3-dimethyl-6-{2- ([1-(4-nitrophenyl)-piperidin-4-yl]amino) ethylamino} -2,4(1 H,3H)-pyrimidinedione oxalate (compound 61 ):
02N~F + HN~}0 ; 02N~N~0 (compound 62) H2NCHzCHzNH~N-CH~
N~
(compound 63) CH~
(COOH)2/CH30H
o o2N ~ -N 3 NHCH2CH2NH ~ N-CHJ
N~ (C00H) 2 (compound 61) CH~
(1) Preparation of 1 -(4-nitrophenyl)-4-oxopiperidine .~
.
2~389 _ 144 -(compound 62):
In 20 ml of acetonitrile were dissolved 2.8 g of 4-nitrofluorobenzene, 3 g of 4-piperidone hydrochloride and 6.9 ml of triethylamine, and the solution was then heated under reflux for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water, and the deposited crystals were collected by filtration. The crystals were washed with water and then with ether, and they were recrystallized from isopropanol/hexane (1/1 in terms of volume ratio), collected by filtration, washed, and dried in order to obtain 3.47 g of 1-(4-nitrophenyl)-4-oxopiperidine (compound 62).
(2) Preparation of 1,3-dimethyl-6-{2-([1-(4-nitro-phenyl)piperidin-4-yl]amino)ethylamino}-2,4-(1H,3H)-pyrimi-dinedione oxalate (compound 61):
In 30 ml of methanol were suspended 0.5 g of the aboveprepared compound 62 and 1.8 g of 6-(2-aminoethylamino)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 63), and 0.58 ml of a 4 N HCl/dioxane solution was added dropwise to the resulting suspension at 0~C, followed by stirring at the same temperature for 1 hour.
Next, the bulk temperature of the reaction mixture was maintained at 0~C, and 0.14 g of sodium cyanoborohydride was added thereto little by little and stirring was then performed at the same temperature for 3 hours.
2Q~)1389 Then, a small amount of water was added to the reaction mixture, and methanol was distilled off under reduced pressure. The resulting residue was dissolved in 0.5 N
hydrochloric acid.
Potassium carbonate was added to this hydrochloric acid solution to make it alkaline, followed by extracting with chloroform.
Afterward, the extract (organic layer) was washed with water and then dried over anhydrous sodium sulfate, and the used solvent was distilled off under reduced pressure.
Afterward, the residue was then purified through a silica gel column chromatograph (chloroform/methanol = 50/1 to 25/1 in terms of volume ratio), thereby preparing 0.6 g of 1,3-dimethyl-6-~2-([1-(4-nitrophenyl)piperidin-4-yl]amino~-ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
NMR (CDC13) ~ppm: 1.5 (m, 4H), 2.2-3.2 (m, 7H), 3.30 (s, 3H), 3.41 (s, 3H), 4.0 (m, 2H), 4.86 (s, 1H), 6.93 (d, 2H), 8.17 (d, 2H) Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.52 g of 1,3-dimethyl-6-{2-([1-(4-nitrophenyl)-piperidin-4-yl~amino)ethylamino3-2,4(1H,3H)-pyrimidinedione oxalate (compound 61).
Analytical results of the crystalline compound 61 thus obtained:
Melting point: 216-217~C (decomposed) IR V KBrmax (cm-1): 2500, 1690, 1620, 1600, 1540, 1330, 810 Values of elemental analysis [as C1gH26N604-(COOH)2]:
Calcd. (%): C 51.22; H 5.73; N 17.06 Found (96): C 51.08; H 5.69; N 16.58 Example 38 Preparation of 1,3-dimethyl-6-{2-[4-(4-nitrophenyl)-piperazin-1 -yl]ethylamino}-2,4(1 H,3H)-pyrimidinedione oxalate (compound 64):
HN NH
OzN~F ~ OzN~N~ NH
(compound 66) CH3 /3So3CHzCHzNH~N~CH3 (compound 65) CH~
(COOH)2/CH30H
2~389 -~ 02N ~ N~_,N-CH2CH2NH ~ N-CH3 N ~ (COOH) 2 (compound 64) CH3 (1) Preparation of 1,3-dimethyl-6-[2-(p-toluene-sulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 65):
o ~ ~N-CH~
Cl N O
HOCH2CH2NH2 CH3 ~ SO2Cl >
-~ CH3 ~ SO~-CH2CH2NH ~ N-CH3 (compound 65) ~N O
First, 35 g of 2-aminoethanol was heated up to 90~C, and it was then taken out of the oil bath. Afterward, 50.0 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione was added thereto, so that reaction was performed. At this time, a rate of the addition was such that reaction temperature was maintained in the range of 90 to 110~C.
2~1389 After completion of the addition, the reaction mixture was stirred for 10 minutes, and 300 ml of dioxane/methanol (10/1 in terms of volume ratio) was added thereto, followed by standing onvernight. The resulting crystals were then 5 washed with a small amount of dioxane, and dried to obtain 49.0 g of white crystalline 1,3-dimethyl-6-(2-hydroxyethyl-amino)-2,4(1 H,3H)-pyrimidinedione.
Next, 200 ml of a pyridine suspension of this white crystals (49.0 g) was cooled to -5~C, and 40.0 g of 10 p-toluenesulfonyl chloride was added at such a rate that the reaction temperature did not exceed a level of 5~C.
Furthermore, 51.0 g of p-toluenesulfonyl chloride was additionally used to completely eliminate the turbidity of the reaction mixture.
Afterward, the reaction mixture was poured into 1.5 liters of ice water containing 70 g of K2CO3 and then allowed to stand overnight. The resulting crystals were collected by filtration, washed with water, and dried under reduced pressure in order to obtain 50.5 g of light yellow 20 crystalline 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethyl-amino]-2,4(1H,3H)-pyrimidinedione (compound 65).
Analytical results of the crystalline compound 65 thus obtained:
Melting point: 146.0-149.0~C
IR ~ KBrmax (cm-1): 3270, 1682, 1615, 1550, 2C~01389 1480, 1435, 1350, 1190, 1178, 1010, 903, 780 (2) Preparation of 1 -(4-nitrophenyl)piperazine (compound 66):
A mixture of 2.8 g of 4-nitrofluorobenzene, 15 g of piperazine and 20 ml of acetonitrile was heated under reflux for 6 hours. After cooling, chloroform was added to the reaction mixture, and the resulting solution was washed with water, dried (over anhydrous sodium sulfate), and concen-trated under reduced pressure to obtain N-(4-nitrophenyl)-piperazine (compound 66).
(3) Preparation of 1,3-dimethyl-6-{2-[4-(4-nitro-phenyl)piperazin-1-yl]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 64):
With 0.6 g of the above N-(4-nitrophenyl)piperazine (compound 66) was mixed 0.5 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione (compound 65), and the mixture was then heated at 80~C for hour. After cooling, the reaction mixture was diluted with 5 ml of acetonitrile.
Next, the diluted solution was then poured into 20 ml of a dilute aqueous sodium hydroxide solution, and the resulting mixture was extracted with chloroform. The resulting organic layer was washed with water, dried (over anhydrous sodium sulfate), and concentrated to dryness.
The residue (concentrate) was purified through a silica 2~ 89 gel column chromatograph (chloroform/methanol = 30:1 in terms of volume ratio) to obtain 1,3-dimethyl-6-~2-[4-(4-nitrophenyl)piperazin-1-yl]ethylamino~-2,4(1H,3H)-pyrimi-dinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3) ~ppm: 2.8-3.8 (m, 12H), 3.36 (s, 3H), 3.41 (s, 3H), 4.86 (s, 1H), 6.87 (d, 2H), 8.16 (d, 2H) This pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 0.36 g of 1,3-dimethyl-6-{2-[4-(4-nitrophenyl)piperazine-1-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 64).
Analytical results of the crystalline compound 6 thus obtained:
IR V KBrmax (cm~1): 1680, 1640, 1600, 1540, 1320, 830 Values of elemental analysis (as C20H24N6o4-2(cooH)2 4H20) Calcd. (%): C 43.38; H 5.46; N 12.65 Found (%): C 42.91; H 5.19; N 13.24 Example 39 Preparation of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethylamino]ethylamino}-2,4(1H,3H)-2~1389 pyrimidinedione oxalate (compound 67):
CH~
CH~NHCH2CH2NCH2CH2NHCH~
02N ~ F
02N ~ NCH2CH2NCH2CH2NHCH~
(compound 68) Cl ~ -CH3 N ~ (COOH) 2 /CH 3 OH
Cl~3 Cl~3 Cl~3 0 02N~NCI12CH2NCH2CH2N~A:-CH3 N~ - (COOH~ 2 (compound 67) CH 3 (1) Preparation of N,N',N"-trimethyl-N-(4-nitro-phenyl)diethylenetriamine (compound 68):
In 7 ml of dimethyl sulfoxide were dissolved 1.41 g of p-fluoronitrobenzene and 14 g of N,N',N"-trimethyldiethylene-triamine, and the mixture was then stirred at 120~C for 3 2~01389 hours.
The solvent was then distilled off from the reaction mixture under reduced pressure, and the residue was then dissolved in chloroform. This chloroform solution was washed with a small amount of water, and then dried over anhydrous sodium sulfate. The used solvent was distilled off under reduced pressure, so that 2.1 g of N,N',N"-tri-methyl-N-(4-nitrophenyl)diethylenetriamine (compound 68) was obtained in a yellow oily state.
(2) Preparation of 1,3-dimethyl-6-{N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethylamino]ethylamino3-2,4(1H,3H)-pyrimidinedione oxalate (compound 67):
In 10 ml of ethanol were suspended 2.1 g of the above prepared N,N',N"-trimethyl-N-(4-nitrophenyl)diethylenetri-amine (compound 68), 1.22 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione and 2 ml of triethylamine, and the suspension was then heated under reflux for 1 hour. The resulting reaction mixture was then concentrated to dryness, and the residue was purified through a silica gel column chromatograph (chloroform/methanol = 50/1 to 25/1, v/v) and then recrystallized from acetone/water (1/1 in terms of volume ratio), thereby preparing 1.87 g of 1,3-dimethyl-6-~N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethyl-amino]ethylamino~-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystals thus obtained:
2~ 389 Melting point: 65~C
NMR (CDCl3), ~ppm: 2.40 (s, 3H), 2.82 (s, 3H), 3.38 (s, 3H), 3.50 (s, 3H), 3.54 (s, 3H), 2.78 (m, 2H), 3.13 (m, 2H), 3.80 (m, 2H), 5.40 (s, 1H), 6.78 (m, 2H), 8.62 (m, 2H) Values of elemental analysis (as C1gH2gN6O4) Calcd. (~): C 56.42; H 6.98; N 20.78 Found (~): C 56.63; H 7.31; N 19.98 The thus obtained 1,3-dimethyl-6-{N-methyl-2-[N-methyl-2-(N-methyl-4-nitroanilino)ethylamino]ethylamino}-2,4-(1H,3H)-pyrimidinedione was treated with an oxalic acid/-methanol solution in a usual manner to obtain 1.91 g of 1,3-dimethyl-6-~N-methyl-2-[N-methyl-2-(N-methyl-4-nitro-anilino)ethylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 67).
Analytical results of the crystalline compound 67 thus obtained:
Melting point: 184-185~C (decomposed) IR ~ KBrmax (cm-1): 3460, 1700, 1642, 1545, 1480, 1310, 1200, 1100, 833, 722 Values of elemental analysis (as C1gH26N6O4-(cOoH)2-2H2o) Calcd. (%): C 50.09; H 6.21; N 16.69 Found (~): C 50.29; H 6.29; N 16.11 ~ ~ Q ~ 3 8 ~1 . .
_ 154 -Example 40 Preparation of 1,3-dimethyl-6-{4-[3-(N-methyl-4-nitro-anilino)propyl]piperazin-1 -yl3 -2,4(1H,3H)-pyrimidinedione oxalate (compound 69):
02N ~ NHCH2CH2CH2N~_,N ~ -CH3 (compound 58') CH~
CH~I (COOH)2/CH.OH
CH, O
02N ~ NCH2CH2CH2N N ~ -CH3j ~-~ ,N-~3 ~ (COOH)2 (compound 69) C H, At room temperature, 0.12 g of sodium hydride (60%
( dispersion in mineral oil) was added to a suspension obtained by suspending 0.1 g of 1,3-dimethyl-6-{4-t3-(4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione (compound 58') obtained in Example 36 in 15 ml of anhydrous dimethylformamide, and they were stirred for 30 minutes. Afterward, 0.29 g of methyl iodide was further added thereto.
This mixture was stirred at room temperature for 10 B
~1389 minutes, and a small amount of methanol and then 50 ml of chloroform were added thereto. Afterward, the resulting reaction mixture was poured into 50 ml of water. The separated organic layer was taken out, washed with water, and dried (over anhydrous sodium sulfate). The used solvent was distilled off, and the residue was crystallized from a methanol/ether solution (1/1 in terms of volume ratio), collected by filtration, washed, and dried in order to obtain 0.62 g of 1,3-dimethyl-6-[4-{3-(N-methyl-4-nitro-anilino)propyl3piperazin -1-yl]-2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
IR V KBrmax (cm~1): 1690, 1640, 1588, 1520, 1480, 1425, 1282, 1205, 1101, 815 NMR (d6-DMSO), Sppm: 1.82 (m, 2H), 2.13-2.73 (m, 6H), 2.73-3.07 (m, 4H), 3.10 (s, 3H), 3.17 (s, 3H), 3.30 (s, 3H), 3.57 (t, 2H), 5.22 (s, 1H), 6.87 (d, 2H), 8.10 (d, 2H) Values of elemental analysis (as C20H28N6~4 2H2~) Calcd. (%): C 57.13; H 7.67; N 19.99 Found (~): C 57.49; H 7.02; N 20.16 This pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[3-(N-methyl- 4-nitroanilino)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate 2 ~ ~ ~ 3 8 ~
_ _ _ 156 (compound 69).
Analytical results of the crystalline compound 69 thus obtained:
Values of elemental analysis 5(as C20H28N6o4~(cooH)2-2H2o) Calcd. (%): C 51.76; H 6.71; N 16.46 Found (~): C 52.05; H 6.08; N 16.56 Example 41 Preparation of 1,3-dimethyl-6- {4-t3-(N-methansulfonyl-104-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 70):
02N~NHCH2CH2CH2N~_N~II-CH, (compound 58') - CH, CH,SO,Cl (COOH)2/CH,OH
SO2CH, O
2002N~NCHzCH2CH2N~ N~ ~ (COOH)z (compound 70) CH ~
In 20 ml of chloroform were dissolved 0.4 g of 1,3-dimethyl-6- {4-[3-(4-nitroanilino)propyl]piperazin-1 -yl3 -252,4(1H,3H)-pyrimidinedione (compound 58') obtained in '~
2~01;~89 _ 157 -Example 36 and 0.4 g of triethylamine, and 0.2 g of methanesulfonyl chloride was further added to the resulting solution under ice cooling.
This mixture was allowed to stand overnight at room temperature, and a small amount of water was added thereto, followed by stirring at room temperature for 30 minutes.
Furthermore, 20 ml of a dilute aqueous alkaline solution was added to the reaction mixture, and the separated chloroform layer was washed with water and then dried over anhydrous sodium sulfate. Afterward, the dried chloroform layer was treated under reduced pressure to distill off the solvent. The resulting residue was purified through a silica gel column chromatograph (chloroform/-methanol = 100/1 to 25/1 in terms of volume ratio), thereby preparing 0.35 g of 1,3-dimethyl-6-{4-[3-(N-methanesulfonyl-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione.
This pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{4-[3-(N-methanesulfonyl-4-nitroanilino)-propyl]piperazin -1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 70).
Analytical results of the crystalline compound 70 thus obtained:
Melting point: 204.0-204.5~C
Z~ 89 _ 158 -Values of elemental analysis (as C20H28N6o6s-(cooH)2-2H2o) Calcd. (%): C 43.56; H 5.65; N 13.85; S 5.29 Found (~): C 43.81; H 5.24; N 13.35; S 5.52 IR ~ KBrmax (cm~1): 1780, 1695, 1630 (br), 1350, 1340, 1205, 1155 Example 42 Preparation of 1,3-dimethyl-6-~2-[N-ethyl-2-(4-nitro-anilino)ethylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 71):
n2N~ NHCH2CH2NH + CN ~ N-CH3 (compound 72) CH 3 HC1/CH~OH
CH2CH~ O
02N ~ NHCH2CH2NCH2CH2-NH ~ N-CH~
- N~ (CO2H)2 (compound 71) / o (1) Preparation of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 72):
2(~ 89 CH9~ SO9-CHZCH2NH~ N-CH9 (compound 6 5) CH~
NaH /DblSO CN~ N-CH3 (COmPOUnd 72) CH3 TO 150 ml of an anhydrous dimethyl sulfoxide containing 47 2 g of the compound 65 obtained in Example 38-(1) was slowly added 6. 24 g of sodium hydride (60% dispersion in mineral oil) at room temperature. This reaction mixture was stirred vigorously at room temperature for 5 hours, and then cooled. Afterward, a small amount of water was added thereto so as to bring reaction to an end. This solution was poured into 1 liter of water containing 70 g of potassium carbonate, and then extracted with 200 ml of chloroform three times. The combined organic layer was dried over anhydrous sodium sulfate and then concentrated, and 300 ml of ether was added to the resulting concentrate.
Afterward, the solution thus obtained was allowed to stand overnight.
Light yellow crystals which had been deposited by the _ 160 -overnight standing were collected by filtration, washed with ether, and dried under reduced pressure in order to obtain 15.2 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimi-dinedione (compound 72).
Analytical results of the crystalline compound 72 thus obtained:
Melting point: 126.0-126.5~C
IR ~ KBrmax (cm 1): 1705, 1650, 1612, 1470, 1440, 1305, 1150, 783, 490 lH-NMR (CDC13), sppm: 2.34 (s, 4H), 3.35 (s, 3H), 3.56 (s, 3H), 5.25 (s, 3H) (2) Preparation of 1,3-dimethyl-6-{2-[N-ethyl-2-(4-nitroanilino)ethylamino]ethylamino)-2,4(1H,3H)-pyrimidine-dione oxalate (compound 71):
In 5 ml of chloroform were dissolved 1.32 g of N-ethyl-N'-(4-nitrophenyl)ethylenediamine and 1.12 g of the above obtained 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 72), and the resulting reaction mixture was concentrated under reduced pressure. To the residue (concentrate) was added 10 mg of Amberlist 15 (trade mark; made by Rohm & Haas Co.), and the mixture was then heated at 80~C for 1 hour.
Next, the resulting reaction mixture was dissolved in 5 ml of ethyl acetate, and Amberlist 15 was then removed therefrom by filtration. Afterward, n-hexane was added to 2~ 9 the filtrate.
Furthermore, the resulting solution was allowed to stand overnight, and deposited crystals were collected by filtration, washed with n-hexane, and dried under reduced pressure in order to obtain 1.5 g of 1 ,3-dimethyl-6-{2-[N-ethyl-2-(4-nitroanilino)ethylamino]ethylamino~ -2,4(1H,3H)-pyrimidinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
1H-NMR (CDC13), ~ppm: 1.12 (t, 3H), 2.52-2.98 (m, 6H), 2.98-3.25 (m, 2H), 3.28 (s, 6H), 3.28-3.48 (m, 2H), 4.78 (s, 1H), 5.27 (m, 1H), 5.45 (m, 1H), 6.59 (d, 2H), 8.08 (d, 2H) Furthermore, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to obtain 1.4 g of 1,3-dimethyl-6-{2-[N-ethyl-2-(4-nitroanilino)ethylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (compound 71 ).
Analytical results of the crystalline compound 71 thus obtained:
Melting point: 175.0-176.5~C
values of elemental analysis (as C18H26N6~4-(C~~H)2) Calcd. (%): C 50.00; H 5.87; N 17.49 Found (96): C 49.81; H 6.02; N 17.22 2Qal1389 Example 43 Preparation of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-nitro-anilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 73):
OZN~3~NHCH2CH2CH2NH + C N ~ N-CH3 (compound 72) CH 3 HCl/CH30H
02N ~ NHCH2CH2CH21~lCH2CH2-NH ~ N-CH3 ~ i HCl (compound 73) C/H 3 O
The same procedure as in Example 42-(2) was repeated with the exception that N-ethyl-N'-(4-nitrophenyl)ethylene-diamine was replaced with 1.45 g of N-ethyl-N'-(4-nitro-phenyl)-1,3-propylenediamine as a starting material, in order to obtain crystals of 1,3-dimethyl-6-~2-[N-methyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimi-dinedione.
Analytical results of the crystalline pyrimidinedione derivative thus obtained:
- 2(~1389 NMR (DMSO-d6), sppm: 1.05 (t, 3H), 1.6-1.9 (m, 2H), 2.4-2.8 (m, 6H), 3.0-3.4 (m, 4H), 3.1 (s, 3H), 3.25 (s, 3H), 4.65 (s, 1H), 6.4 (br, 1H), 6.6 (d, 2H), 7.2 (br, 1H), 8.0 (d, 2H) The thus obtained crystals were treated with a hydrochloric acid/methanol solution in a usual manner to obtain 1,3-dimethyl-6-{2-[N-ethyl-3-(4-nitroanilino)propyl-amino]ethylamino} -2,4(1 H,3H)-pyrimidinedione hydrochloride (compound 73).
Analytical results of the crystalline compound 73 thus obtained:
Values of elemental analysis (as C19H28N6O4-2HCl) Calcd. (%): C 47.80; H 6.33; N 17.60; Cl 14.85 Found (%): C 47.52; H 6.49; N 17.31; Cl 14.76 Example 44 Preparation of 1,3-dimethyl-6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1 -yl]ethylamino} -2,4(1 H,3H)-pyrimi-dinedione oxalate (compound 74):
~N-CH2CHzOH
02N ~N~JNH
(compound 66) ~n ~ ~ ~ 8 9 _ 164 --~ 02N ~ N~_N-CH2CH2NH
(compound 75) ~
Cl ~ ~ N-CHs CH, ~ (COOH)z/CH~OH
( 02N ~ N~_JN-CH2CH2N ~ (COOH)2 (compound 74) CH~
(1) Preparation of 1-[2-(2-hydroxyethylamino)ethyl]-4-(4-nitrophenyl)piperazine (compound 75):
In 20 ml of chloroform was dissolved 4 g of 1-(4-( nitrophenyl)piperazine (compound 66) and 0.52 ml of 1-(2-hydroxylethyl)aziridine, and the solvent was distilled off from the resulting reaction mixture under reduced pressure. To the residue was added 10 mg of Amberlist 15 (trade name; made by Rohm & Haas Co.), and the mixture~was then heated with stirring at 100~C for 3 hour. Afterward, the temperature of the reaction mixture was returned to room temperature. To the reaction mixture was added 20 ml of . . .
Z~0~389 - 165 _ chloroform, and insoluble matters were then removed therefrom by filtration. The filtrate was concentrated, and the resulting residue (concentrate) was purified through a silica gel column chromatograph (chloroform/methanol = 100/1 to 25/1 in terms of volume ratio), thereby preparing 1 g of 1-[2-(2-hydroxyethylamino)ethyl]-4-(4-nitrophenyl)piperazine (compound 75).
(2) Preparation of 1,3-dimethyl-6-~N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1-yl]ethylamino3-2,4(1H,3H)-pyrimidinedione oxalate (compound 74):
To 10 ml of ethanol were added 1.0 g of the thus obtained compound 75, 0.52 g of 6-chloro-1,3-dimethyl-2,4(1H,3H)-pyrimidined one and 2 ml of triethylamine as starting materials, and the resulting mixture was treated in the same procedure as in Example 39-(2) to obtain 0.73 g of 1,3-dimethyl-6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)-piperazin-1-yl]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.65 (m, 6H), 2.9-3.4 (m, 8H), 3.31 (s, 3H), 3.47 (s, 3H), 3.82 (m, 2H), 5.32 (s, 1H), 6.86 (d, 2H), 8.12 (d, 2H) Then, 0.7 g of this pyrimidinedione derivative was further treated with an oxalic acid/methanol solution in a usual manner to obtain crystals of 0.35 g of 1,3-dimethyl-Z~389 _ 166 -6-{N-(2-hydroxyethyl)-2-[4-(4-nitrophenyl)piperazin-1-yl]-ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 74).
Analytical results of the crystalline compound 74 thus obtained:
Values of elemental analysis [as C20H28N6os-1.5(cooH)2-H2o]
Calcd. (%): C 47.18; H 5.68; N 14.35 Found (%): C 47.37; H 5.94; N 14.08 Example 45 Preparation of tablets containing, as an effective component, 1,3-dimethyl-6-{4-[3-(4-nitroanilino)propyl]-piperazin-1-ylJ-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 58) which can be prepared by the process of Example 36:
With 20 g of corn starch were sufficiently mixed 1 g of the above pyrimidinedione derivative hydrochloride (compound 58) and 123 g of lactose, and the mixture was further mixed with a solution prepared by dissolving 5 g of hydroxypropyl cellulose in 100 ml of water, so as to form grains, followed by drying the grains at 50~C for 4 hours. Afterward, 1 g of magnesium stearate was added to the dried grains and then mixed sufficiently. The mixture was then formed into tablets by the use of a tableting machine, the weight of each tablet being 150 mg.
20~1389 Example 46 Preparation of capsules containing, as an effective component, 1,3-dimethyl-6-~2-~[1-(4-nitrophenyl)piperidin-4-yl]amino)ethylamino}-2,4(1H,3H)-pyrimidinedione hydro-chloride (compound 61) which can be prepared by the processof Example 37:
With 25 g of corn starch were sufficiently mixed 5 g of the above pyrimidinedione derivative hydrochloride (compound 61) and 120 g of lactose, and hard capsules were filled with the resulting mixture by the use of a capsule filling machine to prepare capsules, the content of the mixture in each capsule being 150 mg.
Example 47 Preparation of an injection containing, as an effective component, 1~3-dimethyl-6-{2-(N-methyl-N-[3-(4-nitroanilino) propyl]amino)ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 73) which can be prepared by the process of Example 43:
In distilled water for injection were dissolved 20 mg of the above pyrimidinedione derivative hydrochloride (compound 73) and 0.85 g of sodium chloride, and the total volume of the liquid was regulated to be 100 ml, thereby preparing an injection.
Pharmacological Test 3 Following the same procedure as in Pharmacological Test 1, ADP7s and ERP of the respective compounds prepared in the above examples in Table 6 were calculated. The results are set forth in Table 6.
Toxicity Test 3 Following the same procedure as in Toxicity Test 1, toxicity of the respective compounds prepared in the above examples in Table 7 was tested to calculate a mortality rate of mice. The results are set forth in Table 7.
Administration was made by oral administration (p.o.) in an amount of 300 mg/kg of each compound for one mouse.
Table 6 (results of pharmacological test) Com- APD75 (%) ER? (%) pound Dose (lls~ml) Dose mg/kg,i.v.) 15No. 0.31.0 3.0 10.0 0.10. 1.0 3.0 61 - - - - 8.38.3 8.3 64 8 23 32 - 21.428.6 28.6 20 69 - - 11 13 6.76.7 13.3 20.0 71 - 8 15 17 6.77.7 13.4 16.6 Table 7 (results of toxicity test) Compound Number Mortality Rate (%) 2~1389 Example 48:
Preparation of 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrophenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 76) N, o BrcHzcHzcHzoH ~ HocHzcH2cH2N N ~,N-CH3 0 2 N ~ COCH3 OH(COOH) 2 /CH 3 OH
02N~ocH2CH2CH2N,~N)~N-CH3 3 CH3 ~(COOH)2 (Compound 76) (1) Preparation of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione:
14.1 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione, 11.7 g of 3-bromo-1-propanol and 13 g of triethylamine were reacted by heating them under reflux for 20 hours in 250 m~ of ethanol. After completion of the reaction, the reaction mixture was concentrated to dryness and the residue was dissolved in 300 m~ of chloroform. The resultant solution was washed twice with 100 m~ of water. After the washing, the organic layer was dried 2~01389 over anhydrous magnesium sulfate. The organic layer was heated under reduced pressure, whereby the solvent was distilled off to obtain 20.5 g of a reaction product in a crude form. Ether was added to the crude reaction product to crystallize it. Resulting crystals were collected by filtration, washed with chilled ether, and then dried to obtain 12.4 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione(yield: 69.8%).
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 119-121~C.
NMR (CDC13), ~ ppm: 1.8 (dt,2H), 2.7(m,6H), 3.02(m,4H), 3.36(s,3H), 3.43(s,3H), 3.82(t,2H), 4.34(br,1H), 5.26(s,1H).
IR vmBax (cm 1): 3380(Br), 3180(s), 2830, 1695, 1650, 1605, 1440, 1213, 1068, 1000, 921, 760.
(2) Preparation of 1,3-dimethyl-6-~4-[3-(2-acetyl-4-nitrophenoxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 76):
Into a suspension which had been obtained by mixing 0.6 g of the pyrimidinedione derivative obtained in the above procedure (l), 0.54 g of 2-hydroxy-5-nitroacetophenone and 0.69 g of triphenylphosphine in 10 m~ of anhydrous tetrahydrofuran, 0.42 m~ of diethyl azodicarboxylate was added dropwise under stirring at room temperature.
Next, the resulting mixture was stirred for 30 minutes at room temperature and then concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/l by volume), whereby 0.7 g of 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrophenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione was obtained as an oily matter.
Analytical results of the thus-obtained pyrimidinedione derivative:
NMR (CDC13), ~ ppm: 8.47(m,1H), 7.54(m,1H), 6.91(d,1H), 5.23(s,1H), 4.26(m,2H), 3.37(s,3H), 3.30(s,3H), 2.98(m,4H), 2.60(m,6H), 2.63(s,3H), 2.16(m,2H).
Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.73 g of 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitrophenoxy)propyl]-Z~6~1389 piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate tCompound 76).
Analytical results of Compound 76 thus obtained:
Melting point: 122-124~C (decomposed).
IR vmax (cm 1): 3400, 3020, 2600, 1690, 1640, 1520, 1340, 1280, 1120, 820, 750, 700.
Elemental analysis for C21H27N506 ( 2 2 Calculated (%): C, 48.33; H, 5.82; N, 12.25.
Found (~): C, 48.22; H, 5.69; N, 11.93.
Example 49:
Preparation of 1,3-dimethyl-6-{4-[3-(4-acetyl-2-nitrophenoxy1propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 77):
HOCHzCHzCH2N~JN ~ N-CH3 N o CH 3 CO~ rNOz ~ OH (COzH)2/CH30H
3CO~OCH2CH2CH2N~JN~N-CH3 CH3 ~(COOH)2 (Compound 77) Z~ 89 By a procedure similar to Example 48-(2) except for the use of 4-hydroxy-3-nitroacetophenone in lieu of 2-hydroxy-5-nitroacetophenone, 1,3-dimethyl-6-{4-[3-(4-acetyl-2-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 77) was obtained.
Analytical results of the pyrimidinedione derivative (Compound 77) thus obtained:
Melting point: 119-123~C ~decomposed).
IR vKBr (Cm-l~ 3380, 2250, 1700, 1640, max 1530, 1350, 1020, 760, 700.
Elemental analysis for C21H27N5O6 ( 2 2 Calculated (~): C, 46.86; H, 5.98; N, 11.28.
Found (~): C, 46.79; H, 5.43; N, 11.51.
Example 50:
Preparation of 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 78):
HOCH2CHzCHz~ N ~ ~-CH3 o ~, N 0 2 OH, (COOH) z/CH30H
2~0~3~39 2cH2cH2N~N~N-CH3 CH3 (COOH)2 (Compound 78) By a procedure similar to Example 48-(2) except for the use of 4-hydroxy-3-nitroacetophenone in lieu of 2-hydroxy-5-nitroacetophenone, 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 78) was obtained.
Analytical results of the pyrimidinedione derivative (Compound 78) thus obtained:
Melting point: 168-171~C (decomposed).
IR vma (cm 1): 3400, 3050, 1730, 1630, 1540, 1350, 1080, 760, 700.
Y 26 29N5~6 (COOH)2 H2O
Calculated (%): C, 54.63; H, 5.40; N, 11.38.
Found (%): C, 54.99; H, 5.29; N, 11.30.
Example 51:
Preparation of 1,3-dimethyl-6-{4-t3-(3-acetyl-4-nitrophenoxy)propyl3piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 79):
2~1389 HOCH2CHzCHzN~ - ~ N-CH3 N o CH3CO ~ OH (COOH)z/CH3OH
2N ~ 2 2 2 ~_~ ~ 3 CH3 ~(COOH)2 (Compound 79) By a procedure similar to Example 48-(2) except for the use of 5-hydroxy-2-nitroacetophenone in lieu of 2-hydroxy-5-nitroacetophenone, 1,3-dimethyl-6-{4-[3-(3-acetyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 79) was obtained.
Analytical results of the pyrimidinedione derivative (Compound 79) thus obtained:
Melting point: 223-224~C (decomposed).
IR vmax (cm 1): 3440, 3000, 2600, 1730, 1600, 1520, 1350, 1020, 810.
Elemental analysis for C21H27N5O6 ( 2 2 Calculated (%): C, 48.33; H, 5.82; N, 12.25.
Found (%): C, 48.17; H, 5.62; N, 12.05.
Example 52:
1i 389 Preparation of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 80):
OzN~CI OzN~OH
~=0 ~ ~=0 HOCHz CHz CHzN N ~-CH3 '-- N~- (COOH) z/CH~OH
CH~
02N~oCH2CH2CH2N\JN~N-CH3 ~ CH3 ~(COOH) 2 (Compound 80) (1) Preparation of 2-hydroxy-5-nitrobenzophenone:
In an autoclave, a suspension which had been obtained by suspending 3 g of 2-chloro-5-nitrobenzo-phenone and 1.1 g of potassium hydroxide in 30 mQ of water was heated under stirring at 150~C for 5 hours.
After completion of the heating, the autoclave was allowed to cool down. The resultant reaction mixture was added with 30 mQ of water, followed by the addition of hydrochloric acid to acidify the reaction mixture. Crystals precipitated upon the acidification were collected by filtration.
Z~11389 The thus-obtained crystals were recrystallized from ethanol to obtain 2.3 g of 2-hydroxy-S-nitro-benzophenone.
Analytical results of the crystals thus obtained:
Melting point: 125-126~C.
NMR (CDC13), ~ ppm: 7.21(m,2H), 7.68(m,4H), 8.41(m,2H), IR vmax (cm 1): 3040, 1600, 1520, 1330 1280, 1210, 1080, 960, 690.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 80):
By a procedure similar to Example 48-(2), 0.73 g of 2-hydroxy-5-nitrobenzophenone obtained in the above procedure (1), 0.5 g of 1,3-dimethyl-6-[4-(3-hydroxy-propyl)piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione, 0.58 g of triphenylphosphine and 0.34 m~ of diethyl azodicarboxylate were reacted in 10 m~ of anhydrous tetrahydrofuran, whereby 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione was obtained as a syrup-like matter (0.7 g).
Analytical results of the pyrimidine derivative thus obtained:
2C~)1389 NMR (CDC13), ~ ppm: 8.36(m,2H), 7.0-7.8(m,6H), 5.14(s,1H), 4.14(t,2H), 3.26(s,3H), 3.34(s,3H), 3.0 (m,4H), 2.2-2.5(m,6H), l.9(m,2H).
Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.71 g of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 80).
Analytical results of the pyrimidinedione derivative (Compound 80) thus obtained:
Melting point: 200-202~C (decomposed).
IR vmax (cm 1): 3450, 2910, 1690, 1650, 1510, 1330, 1280, 1150, 1080, 760, 700.
Elemental analysis for C26H29N5O6-~(COOH)2-~H2O:
Calculated (%): C, 57.85; H, 5.39; N, 12.49.
Found (%): C, 57.71; H, 5.54; N, 12.24.
Example 53:
Preparation of Compounds 87-92:
~ ~i13 By a procedure similar to Example 52-(1) except for the use of Compounds 81-86 of the following structural formula (1) - in which Xl means the groups set out below respectively - in place of 2-chloro-5-nitrobenzophenone, phenol derivatives of the below-described structural formula (I') in which Xl varies respectively were obtained as Compounds 81'-86'.
O2N ~ Cl (I) ~7 X
O2N ~ OH (I') xl Compound No. Xl 81, 81' -CO ~ Br 82, 82' -CO ~ NH
83, 83' -CO~
N
84, 84' -CO
85, 85' -CO ~
86, 86' -CO ~ N
2~ 389 Analytical results of Compound 81' thus obtained:
NMR (CDC13), ~ ppm: 8.38(m,2H), 7.70(m,4H), 7.41(m,1H), Elemental analysis for C13H8NO4Br:
Calculated (%): C, 48.47; H, 2.50; N, 4.35;
Br, 24.81.
Found (%): C, 48.52; H, 2.31; N, 4.45;
Br, 24.42.
Analytical results of Compound 83' thus obtained:
IR vmax (cm 1): 1690, 1560, 1400, 1310, 770, 750.
Analytical results of Compound 84' thus obtained:
IR vmax (cm 1): 1660, 1520, 1340, 1270, 1040, 730.
By a procedure similar to Example 52-(2) except that the phenol derivatives, i.e, Compounds 81'-86' were used respectively instead of 2-hydroxy-5-nitro-benzophenone, pyrimidinedione derivative oxalates (Compounds 87-92) having the following physical properties and the following structural formula (II) in which Xl means the below-described groups respective-ly were obtained.
O2N ~ lH2CH2CH2N~_~N ~ ~N_cH3 (II) CH3 ~(COOH)2 2~389 Analytical results of Compound 87 (in which Xl has the same meaning as in Compound 81):
Melting point: 134-135~C (Decomposed).
IR vmax (cm 1): 2900, 1710, 1640, 1530, 1340, 840, 790.
Elemental analysis for C26H28Ns~6Br-(C~~H)2-3H2~
Calculated (%): C, 46.04; H, 4.97; N, 9.59;
Br, 10.94.
Found (%): C, 46.26; H, 5.16; N, 9.92;
Br, 10.53.
Analytical results of Compound 88 (in which Xl has the same meaning as in Compound 82):
Melting point: 171-174~C (Decomposed).
IR vmax (cm 1): 3450, 1710, 1640, 1550, 1440, 1350, 1200, 760.
Elemental analysis for C23H27N7O6-2(COOH)2:
Calculated (%): C, 47.86; H, 4.61; N, 14.47;
Found (%): C, 47.38; H, 5.17; N, 14.40.
Analytical results of Compound 89 (in which Xl has the same meaning as in Compound 83):
Melting point: 149-151~C (Decomposed).
IR vmax (cm 1): 2550, 1700, 1660, 1520, 1340, 850, 800.
e ent n ys s 24H27N7~6 2(COo )2 2 2~
Calculated (%): C, 45.22; H, S.02; N, 13.19;
Found (%): C, 45.60; H, 5.18; N, 13.59.
2~1389 Analytical results of Compound 90 (in which Xl has the same meaning as in Compound 84):
Melting point: 177-178~C (Decomposed).
IR vmax (cm 1): 2950, 1720, 1650, 1520, 51320, 1260, 860, 760.
Element 1 na ys s 25H28N6~6 2(C )2 2 Calculated (%): C, 48.07; H, 5.01; N, 11.60.
Found (%): C, 48.02; H, 5.05; N, 11.31.
Analytical results of Compound 91 (in which Xl has the same meaning as in Compound 85):
Melting point: 104-107~C (Decomposed).
IR vKBr (cm~l~ 2700, 1690, 1630, 1540, max 1340, 1280, 800.
Y 25 28 6 6 ( )2 2 Calculated (%): C, 46.90; H, 5.16; N, 11.32.
Found (%): C, 46.88; H, 5.42; N, 11.38.
Analytical results of Compound 92 (in which Xl has the same meaning as in Compound 86):
Melting point: Amorphous.
IR vmax (cm 1): 1740, 1690, 1600, 1550, 1350, 1260, 780, 700.
Elemental analysis for C25H28N6O6 ( 2 2 Calculated (%): C, 46.29; H, 4.85; N, 11.89.
Found (%): C, 48.85; H, 4.97; N, 11.44.
Example 54:
Preparation of 1,3-dimethyl-6-{4-[2-(2-acetyl--_ - 183 - 2 n ~ 1 ~ 8 9 4-nitrophenoxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 93):
o HOCH2CH2N NH+ Cl ~N-CH3 N o ) HOCHzCH2N N ~ ~-CHs I N
02N~ COCH3 (COOH)2/CH3OH
CH3 ~(COOH)2 (Compound 93) (1) Preparation of 1~3-dimethyl-6-t4-(2-hydroxyethyl) ( piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione:
2.7 g of 6-chloro-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione, 4 ml of 1-(2-hydroxyethyl)pipera2ine and 12 ml of triethylamine were dissolved in 70 ml of isopropanol. The resultant solution was heated under reflux for 3 hours.
After completion of the heating, the reaction mixture was allowed to cool down, the solvent was removed under reduced pressure from the reaction .,, ~,...
2(~:)1389 mixture, and the residue was dissolved in 60 m~ of chloroform. The chloroform solution thus obtained was washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure to obtain the reaction product in a crude form.
Next, a mixed solvent of ethanol and ethyl ether was added to the crude reaction product. Precipitated crystals were collected by filtration. Those crystals were then recrystallized from hexane/ethanol to obtain 3.72 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 5.21(s,1H), 3.69~t,2H), 3.35(s,3H), 3.26(s,3H), 2.5-3.1(m,10H).
(2) Preparation of 1,3-dimethyl-6-{4-t2-(2-acetyl-4-nitrophenoxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 93):
0.5 g of the pyrimidinedione derivative obtained by the above procedure (1), 0.65 g of 2-hydroxy-5-nitroacetophenone, 0.6 g of triphenylphosphine and 2~1389 0.36 m~ of diethyl azodicarboxylate were reacted in a similar manner to Example 48-(2) to obtain 0.65 g of 1,3-dimethyl-6-{4-[2-(2-acetyl-4-nitrophenoxy)ethyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 8.2-8.6(m,2H), 7.08(m,1H), 5.26(s,1H), 4.35(m,2H), 3.42(s,3H), 3.34(s,3H), 2.72(s,3H), 2.7-3.2(m,10H).
Next, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known Per se in the art to obtain 0.68 g of 1,3-dimethyl-6- {4-[2-(2-acetyl-4-nitrophenoxy)ethyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 93):
Analytical results of the pyrimidinedione derivative (Compound 93) thus obtained:
Melting point: 193-195~C (Decomposed~.
IR vKar (cm 1): 3290, 2650, 1720, 1640, 1520, 1340, 1270, 1120, 2~1389 830, 760, 7~0.
Elemental analysis for C20H25N5O6 (C 2 2 Calculated (%): C, 48.98; H, 5.42; N, 12.98.
Found (%): C, 49.02; H, 5.22; N, 12.90.
Example 55:
Preparation of Compounds 99-103:
Using phenol derivatives (Compounds 94-98) having the below-described structural formula (III) in which R7, R8 and R9 mean the below-described groups respectively, pyrimidinedione derivative oxalates (Compounds 99-103) having the physical properties set out below and the below-described structural formula (IV) in which R7, R8 and R9 are different from one compound to another were obtained respectively in a similar manner to Example 54-(2).
R7 ~ OH (III) 2~1389 Compound 94 -H -CO ~ -NO2 A
Compound 95 -H -CO ~ Br -NO2 Compound 96-COCH3 -H -NO2 Compound 97 -H -No2 -COCH3 Compound 98 -H -NO2 -CO
~ 2 2 ~ 3 R R CH3 ~ (COOH)2 (IV) Compound 99 (R7, R8 and R9 are as defined with respect to Compound 94):
Melting point: 160-162~C (decomposed).
IR vmBax (cm 1): 2530, 1700, 1640, 1520, 1340, 760, 700.
Elemental analysis for C25H27N5O6 ( 2 2 Calculated (%): C, 52.34; H, 5.37; N, 11.30.
Found (%): C, 52.14; H, 5.18; N, 11.42.
- 2~ 89 Compound 100 (R7, R8 and R9 are as defined with respect to Compound 95):
Melting point: 136-138~C (decomposed).
IR vKBr (cm-l) 2600, 1700, 1600, 1530, max 1340, 800, 700.
Elemental analysis for C25H26BrN5O6 (C 2 2 Calculated (%): C, 46.43; H, 4.62; N, 10.03;
Br, 11.44.
Found (%): C, 46.64; H, 4.43; N, 10.30;
Br, 11.25.
Compound 101 (R7, R8 and R9 are as defined with respect to Compound 96):
Melting point: 110~C (amorphous).
IR VKBr (cm-l~ 2990, 2550, 1700, 1630, max 1520, 1320, 1180, 800.
Y 20 25N5~6 (COOH)2 3H2O
Calculated (%): C, 45.91; H, 5.78; N, 12.17.
Found (%): C, 45.76; H, 5.54; N, 12.07.
Compound 102 (R7, R8 and R9 are as defined with respect to Compound 97):
Melting point: 139-141~C (decomposed).
IR vKBr (Cm-l~ 3300, 2950, 1700, 1640, max 1530, 1360, 1270, 800, 760.
Elemental analysis for C20H25N5~6-(COOH)2-H2~
Calculated (%): C, 48.98; H, 5.42; N, 12.98.
Found (%): C, 49.08; H, 5.97; N, 12.97.
2C~01389 Compound 103 (R7, R8 and R9 are as defined with respect to Compound 98):
Melting point: 133-135~C (decomposed).
IR vKax (cm 1): 3000, 2550, 1740, 1630, 51540, 1340, 1280, 760, 700.
Elemental analysis for C25H27N5O6 ( 2 2 Calculated (~): C, 53.91; H, 5.19; N, 11.64.
Found (%): C, 53.66; H, 4.96; N, 11.86.
Example 56:
Preparation of 1,3-dimethyl-6-{4-<3-t2-(2-hydroxybenzoyl)-4-nitrophenoxy]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 104):
~5 O
O2N ~ O-(CH2)3N N ~ -CH3 CH3 ~ (COOH)2 OH
(Compound 104) (1) Preparation of 2,2'-dihydroxy-5-nitrobenzophenone (Compound 104'):
~o ~ OH
(Compound 104') A reaction mixture, which had been obtained by suspending 3 g of 2,2'-dichloro-5-nitrobenzophenone and 1.1 g of potassium hydroxide in 30 m~ of water, was heated under stirring at 150~C for S hours in an autoclave.
After allowing the reaction mixture to cool down, 30 m~ of water were added to the reaction mixture. Hydrochloric acid was then added to acidify the reaction mixture, and precipitated crystals were collected by filtration.
Those crystals were dried under reduced pressure to obtain 1.9 g of 2,2'-dihydroxy-S-nitrobenzophenone (Compound 104'). Those crystals were used in the following reactions without any further purification.
(2) Preparation of 1,3-dimethyl-6-t4-<3-C2-(2-hydroxy-benzoyl)-4-nitrophenoxy]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 104):
In a similar manner to Example 48-(2), 0.7S g of 2,2'-dihydroxy-S-nitrobenzophenone obtained in the above procedure (1), O.S g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidine-dione, O.S8 g of triphenylphosphine and 0.34 m~ of diethyl azodicarboxylate were reacted in 10 m~ of anhydrous tetrahydrofuran, and the reaction mixture was treated to obtain 0.6 g of 1,3-dimethyl-6-{4-<3-[2-(2-hydroxybenzoyl)-4-nitrophenoxy]propyl>piperazin-1-yl}-Z6~,389 2,4(lH,3H)-pyrimidinedione.
Next, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain O.6 g of 1,3-dimethyl-6-{4-<3-[2-(2-hydroxybenzoyl~-4-nitro-phenoxy]propyl>-piperazin-l-yl}-2,4tlH,3H)-pyrimidinedione oxalate (Compound 104):
Analytical results of the pyrimidinedione derivative (Compound 104) thus obtained:
Melting point: 144-146~C (decomposed).
IR vmBr (cm~l): 3550, 2900, 2550, 1710, 1640, 1530, 1340, 840, 730, 700.
Y 2 6H29N5~7 2 ( COOH ) 2 H20 Calculated (%): C, 49.93; H, 4.89; N, 9.73.
Found (%): C, 49.83; H, 5.07; N, 9.43.
Example 57:
Preparation of 1,3-dimethyl-6-{4-[3-[2-(2-chlorobenzoyl)-4-nitrophenoxy]propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 105):
~ OCH3 ~ Cl OCH3 02N COCl > 02N ~ CO-- 192 - ~ 3 8 9 ,~,, ~~
) 02N ~ CO
Sr~ ~
HOCH2CH2CH2N N ~ N-CH3 'J N~o (COOH)z/CH30H
~0 2 ~ ~CH2cH2cH2N N ~ -C~3 lOCO ~ CH3 ~ (C~~H)2 (Compound 105) (l) Preparation of 3-(2-chlorobenzoyl)-4-methoxynitro-benzene:
4.0 g of 2-methoxy-5-nitrobenzoyl chloride were dissolved in 100 ml of anhydrous tetrahydrofuran, followed by the addition of 2.72 g of 4-(N,N-dimethyl-amino)pyridine at room temperature. The resultant mixture was then vigorously stirred for 1 hour.
Added dropwise to the reaction mixture at -10~C
after completion of the stirring were 28 ml of a Grignard reagent which had been prepared from 3.82 g of 2-chlorobromobenzene and 0.48 g of metal magnesium in ethyl ether.
After completion of the dropwise addition, the temperature of the reaction mixture was allowed to B
gradually rise to room temperature over 3 hours. Water was then added to the reaction mixture, followed by concentration to dryness. Next, the residue was dissolved in 50 mQ of chloroform and the solution thus obtained was washed with water. The solution was thereafter washed successively with 50 mQ of a 1 N
aqueous sodium hydroxide solùtion, 50 mQ of 1 N
hydrochloric acid and a saturated NaCl solution.
The thus-washed solution was dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was was purified by chromatography on a silica gel column (eluent:
chloroform/hexane = 1/50-1/20, by volume) to obtain 1.55 g of 3-(2-chlorobenzoyl)-4-methoxynitrobenzene.
Analytical results of the compound thus obtained:
NMR (CDC13), ~ ppm: 3.80(s,2H), 6.92-7.75(m,5H), 8.28-8.69(m,2H).
(2) Preparation of 3-(2-chlorobenzoyl)-4-hydroxynitro-benzene:
1.55 g of 3-(2-chlorobenzoyl)-4-methoxynitro-benzene obtained in the above procedure (1) were dissolved in 30 mQ of chloroform, followed by the addition of 5.31 g of iodotrimethylsilane. The thus-obtained solution was then heated under reflux and stirring for 2 hours. The reaction mixture was allowed 2~01389 to cool down, washed with 30 m~ of water, and then extracted twice with a 1 N aqueous sodium hydroxide solution.
Hydrochloric acid was added to the alkaline layer obtained by the above extraction, followed by extraction with chloroform. The organic layer obtained by the chloroform extraction was washed with water and dried over anhydrous sodium sulfate. The solvent was thereafter distilled off from the organic layer, thereby obtaining 0.5 g of 3-(2-chlorobenzoyl)-4-hydroxynitrobenzene in the form of a pale yellow oil.
Analytical results of the pale-yellowish oily compound thus obtained:
NMR (CDC13), ~ ppm: 7.33(d,1H,J=lO,OHz) 7.46-7.83(m,5H), 8.35(d,1H,J=2.5Hz), 8.50(dd,1H,J=2.5,10.0Hz).
(3) Preparation of 1,3-dimethyl-6-{4-<3-[2-(2-chloro-benzoyl)-4-nitrophenoxy]propyl>piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 105):
By a similar procedure to Example 4B-(2) except for the use of 3-(2-chlorobenzoyl)-4-hydroxynitro-benzene obtained by the above procedure (2) in place of 2-hydroxy-S-nitroacetophenone, 0.5 g of 1,3-dimethyl-6-{4-<3-[2-(2-chlorobenzoyl)-4-nitrophenoxy]propyl>-2~)1389 piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 105) was obtained as white crystals.
Analytical results of crystals of Compound 105 thus obtained:
Melting point: Amorphous.
IR vKax (cm 1): 1685, 1650, 1602, 1425, 1335, 1285, 1080, Y 2 6H2 8ClN506 ( COOH ) 2 H20 Calculated (%): C, 51.74; H, 4.96; N, 10.77;
Cl, 5.45.
Found (%): C, 51.50; H, 5.11; N, 10.97;
Cl, 5.71.
Example 58:
Preparation of 1,3-dimethyl-6-{4-<3-[4-nitro-2-(2-pyridinecarbonyl)phenylthio]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 106):
0 2N~Cl OzN /~SCH2CHzCHzCl ~ 0 HSCHzCHzCHzCl ~ 0 ' HN N~N-CH3 - '' N~o CH3 (COOH) z/Cl~H
2~0~389 O N~SCH2cH2cH2N\ - N~-cH3 ~ N CH ~ (COOH)2 (Compound 106) (1) Preparation of l-chloro-3-[2-(2-pyridinecarbonyl)-4-nitrophenylthio]propane:
1.58 g of 4-chloro-3-(2-pyridinecarbonyl)nitro-benzene, 0.66 g of 3-chloro-l-propanethiol and 2 m~ of triethylamine were dissolved in 5 ml of dimethyl-sulfoxide. The resultant solution was heated under stirring at 80~C for 3 hours.
After completion of the heating, the reaction mixture was concentrated and the concentrate thus obtained was dissolved in chloroform. The chloroform solution was washed with water and then dried over anhydrous sodium sulfate.
Next, the solvent was distilled off from the thus-dried solution. The residue was purified by chromatography on a silica gel column (eluent:
chloroform) and then crystallized from a mixed solvent of hexane and ether to obtain 1.0 g of 1-chloro-3-t2-(2-pyridinecarbonyl)-4-nitrophenylthio]propane.
Analytical results of crystals of the compound thus obtained:
Elemental analysis for C15Hl3ClN2O3S:
Calculated (%): C, 53.49; H, 3.89; N, 8.32, S, 9.52; Cl, 10.53.
Found (%): C, 53.29; H, 3.79; N, 8.25;
S, 9.35; Cl, 10.37.
(2) Preparation of 1,3-dimethyl-6-{4-<3-t4-nitro-2-(2-pyridinecarbonyl)phenylthio]propyl>piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 10~):
0.93 g of 1-chloro-3-[2-(2-pyridinecarbonyl)-4-nitrophenylthio]propane, 0.62 g of 1,3-dimethyl-6-(piperazin-l-yl)-2,4(lH,3H)-pyrimidinedione and 2 m~
of triethylamine were dissolved in 10 ml of dimethyl sulfoxide, followed by heating under stirring at 120~C
for 4 hours.
After completion of the heating, the reaction mixture was allowed to cool down, the solvent was distilled off under reduced pressure from the reaction mixture, and the residue was dissolved in chloroform.
The thus-obtained solution was washed with water and then dried over anhydrous sodium sulfate, followed by purification by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1, by volumw) to obtain 0.69 g of 1,3-dimethyl-6-{4-<3-t4-nitro-2-(2-pyridinecarbonyl)phenylthio~propyl>piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione in a yellow solid form.
2C~)1389 Analytical results of the pyrimidinedione derivative thus obtained:
Melting point: 182~C (decomposed).
NMR (CDC13), ~ ppm: 1.89(m,2H), 2.56(m,6H), 3.01(m,4H), 3.36(s,3H), 3.42(s,3H), 3.46(m,2H), 5.28(s,lH), 7.5-8.9(m,7H).
Elemental analysis for C25H28N6O5S-~H2O:
Calculated (%): C, 56.27; H, 5.48; N, 15.75;
Cl, 6.01.
Found (%): C, 56.37; H, 5.36; N, 15.55;
Cl, 5.79.
The pyrimidinedione derivative obtained in the yellow solid form was treated in an oxalic acid/
methanol solution by a method known E~ se in the art to obtain 0.62 g of 1,3-dimethyl-6-{4-<3-t4-nitro-2-(2-pyridinecarbonyl)phenylthio]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 106).
Analytical results of Compound 106 thus obtained:
Melting point: 138~C (decomposed).
IR vKBr (cm~l) 3460, 1693, 1648, 1600, max 1454, 1435, 1346, 722, 500.
Elemental analysis for C25H28N6O5-(COOH)2 ~H2O
Calculated (%): C, 52.00; H, 5.01; N, 13.48;
2~389 S, 5.14.
Found (%): C, 51.81; H, 4.86; N, 13.24;
S, 5.06.
Example 59:
Preparation of 3-methyl-6-{4-[3-(4-nitro-2-~enzoylphenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 107):
OzN ~ ocHzcHzcH2-Br HN NH
OzN ~ OCH2CHzCHzN NH
o Cl ~ N-CH3 N~o (COOH)2/CH30H
, ~ 2 N ~O - CH 2 CH 2 CH - N/--\N ~N - CH
CO H/ O
~ ~ ( COOH ) 2 ( Compound 10 7 ) 2C~1389 (1) Preparation of 1-[3-(2-benzoyl-4-nitrophenoxy)-propyl]piperazine:
3.5 g of 3-benzoyl-4-(3-bromopropyloxy)nitro-benzene and 7.8 g of piperazine were dissolved in 5 30 m~ of chloroform. The resultant solution was heated under reflux for 4 hours.
The resultant reaction mixture was allowed to cool down, washed with water, and dried over anhydrous sodium sulfate. The solvent was thereafter distilled off from the reaction mixture and the residue was crystallized from hexane/ethanol to obtain 3.5 g of 1-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazine.
(2) Preparation of 3-methyl-6-{4-[3-(4-nitro-2-benzoyl-phenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidine-dione oxalate (Compound 107):
1 g of 1-[3-(2-benzoyl-4-nitrophenoxy)propyl]-piperazine, 0.34 g of 6-chloro-3-methyl-2,4(lH,3H)-pyrimidinedione and 0.72 m~ of triethylamine were dissolved in 3 m~ of 2-propanol, followed by heating under reflux for 6 hours.
Precipitated crystals were collected by filtration from the reaction mixture and then recrystallized from isopropanol to obtain 1.9 g of 3-methyl-6-{4-[3-(4-nitro-2-benzoylphenoxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
2~1389 Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 8.41(m, 2H), 7.1-7.9(m,6H), 4.77(s,1H), 4.13(m,2H), 3.15(s,3H), 2.0-2.4(m,10H), 1.74(m,2H).
The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.67 g of 3-methyl-6-{4-t3-(4-nitro-2-benzoylphenoxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 107).
Analytical results of Compound 107 thus obtained:
Melting point: 144-146~C (decomposed).
IR vmBax (cm 1): 3360, 2610, 1710, 1660, 1610, 1520, 1350, 1290, 1100, 750, 700.
Y 2 5 H2 7Ns~6 ( COOH ) 2 2 H20:
Calculated (%): C, 52.34; H, 5.37; N, 11.30.
Found (%): C, 51.89; H, 5.04; N, 11.23.
Example 60:
Preparation of 1,3-dimethyl-6-{2-t3-(2-benzoyl-4-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 108):
2~1389 02N- ~ OH BrCH2CHzCH2Br OzN ~ OCH2CHzCH2-Br ~=0 > ~0 ¢I~N - C H 3 NH2CH2CH2NH N~ tCOOH) 2/C~)H
o O2N ~ O-cH2cH2cH2NHcH2cH2NH ~ -CH
(COOH)2 (Compound 108) (1) Preparation of 3-(2-benzoyl-4-nitrophenoxy)propyl bromide:
1.5 g of 2-hydroxy-5-nitrobenzophenone, 6 ml of 1,3-dibromopropane and 3 g of anhydrous potassium carbonate were heated and reacted under reflux for 6 hours in 10 m~ of 2-butanone.
After completion of the reaction, the reaction mixture was allowed to cool down and unnecessary matters were filtered off. The filtrate was concentrated to obtain a syrup, which was purified by chromatography on a silica gel column (eluent:
hexane/ethyl acetate = 4/1, by volume) and then crystallized form hexane to obtain 1.0 g of 3-(2--benzoyl-4-nitrophenoxy)propyl bromide.
Analytical results of the propyl bromide derivative thus obtained:
Melting point: 86~C.
(2) Preparation of 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitrophenoxy)propylamino]ethylamino}-2,4(1H,3H)-pyrimidi nedione oxalate (Compound 108):
0.77 g of the propyl bromide derivative obtained in the above procedure (1), 0.5 g of 1,3-dimethyl-6-(2-aminoethylamino)-2,4(lH,3H)-pyrimidinedione and 0.7 m~ of triethylamine were reacted at 80~C for 4 hours in 10 ml of dimethylformamide. After distilling off the solvent from the resultant reaction mixture under reduced pressure, chloroform was added to the residue, and the solution thus formed was washed with water, dried and then concentrated to obtain a syrup.
The syrup was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 40/1, by volume~ to obtain 0.51 g of 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.1-8.1(m,8H), 5.14(s,1H), 4.33(t,2H), 3.22(s,3H), 3.36(s,3H), 2 ~ ~ ~ 3 8 9 2.7-3.2tm,6H), 2.1(m,2H).
The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known Per se in the art to obtain 0.43 g of 1,3-dimethyl-6-{2-[3-(2-benzoyl-4-nitrophenoxy)propylamino]ethyl-amino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 108).
Analytical results of Compound 108 thus obtained:
Melting point: 111-113~C (decomposed).
IR ~max (cm 1): 3050, 1730, 1700, 1640, 1520, 1360, 770, 700.
Elemental analysis for C24H27N5O6-(COOH)2 3H2O
Calculated (%): C, 49.92; H, 5.69; N, 11.20.
Found (%): C, 50.11; H, 5.35; N, 11.00.
Example 61:
Preparation of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 109):
< ~ C ~ OH BrCHzCHzCHzBr ~ -CO ~ OCH2CH2CHzBr cH~cu2~2 r~
CO~ OCHZcH2cH2NHcHzcH3 CN~¢~NO (COOH)2/CH30H
3 ~ ~
O CH2CH3 - o <~C~O-CH2CH2CH2NcH2cH2NH~_cH3 NO2 CH3 ~
~ (COOH)2 (Compound 109) (1) Preparation of 5-benzoyl-2-(3-bromopropyloxy)-nitrobenzene:
1.5 g of 4-hydroxy-3-nitrobenzophenone and 1 g of potassium carbonate were added to 5 ml of methyl ethyl ketone. The resultant mixture was heated under stirring for 30 minutes, followed by the addition of 2.0 mQ of dibromopropane. The thus-obtained mixture was stirred for further 4 hours. After allowing the reaction mixture to cool down, insoluble matters were filtered off. The filtrate was then concentrated and cooled to 0~C. Under those conditions, the reaction mixture was added with 10 ml of hexane to conduct sludging. The resultant precipitate of 5-benzoyl-2-26~1389 (3-bromopropyloxy)nitrobenzene was collected by filtration.
Analytical results of the precipitate:
NMR (CDC13), ~ ppm: 7.2-8.3(m,8H), 4.40(t,2H), 3.69(t,2H), 2.47(m,2H).
2.0 g of the precipitate of 5-benzoyl-2-(3-bromopropyloxy)nitrobenzene were employed in the subsequent reaction without purification.
(2) Preparation of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate ~Compound 109):
1.8 g of the 5-benzoyl-2-(3-bromopropyloxy)-nitrobenzene precipitate obtained in the above procedure (1) were reacted with 10 m~ of ethylamine (70 wt.% of solution in water) at 70~C for 1 hour in an autoclave. Thereafter, excess ethylamine was distilled off. The reaction mixture was added with 30 m~ of chloroform and then washed twice with water.
The water-washed chloroform layer was then concentrated to obtain 2.1 g of 5-benzoyl-2-(3-ethyl-aminopropyloxy)nitrobenzene as a roughly-purified oily product.
1.0 g of the roughly-purified oily product, 0.4 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (Compound ~) and 0.05 g of p-toluene-2~,389 sulfonic acid were reacted at 80~C for 3 hours in a solventless state. The reaction mixture was directly subjected to chromatographic purification on a silica gel column (eluent: CHC13/CH30H = 40/1, by volume), thereby obtaining 0.61 g of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.4-8.2(m,8H), 4.99(s,1H), 4.16(t,2H), 3.36, 3.44(s,3H), 2.4-3.0(m,8H), 2.11(m,2H), l.lO(t,3H).
lS The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known per se in the art to obtain O.Sg of 1,3-dimethyl-6-{2-[N-ethyl-3-(4-benzoyl-2-nitrophenoxy)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 109).
Analytical results of Compound 109 thus obtained:
IR vmax (cm 1): 3400, 1690, 1620, 1530, 1360, 1250, 720, 700.
Elemental analysis for C26H31N5O6 ( 2 2 Calculated (%): C, 52.91; H, 5.87; N, 11.02.
Found (%): C, 52.50; H, 5.77; N, 10.92.
2~1389 Example 62:
Preparation of 6-{4-[2-(2-benzoyl-4-nitrophenyl-thio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione oxalate 5(Compound 110):
02N- ~ Cl HSCH2CH20H 02N ~ -SCH2CH20H
O ~ \~0 HN N ~ ~-CH3 '~ N~j (COOH)2/CH30H
o 2 ~ C~2 2 ~ ~ ~ 3 ~ (COOH)2 (Compound 110) (1) Preparation of 2-(2-hydroxyethylthio)-5-nitrobenzo-phenone:
2.0 g of 2-chloro-5-nitobenzophenone and 2.0 g of triethylamine were dissolved in 10 m~ of dimethyl-sulfoxide, followed by the addition of 0.63 g of 2-mercaptoethanol. The resultant mixture was heated under stirring at 80~C for 5 hours. The reaction mixture was poured into water and then extracted with 2~01389 100 m~ of chloroform. After washing the extract with water and then drying it over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 2.0 g of 2-(2-hydroxyethylthio)-5-nitrobenzo-phenone as pale yellow crystals.
Analytical results of the benzophenone derivative thus obtained:
NMR (CDC13), ~ ppm: 8.16-8.50(m,2H), 7.23-8.06(m,6H), 3.86(t,2H), 3.21(t,2H), 2.63(br.s,lH).
(2) Preparation of 6-{4-[2-(2-benzoyl-4-nitrophenyl-thio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione oxalate (Compound 110):
2.0 g of 2-(2-hydroxyethylthio)-5-nitrobenzo-phenone obtained in the above procedure (1) were dissolved in 20 m~ of chloroform, ~ollowed by the addition of 1.6 g of triethylamine. Further, 0.91 g of methanesulfonyl chloride was added at 0~C.
After stirring the resultant mixture at 0~C for 10 minutes, it was stirred at room temperature for further 16 hours. The reaction mixture thus obtained was diluted with 80 mQ of chloroform and then poured into water. The resulting mixture was allowed to separate into layers. The organic layer was washed successively with a 1 N aqueous sodium hydroxide 2C~)1389 solution, water and saturated NaCl solution. Next, the organic layer thus washed was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.50 g of a mesylate as a roughly-purified product.
To a solution of the mesylate in 15 ml of dimethyl sulfoxide, 1.80 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(lH,3H)-pyrimidinedione were added.
The resultant mixture was heated at 80~C for 6 hours.
The thus-obtained reaction mixture was poured into 100 m~ of water in which 2.0 g of potassium carbonate were contained, and was then extracted twice with 50 m~
portions of chloroform. The extracts were combined together, washed with water and then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 25/1, by volume), thereby obtaining 2.0 g of 6-{4-t2-(2-benzoyl-4-nitrophenylthio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione as pale yellow crystals.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDCl3), ~ ppm: 8.27-8.54(m,2H), 7.44-8.07(m,6H), 5.28(s,lH), 3.39(s,3H), 20~)1389 3.35(s,3H), 2.44-3.27(m,12H).
The pyrimidinedione derivative was next treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 6-{4-[2-(2-benzoyl-4-nitrophenylthio)ethyl]piperazin-l-yl}-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione ~Compound 110) as white crystals.
Analytical results of Compound 110 thus obtained:
Melting point: 201.0-202.5~C.
Elemental analysis for C25H27N5O4S-(COOH)2:
Calculated (%): C, 55.57; H, 5.01; N, 12.00;
S, 5.49.
Found (%): C, 55.51; H, 5.55; N, 12.16;
S, 5.38.
Example 63:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-t3-(4-benzoyl-2-nitrophenoxy)propyl]piperazin-l-yl}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 78) available by the process of Example 50:
1 g of the pyrimidinedione derivative oxalate (Compound 78), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of S g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant z~ 389 particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 64: -Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenoxy)propyl]piperazin-1-yl}-2,4-llH,3H)-pyrimidinedione oxalate (Compound 811 available by the process of Example 52:
5 g o~ the pyrimidinedione derivative oxalate (Compound 81), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 65:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-chlorobenzoyl-4-nitrophenoxy]propyl]piperazin-1-yl}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 105) available by the process of Example 57:
20 mg of the pyrimidinedione derivative oxalate (Compound 105) and 0.85 g of sodium chloride were 26~C)1389 weighed. They were dissolved in distilled water for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 4:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 8 and obtained in the corresponding examples described above were determined. The results are summarized in Table 8.
Table 8 Result of Pharmacological Test 75 (~) ERP (~) Compound Dose (~g/m~) Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.03.0 76 16.0 21.0 - 2.4 4.3 12.616.5 78 19.0 42.0 - 6.7 13.3 20 26.7 19.0 30.0 34.0 2.6 9.7 21.9 89 19.0 30.0 - 5.6 11.1 11.1 22.0 31.0 - 20.5 20.5 14.3 99 9.0 22.0 29.0 9.8 14.7 23.1 102 7 20.0 - - - - -104 - 16.0 25.0 105 11.0 23.0 28.0 0 0 6.36.3 Toxicity Test 4:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 9 and obtained in Z~301;~89 the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 9.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table 9 Compound No. Mortality rate (%) 100 o 105 o Example 66:
Preparation of 1,3-dimethyl-6-{4-~3-(2-benzoyl-4-nitroanilino)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 111):
O O
25 1 ~ ~NK + BrCHzCH2CHz8r ~ ~ ~NCH2CH2CH2Br O O
2~1389 HN N ~ N-CH3 N~o ~NCH2CHzCH2N~N ~Y-CH
NH2CHzCH2CH2N N ~ ~-CH302N ~ CO
(COOH)2/CH30H
>
~o O2N ~ N~CH2CH2CH2N N ~ N-CH3 CO CH3 (COOH)2 (Compound 111) (1) Preparation of 1,3-dimethyl-6-{4-(3-aminopropyl)-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione (Compound 158):
A suspension of 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane in 100 ml of dimethylformamide was heated under stirring at 120~C
for 6 hours to react them. Insoluble matters were then filtered off from the reaction mixture and the filtrate was then concentrated to dryness under reduced pressure. The residue was washed with hexane and then 2001~89 recrystallized from ethanol-water. Resulting crystals were collected by filtration, washed and then dried to obtain 13.8 g of N-(3-bromopropyl)phthalimide.
A suspension which had been obtained by suspending 13.0 g of the N-(3-bromopropyl)phthalimide, 10.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4-(lH,3H)-pyrimidinedione (Compound 157) and 20 g of triethyl-amine in 200 m~ of dioxane was heated under reflux for 6 hours.
Further, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated to dryness under reduced pressure. The residue (dry concentrate) was recrystallized from ethyl acetate/n-hexane. Resultant crystals were collected by filtration, washed and then dried, thereby obtaining 12.5 g of 1,3-dimethyl-6-t4-(3-phthaloylaminopropyl)-piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione.
Next, a suspension of 12.5 g of those crystals and 6.0 g of hydrazine hydrate in 200 m~ of ethanol was heated under reflux for 4 hours. After allowing the suspension to cool down, resultant insoluble matters were filtered off. The filtrate was concentrated to dryness under reduced pressure. The residue (dry concentrate) was then dissolved in water, to which dilute hydrochloric acid was added to adjust the pH to about 3. Insoluble matters formed by the pH
2~:;L38~3 adjustment were filtered off. After adding a large amount of potassium carbonate to the filtrate, the resultant mixture was extracted with chloroform.
Subsequent to the completion of the extraction, the resulting organic layer was dried over anhydrous sodium sulfate and then heated under reduced pressure to distill off the solvent, whereby 6.80 g of 1,3-dimethyl-6-[4-(3-aminopropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 158) were obtained as a colorless syrupy substance. The syrupy substance was crystallized when allowed to stand overnight.
(2) Preparation of 1,3-dimethyl-6-t4-[3-(2-benzoyl-4-nitroanilino)propyl~piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 111):
0.9 g of 1,3-dimethyl-6-[4-(3-aminopropyl)-piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione and 1.0 g of 2-chloro-5-nitrobenzophenone were added to 10 m~ of dimethyl sulfoxide. The resultant mixture was heated at 110~C for 20 hours. After allowing the reaction mixture to cool down, the reàction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with chloroform.
An organic layer (chloroform layer) obtained by the extraction was separated, washed with water, dried over anhydrous sodium sulfate, and then concentrated to -2~389 dryness. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 20/1, by volume), thereby obtaining 0.95 g of 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitroanilino)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as a yellow oily substance.
Analytical results of the oily substance of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.04(m,2H), 2.65(m,6H), 3.04(m,4H), 3,36(s,3H), 3.42(s,3H), 3.57(t,2H), 5.30(s,1H), 6.90(d,1H), 7.69(s,5H), 8.35(dd,lH), 8.95(d,lH), 9.50(s,1H).
Further, the oily substance was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 1.0 g of 1,3- dimethyl-6-{4-[3-(2-benzoyl-4-nitroanilino)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 111).
Analytical results of Compound 111 thus obtained:
Melting point: Amorphous.
Elemental analysis for C26H30N6O5-(COOH)2:
Calculated (%): C, 56.37; H, 5.41; N, 14.09.
Found (%): C, 56.92; H, 5.40; N, 14.20.
Example 67:
8~
Preparation of Compounds 120-127:
sy a similar procedure to Example 66-(2) except for the use Compounds 112-119 having the below-described structural formula (I) - in which R7, R8 and R9 mean the below-described groups respectively - in place of 2-chloro-5-nitrobenzophenone, pyrimidinedione derivative oxalates having the physical properties set out below and the below-described structural formula (II) in which R7, R8 and R9 are different from one compound to another were obtained as Compounds 120-127, respectively.
R8 ~ Cl (I) 2~1389 Compound 112-COCH3 -No2 -H
Compound 113-CO ~ -NO2 -H
Compound 114-CO ~ -NO2 -H
Compound 115-CO ~ -NO2 -H
Compound 116-CO ~ N -NO2 -H
Compound 117 -No2 -COCH3 -H
Compound 118 -NO2 -CO ~ -H
Compound 119 -H -NO2 -COCH3 R8 ~ NHCH2CH2CH2N N ~ N-CH3 (II) R7 R9 C/H3 .(COOH)2 -~ 2~1389 Compound 120 (R7, R8 and R9 are as defined with respect to Compound 112):
Melting point: 135-137~C (decomposed).
IR ~KBr (cm-l) 3300, 2550, 1720, 1630, max 1560, 1320, 1250, 800, 710.
enta n lysis for C21H28N6O5 (COOH)2 2H2~
Calculated (~): C, 48.42; H, 6.01; N, 14.73.
Found (%): C, 48.14; H, 5.82; N, 14.32.
Compound 121 (R7, R8 and R9 are as defined with respect to Compound 113):
Melting point: 182-183~C (decomposed).
IR vmax (cm 1): 3350, 2550, 1690, 1630, 1540, 1350, 1290, 1100, 810, 770.
Elemental analysis for C25H34N6O5 ( 2 2 Calculated (%): C, 50.46; H, 6.59; N, 13.08.
Found (%): C, 51.04; H, 6.77; N, 12.90.
Compound 122 (R7, R8 and R9 are as defined with respect to Compound 114):
Melting point: Amorphous.
Y 26 29N6O5Cl (COOH)2 ~H2O
Calculated (%): C, 52.54; H, 5.04; N, 13.13;
Cl, 5.54.
Found (%): C, 52.36; H, 5.05; N, 13.14;
Cl, 5.23.
2~01389 Compound 123 (R7, R8 and R9 are as defined with respect to Compound 115):
Melting point: 151~C (decomposed).
IR vmax (cm 1): 3440, 1706, 1645, 1588, 1496, 1441, 1333, 1200, 768, 722, 500.
Elemental analysis for C25H29N7O5~ COOH)2-H2O:
Calculated (%): C, 50.91; H, 5.19; N, 14.84.
Found (%): C, 51.12; H, 5.10; N, 14.81.
Compound 124 (R7, R8 and R9 are as defined with respect to Compound 116):
Melting point: 162-165~C (decomposed).
IR vKBr (Cm-l~ 3400, 1690, 1600, 1550, max 1350, 1260, 1150, 780, 700.
e en y 25 29 7~5 ( )2 2 Calculated (%): C, 48.00; H, 4.83; N, 13.06.
Found (%): C, 48.38; H, 4.92; N, 12.91.
Compound 125 (R7, R8 and R9 are as defined with respect to Compound 117):
Melting point: 148-150~C (decomposed).
IR vKBr (cm 1): 3350, 2600, 1690, 1640, 1530, 1330, 1240, 980, 760, 700.
Elemental analysis for C25H34N6O5-(COOH)2-3H2O:
Calculated (%): C, 50.46; H, 6.59; N, 13.08.
26g~1389 Found (%): C, 51.04; H, 6.77; N, 12.90.
Compound 126 (R7, R8 and R9 are as defined with respect to Compound 118):
Melting point: 202-203~C (decomposed).
IR vKBr (cm-l) 3560, 2550, 1700, 1610, lS30, 1320, 1280, 1110, 810, 710.
Y 26 30 6~5 (C ~ )2 2 Calculated (%): C, 54.72; H, 5.58; N, 13.67.
Found (%): C, 54.68; H, 5.21; N, 13.47.
Compound 127 (R7, R8 and R9 are as defined with respect to Compound 119):
Melting point: about 140~C (amorphous).
IR vKBr (cm~l) 3420, 2600, 1710, 1640, max 1540, 1320, 1220, 1110, 810, 710.
Y 21 28 6~5 (C ~ )2 2 2 Calculated (%): C, 48.24; H, 5.57; N, 14.06.
Found (%): C, 44.11; H, 5.90; N, 13.89.
Example 68:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitroanilino)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 111) available by the process of Example 66:
2~1389 1 g of the pyrimidinedione derivative oxalate tCompound 111), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of S g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 69:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-acetyl-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 120) available by the process of Example 67:
5 g of the pyrimidinedione derivative oxalate (Compound 120), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 70:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitroanilino]propyl]piperazin-1-yl}-2,4-(lH,3H~-pyrimidinedione oxalate (Compound 111) available by the process of 2(~ 389 Example 66:
20 mg of the pyrimidinedione derivative oxalate (Compound 111) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 5:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 10 and obtained in the corresponding examples described above were determined. The results are summarized in Table 10 .
Table 10 15 Result of Pharmacological Test 75 (%) ERP (%) Compound Dose (~g/m~) Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.0 3.0 111 13.0 21.0 - 7.710.9 14.0 21.0 120 16.0 27.0 29.0 125 - 10.0 21.0 126 23.0 45.0 48.0 7.014.0 21.0 Toxicity Test 5:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 11 and obtained in 20~389 the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 11.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table ll Compound No.Mortality rate (%) 122 o Example 71:
Preparation of 1,3-dimethyl-6-{4-(2-benzoyl-4-nitrophenyl)piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 128):
C ~
02N~CO-~> + HN N~l-CH3 --(COOH) 2/CH30H, 2~1!~i~89 CO / O
CH3 ~(COOH)2 ~ (Compound 128) 0.5 g of 1,3-dimethyl-6-(piperazin-1-yl)-S 2,4(1H,3H)-pyrimidinedione (Compound 157) and 0.6 g of 3-benzoyl-4-chloronitrobenzene were added to S ml of dimethylsulfoxide. The resultant mixture was heated at 110~C for 20 hours. After allowing the reaction mixture to cool down, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with chloroform.
An organic layer tchloroform layer) obtained by the extraction was separated, washed with water, dried over anhydrous sodium sulfate, and then concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 20/1, by volume), thereby obtaining 0.2 g of 1,3-dimethyl-6-[4-(2-benzoyl-4-nitrophenyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (d6-DMso)~ ~ ppm: 2.64(m,2H), 3.18(m,6H), 3.28(s,3H), 3,17(s,3H), S.OO(s,lH), 7.3-8.0(m,5H), ~1389 -8.2-8.6(m,3H).
Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.18 g of 1,3-dimethyl-6-[4-(2-benzoyl-4-nitrophenyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione oxalate (Compound 128).
Analytical results of Compound 128 thus obtained:
Melting point: 178-179~C (decomposed).
IR vmBax (cm 1): 3430, 1700, 1660, 1600, 1520, 1320, 1260, 1130, 950, 860, 760, 700.
Elemental analysis for C23H23N5O5-~(COOH)2-~H2O:
Calculated (%): C, 57.25; H, 5.01; N, 13.91.
Found (%): C, 57.55; H, 4.80; N, 13.56.
Example 72:
Preparation of 1,3-dimethyl-6-{3-[4-nitro-2-(3-pyridinecarbonyl)anilino]propylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 129):
~ Cl ~ + H2NCHzCH2CHzNH- ~ -CH3 , (COOH)2/CH30H, 2~ 389 2 ~ 2 2CH2NH ~ CH3 CH3 ~(COOH)2 N
(Compound 129) 0.67 g of 4-chloro-3-(3-pyridinecarbonyl)nitro-benzene and 0.6 g of 1,3-dimethyl-6-(3-aminopropyl-amino)-2,4(1H,3H)-pyrimidinedione were dissolved in 3 m~ of dimethylformamide, followed by the addition of 0.79 m~ of triethylamine. The resultant mixture was heated under stirring at 80~C for 5 hours.
After completion of the heating, the reaction mixture was allowed to cool down and the solvent was then distilled off. The residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume) to obtain 0.39 g lS of 1,3-dimethyl-6-{3-[4-nitro-2-(3-pyridinecarbonyl)-anilino]propylamino}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 9.40(m,lH), 8.84(m,6H), 7.86-8.S7(m,3H), 7.50(dd,1H), 6.85(d,1H), 5.90(m,1H), 4.86(s,1H), 3.23(s,3H), 3.38(s,3H), 3.40(m,4H), 2.1(m,2H).
2~31389 Further, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.36 g of 1,3-dimethyl-6-{3-t4-nitro-2-(3-pyridinecarbonyl)anilino~ -propylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 129).
Analytical results of Compound 129 thus obtained:
Melting point: 136-139~C (decomposed).
IR vmBax (cm 1): 3350, 2550, 1690, 1640, 1550, 1330, 1260, 1110, 770, 700.
Elemental analysis for C21H22N6O5-(COOH)2:
Calculated (%): C, 52.27; H, 4.58; N, 15.90.
Found (%): C, 52.25; H, 4.92; N, 15.51.
~5 Example 73:
Preparation of 1,3-dimethyl-6-t3-(2-benzoyl-4-nitroanilino)propylamino]-2,4(1H,3H)-pyrimidinedione oxalate (Compound 130):
~ Cl ~ NH2CHzCHzCHzNH ~ ~-CH3 >
OzN~ CO- ~ ,N~o (COOH)2/CH30H
>
2 ~ 2C 2CH2NH ~ N CH3 CH3 ~(COOH)2 (Compound 130) By a similar procedure to Example 72 except for the use of 3-benzoyl-4-chloronitrobenzene in place of 4-chloro-3-(3-pyridinecarbonyl)nitrobenzene, 1,3-dimethyl-6-[3-(2-benzoyl-4-nitroanilino)propyl-amino]-2,4(1H,3H)-pyrimidinedione oxalate (Compound 130) was obtained.
Analytical results of Compound 130 thus obtained:
Melting point: amorphous.
IR vmax (cm 1): 3300, 1690, 1620, 1540, 1330, 1110, 990, 850, 760, 700.
Elemental analysis for C22H23N505-~(COOH)2:
Calculated (%): C, 57.26; H, 5.01; N, 14.52.
Found (%): C, 57.16; H, 4.63; N, 14.76.
Example 74:
Preparation of 1,3-dimethyl-6-[2-(2-benzoyl-4-nitroanilino)ethylamino]-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 131):
~ Cl + NH2CH2CH2NH ~ -CH
ozlYJ~-~'C0 ~ N 0 -2C~0~389 02N~NHCH2CH2NH~ CH3 (Compound 131) By a similar procedure to Example 73 except tha~
1,3-dimethyl-6-(2-aminoethylamino)-2,4(lH,3H)-pyrimidinedione was reacted in place of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione with 3-benzoyl-4-chloronitrobenzene, 1,3-dimethyl-6-[2-(2-benzoyl-4-nitroanilino)ethylamino]-2,4(lH,3H)-pyrimidinedione (Compound 131) was obtained.
Analytical results of Compound 131 thus obtained:
Melting point: 207-209~C (decomposed).
IR vmBr (cm 1): 3050, 2950, 1760, 1680, 1560, 1340, 1110, 760, 700.
Y 21H21N5~5 (COOH)2 H20 Calculated (%): C, 51.98; H, 4.74; N, 13.18.
Found (%): C, 51.81; H, 4.87; N, 12.97.
Example 75:
Preparation of 1,3-dimethyl-6-{2-[4-nitro-2-(3-pyridiencarbonyl)phenylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 132):
o CO-~ + NHzCH2CH2NH ~N-CH3 2~01~89 021~NHCH2CH2NH~N--CH3 (Compound 132) By a similar procedure to Example 72 except for the use of 1,3-dimethyl-6-(2-aminoethylamino)-2,4(lH,3H)-pyrimidinedione in place of 1,3-dimethyl-6-(3-aminopropylamino)-2,4(1H,3H)-pyrimidinedione, 1,3-dimethyl-6-{2-[4-nitro-2-(3-pyridinecarbonyl)phenyl-amino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound 132) was obtained.
Analytical results of Compound 132 thus obtained:
Melting point: 148~C.
IR VmBax (cm ): 3380, 3200, 1692, 1630, 1587, 1333, 1265, 1155, 1115 .
Elemental analysis for C20H20N6O5-H2O:
Calculated (%): C, 54.30; H, 5.01; N, 19.00.
Found (%): C, 54.04; H, 4.71; N, 18.84.
Example 76:
- Preparation of 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-1-yl)-2,4(lH,3H)-pyrimidinedione oxalate (Compound 133):
HN NH ((CH 3 ) 3 COCO ) 2 0 02N ~ CHzCHz-Br > >
N0z ~ HzCHzN N-COC(CH 3) 3 - 234 - 20~3~9 ~N-CH3 ~COCl H~ C)~O (COOH) z/CH30H
~ 2 2~_, '1~ 3 CE13 ~ (COOEI)2 \ /
(Compound 133) (1) Preparation of l-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonylpiperazine:
1.7 g of 4-nitrophenethyl bromide and 5 g of piperazine were dissolved in 15 ml of chloroform. The ( resultant solution was heated under reflux for 3 hours.
After completion of the reaction, the reaction mixture was allowed to cool down and washed three times with water to remove excess piperazine from the reaction mixture. Then, the chloroform layer was separated.
Next, the solvent was removed under reduced pressure from the chloroform layer. The residue was dissolved in 15 me of dry tetrahydrofuran, followed by the addition of 1.6 g of di-tert-butyl dicarbonate.
~. .
2~C~1389 The mixture thus obtained was stirred at room temperature for 1 hour and the solvent was distilled off from the reaction mixture.
A hexane/ethanol mixed solvent was added to the residue. The thus-precipitated crystals were collected by filtration and then recrystallized from a hexane/ethanol mixed solvent, thereby obtaining 2.4 g of l-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonyl-piperazine.
Analytical results of the piperazine derivative thus obtained:
Melting point: amorphous.
NMR (CDC13), ~ ppm: 8.14(d,2H), 7.34(d,2H), 3.41(m,4H), 2.74(m,4H), 2.43(m,4H), 1.45(s,9H).
(2) Preparation of 1,3-dimethyl-6-{4-t2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 133):
0.8 g of 1-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonylpiperazine was dissolved in 20 m~ ofdry tetrahydrofuran, followed by the addition of 1 m~
of hexamethylphosphorus triamide. While chilling the resultant mixture at -78~C, 2.9 m~ of a 1 M solution of lithium diisopropylamide in dry tetrahydrofuran were added.
Z¢~ 89 Upon an elapsed tie of 1 hour after completion of the addition, the temperature of the reaction mixture was maintained at -78~C and 0.83 m~ of benzoyl chloride was then added dropwise.
After completion of the dropwise addition, the temperature of the reaction mixture was gradually raised to -30~C, at which the reaction mixture was stirred for 3 hours. The reaction mixture was then poured into ice water, followed by extraction with chloroform.
The extract was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a syrupy substance.
The syrupy substance was dissolved in 30 m~ of ethyl ether, followed by the addition of 2 m~ of hydrochloric acid/dioxane (4 N). The resultant mixture was stirred at room temperature for 30 minutes.
The resultant crystals were collected by filtra-tion and then washed with ether.
The crystals were next dissolved in 20 m~ of isopropanol, to which 0.5 g of 1,3-dimethyl-6-chloro-2,4(1H,3H)-pyrimidinedione and 3 m~ of triethylamine.
The thus-prepared mixture was stirred under reflux for 6 hours.
After completion of the stirring, the solvent was distilled off from the reaction mixture. The Z~1389 residue was dissolved in chloroform. The resultant chloroform solution was washed with water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure.
The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1, by volume) to obtain 0.33 g of 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.3-8.2(m,8H), 5.06(s,1H), 3.28(s,3H), 3.39(s,3H), 2.4-3.0(m,12H).
Next, the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.34 g of 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 133):
Analytical results of Compound 133 thus obtained:
Melting point: 183-185~C (decomposed).
IR vmax (cm 1): 3350, 2850, 2500, 1710, 1660, 1520, 1340, 1210, 840, 800, 750, 700.
Elemental analysis for C25H27N5O5 ( 2 2 2~01389 Calculated (%): C, 55.38; H, 5.34; N, 11.96.
Found (%): C, 55.16; H, 5.11; N, 12.01.
Example 77:
Preparation of 1,3-dimethyl-6-{4-t(2-benzoyl-4-nitrophenyl)methyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 134):
HN NH ((CH 3 ) 3 CO CO ) 2 0 NO2~&:H2Br > >
NO 2~3CH2N~,N-COOC (CH3 ) 3 ~N-CH3 (~COCl H~ Cl Nl o (COOH) 2/CH30H
> > > >
O ~ C ~ 4~
~ CH3 ~(COOH)2 tCompound 134) (1) Preparation of l-t(4-nitrophenyl)methyl]-4-tert-butyloxycarbonylpiperazine:
By a similar procedure to Example 76-(1) except for the use of 1.6 g of 4-nitrobenzyl bromide in place of 4-nitrophenethyl bromide, 1.1 g of 1-[(4-nitro-phenyl)methyl~-4-tert-butyloxycarbonylpiperazine.
2~
Analytical results of the piperazine derivative thus obtained:
NMR (CDC13), ~ ppm: 8.11(d,2H), 7.44(d,2H), 2.96(m,4H), 2.73(m,4H), 1.51(s,9H).
(2) Preparation of 1,3-dimethyl-6-{4-[(2-benzoyl-4 nitrophenyl)methyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 134):
In a manner similar to Example 76-(2) except for the use of 0.77 g of 1-[(4-nitrophenyl)methyl]-4-tert-butyloxycarbonylpiperazine obtained in the above procedure (1) in place of 1-[2-(4-nitrophenyl)ethyl]-4-tert-butyloxycarbonylpiperazine, 0.10 g of 1,3-dimethyl-6-{4-[(2-benzoyl-4-nitrophenyl)methyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 134) was obtained.
Analytical results of Compound 134 thus obtained:
Melting point: amorphous.
IR vKBr (cm~l~ 3350, 1700, 1630, 1530, max 1360, 1120, 860, 760, 700.
y s 24H25N505 1/2(COOH)2 3/2H20:
Calculated (~): C, 56.42; H, 4.92; N, 12.65.
Found (~): C, 56.12; H, 4.77; N, 12.39.
Example 78:
Preparation of 1,3-dimethyl-6-{2-[(2-benzoyl-4-2~1389 nitrophenyl)methylamino]ethylamino}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 135):
OzN ~ Cl CH2(S ~ )2 HgCl2 H~
S CO~
02N ~ CHO
CO,-~>
~
HzNCHzCHzNH-y N-CH3 N~o ( co OH~2/MeOH
02N ~ CH2NHc~2cH2NH ~ -CH3 C~3 ~(COOH)2 (Compound 135) (l) Preparation of 2-benzoyl-4-nitrobenzaldehyde:
3.72 g of bisthiophenylmethane were dissolved in 40 mQ of tetrahydrofuran and the resultant solution was chilled to -20~C. 12 m~ of n-butyl lithium (1.6 M solution in hexane) were added dropwise, followed by stirring at -20~C for l hour.
After completion of the stirring, a solution of 4 g of 3-benzoyl-4-chloronitrobenzene in 20 ml of 2(~ 389 tetrahydrofuran was added dropwise while maintaining the temperature of the reaction mixture at -20~C.
Subsequent to completion of the dropwise addition, they were reacted for 1 hour while controlling the temperature of the reaction mixture within a range of from -78~C to -20~C.
After completion of the reaction, the reaction mixture was poured into water and then extracted with 400 m~ of ether. The extract layer (ether layer) was washed twice with 200 m~ of water and dried over anhydrous magnesium sulfate.
The solvent was next distilled off from the extract under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = lO/l, by volume) to obtain an oily substance.
The oily substance was dissolved in 40 m~ of acetonitrile, to which a solution of 2.0 g of mercuric chloride in 20 m~ of water was added dropwise.
Subsequent to completion of the dropwise reaction, 0.1 g of p-toluenesulfonic acid was added further and was reacted at 60~C for 4 hours.
After completion of the reaction, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated. The resultant concent-rate was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = 10/1, by volume) to obtain 1.1 g of crude 2-benzoyl-4-nitrobenzaldehyde as an oily substance.
(2) Preparation of 1,3-dimethyl-6-{2-t(2-benzoyl-4-nitrophenyl)methylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 135):
A solution of 1.0 g of 1,3-dimethyl-6-(2-amino-ethylamino)-2,4(lH,3H)-pyrimidinedione in 20 m~ of methanol, a solution of 1.1 g of the crude product of 2-benzoyl-4-nitrobenzaldehyde in 10 m~ methanol and 0O3 mQ of a 4 N solution of hydrochloric acid in dioxane were separately cooled to 0~C, mixed together and then reacted at 0~C for 1 hour.
After completion of the reaction, 0.1 g of sodium cyanoborohydride, followed by a reaction at 0 + 5~C for 3 hours.
After the reaction was completed, the reaction mixture was acidified with 1 N hydrochloric acid and then poured into ice water. The resultant mixture was rendered basic with sodium bicarbonate and then extracted twice with 50 mQ portions of chloroform.
Subsequent to completion of the extraction, the chloroform layer was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure.
- 2~1il389 The thus-obtained concentrate was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 10/1, by volume) to obtain 0.7 g of 1,3-dimethyl-6-{2-t(2-benzoyl-4-nitrophenyl)methyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 7.2-8.1(m,8H), 5.68(b,1H), 4.89(s,1H), 3.61(s,2H), 3.34(s,3H), 3.39(s,3H), 3.06(m,4H).
Further, 0.5 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known Per se in the art to obtain 0.11 g of 1,3-dimethyl-6-{2-[(2-benzoyl-4-nitrophenyl)methylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 135).
Analytical results of Compound 135 thus obtained:
Melting point: hygroscopic amorphous.
IR vmax (cm 1): 3400(br), 2700, 2550, 1700, 1620, 1530, 1340, 1120, 820, 720, 700.
Y 22H23N5~5 2(cooH)2 3H20 Calculated (%): C, 46.50; H, 4.95; N, 10.43.
Found (%): C, 46.82; H, 4.65; N, 10.25.
Z~)1389 Example 79:
Preparation of 1,3-dimethyl-6-{4-t3-(4-benzoyl-2-nitrophenyl)propyl~piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 136):
O ' O
C ~ Cl I, ~ C ~ I H2C=CH-COOCH3 NOz NO2 ~ -C ~ -CH=CH-COOCH3 OH
> ~ -CH ~ -CH=CH-COOCH3 'NO2 o ~ -C ~ CH2CHzCHzOH
HN N ~ -CH3 CH3 ~ SOzCl'J N~o HCl/CH30H
CH2CH2N~ ~N~N-CH3 (Compound 136) ~1) Preparation of 4-iodo-3-nitrobenzophenone:
A mixture of 10.44 g of 4-chloro-3-nitrobenzo-phenone, 60 g of sodium iodide and 60 m~ of dimethyl-formamide was heated under reflux for 15 hours.
The reaction mixture was cooled and then poured into 800 m~ of water. Precipitated crystals were collected by filtration.
The precipitated crystals were washed with water, dried under reduced pressure and then purified by chromatography on a silica gel column (eluent:
c~loroform/hexane = 2/1 - 10/1, by volume), thereby obtaining 10.17 g of 4-iodo-3-nitrobenzophenone as yellow crystals.
Analytical results of the benzophenone derivative thus obtained:
i5 NMR (CDC13), ~ ppm: 8.35(d,1H), 8.26(d,1H), 7.40-8.10(m,6H).
(2) Preparation of methyl 4-benzoyl-2-nitrocinnamate:
10.17 g of 4-iodo-3-nitrobenzophenone obtained in the above procedure (1), 4.10 g of methyl acrylate and 4.70 g of triethylamine were dissolved in 130 m~
of acetonitrile and then degasified. The resultant solution was added with 0.65 g of palladium (II) acetate and heated under reflux for 6 hours under a nitrogen gas stream, whereby a reaction was conducted.
After allowing the reaction mixture to cool down, the 2~1389 solvent was distilled off from the reaction mixture under reduced pressure. Benzene was added to the residue. The resultant solution was washed successively with water, 1 N hydrochloric acid, a saturated solution of sodium bicarbonate and a saturated NaCl solution.
The thus-washed organic layer was dried over anhydrous sodium sulfate and the solvent was then distilled off under reduced pressure. The residue was thereafter purified by chromatography on a silica gel column (eluent: chloroform) to obtain 7.12 g of methyl 4-benzoyl-2-nitrocinnamate as pale yellow crystals.
Analytical results of the cinnamic acid derivative thus obtained:
NMR (CDC13), ~ ppm: 8.43(d,1H), 7.48-8.38(m,8H).
6.51(d,1H), 3.84(s,3H).
(3) Preparation of 2-nitro-4-(a-hydroxybenzyl)-cinnamic acid:
7.12 g of methyl 4-benzoyl-2-nitrocinnamate obtained in the above procedure (2) were dissolved in 120 m2 of methanol, followed by the addition of 0.90 g of sodium borohydride at room temperature. After stirring the resultant mixture at the same temperature for 10 hours, a small amount of water was added to terminate the reaction.
2~ 89 The solvent was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in benzene. The resultant solution was washed successively with 200 m~ of water and 200 mQ
of a saturated NaCl solution.
The thus-washed organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, thereby obtaining 7.12 g of methyl 2-nitro-4-(a-hydroxybenzyl)cinnamate as an pale yellow oily substance.
Further, 7.12 g of the pale yellow oily substance were dissolved in 60 m~ of methanol, followed by the addition of 40 m~ of a 1 N aqueous solution of potassium hydroxide at room temperature.
The resultant solution was vigorously stirred for 3 hours at the same temperature. After completion of the stirring, the reaction mixture was poured into water and then neutralized with 1 N hydrochloric acid.
Precipitated crystals were collected by filtration and then washed with water.
The crystals thus obtained were dried under reduced pressure to obtain 6.95 g of 2-nitro-4-(a-hydroxybenzyl)cinnamic acid in a purified form.
Analytical results of the product thus obtained in the purified form:
Elemental analysis for C16H13NO5:
Calculated (%): C, 64.21; H, 4.38; N, 4.68.
Found (%): C, 63.79; H, 4.95; N, 4.21.
(4) Preparation of 3-(4-benzoyl-2-nitrophenyl)-1-propanol:
3.54 g of 2-nitro-4-(a-hydroxybenzyl)cinnamic acid obtained in the above procedure (3), 13.38 g of hydroxyamine-O-sulfonic acid and 9.69 g of hydroxyl-amine sulfate were suspended in 180 m~ of water. The resulting suspension was cooled and while maintaining its internal temperature at 20-30~C, a 50% aqueous solution of sodium hydroxide (about 22 m~ in total) was added dropwise thereto.
After the mixture was stirred at the same temperature for 3 hours to react them, the reaction mixture was ice-cooled. The reaction mixture was then added with 6 N sulfuric acid to acidify same, and precipitated crystals were collected by filtration.
The thus-obtained crystals were washed with water and then dried under reduced pressure to obtain 3.48 g of 3-[2-nitro-4-(a-hydroxybenzyl)phenyl]propionic acid as crystals.
3.3 g of the crystals of the phenylpropionic acid derivative thus obtained were dissolved in 70 mQ
of tetrahydrofuran. The resultant solution was added with 1.4 me of boran-dimethylsulfide complex, followed by stirring. Upon an elapsed time of 6 hours, 2~01389 5 mQ of water was added to the reaction mixture to terminate the reaction. The solvent was distilled off from the reaction mixture under reduced pressure and the residue was dissolved in 100 m~ of chloroform.
The chloroform solution was washed successively with water, a lN aqueous solution of sodium hydroxide and a saturated saline solution. The thus-washed organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 2.90 g of crude 3-[2-nitro-4-(~-hydroxybenzyl)phenyl]propanol.
2.90 g of the crude product were dissolved in 100 m~ of chloroform, followed by the addition of 20 g of celite and 9.0 g of manganese dioxide. The resultant mixture was vigorously stirred for 24 hours at room temperature.
After completion of the stirring, the reaction mixture was filtered and the filtrate was concentrated to dryness to obtain 2.87 g of 3-(4-benzoyl-2-nitro-phenyl)-l-propanol.
Analytical results of the phenylpropanol derivative thus obtained:
NMR (CDC13), ~ ppm: 8.12(d,1H), 7.80(dd,1H), 7.00-7.72(m,6H).
3.64(t,2H), 3.00(t,2H), 1.92(m,2H), 1.84(brs,1H).
2~ 89 (5) Preparation of 1,3-dimethyl-6-{4-~3-(4-benzoyl-2-nitrophenyl)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 136):
1.0 g of 3-(4-benzoyl-2-nitrophenyl)-1-propanol obtained in the above procedure(4) and 1.38 g of pyridine were dissolved in 20 m~ of chloroform. The resultant mixture was added under ice-cooling with 1.34 g of p-toluenesulfonyl chloride. The resultant mixture was stirred for 10 minutes at the same temperature and for additional 16 hours at room temperature.
The thus-obtained reaction mixture was added with 2 m~ of water and then stirred for 3 hours at room temperature. After addition of 50 m~ of chloroform, the reaction mixture was poured into 50 mQ
of water. The thus-formed mixture was allowed to separate into layers. The organic layer was washed successively with 1 N hydrochloric acid, a 1 N aqueous solution of sodium hydroxide and a saturated saline solution and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.51 g of 3-(4-benzoyl-2-nitro-phenyl)-l-propyl p-toluenesulfonate as an oily yellow substance.
Z~)1389 1.51 g of the oily yellow substance were dissolved in 10 m~ of dimethyl sulfoxide. The resultant solution was added with 1.10 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(lH,3H)-pyrimidinedione and then heated at 80~C for 6 hours to react them.
The resultant reaction mixture was poured into a solution which had been obtained by adding 2.0 g of potassium carbonate to 100 m~ of water. The thus-prepared mixture was extracted twice with 50 m~
portions of chloroform.
The organic layers separated by the two extraction operations were combined, washed with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 50/1 - 20/1, by volume), thereby obtaining 0.92 g of 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenyl)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione as pale yellow crystals.
Analytical results of the pyridine derivative thus obtained:
NMR (CDC13), ~ppm: 8.23(d,1H), 7.16-8.10(m,7H), 5.21(s,1H), 3.36(s,3H), 3.29(s,3H), -- - 252 - 2 ~ O ~ 3 8 9 2.26-3.26(m,12H), 1.96(m,2H).
Next, the pyrimidinedione derivative was treated in a hydrochloric acid/methanol solution by a method S known per se in the art to obtain 0.9 g of 1,3-dimethyl-6-{4-[3-(4-benzoyl-2-nitrophenyl)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-( chloride (Compound 136) as white crystals:
Analytical results of Compound 136 thus obtained:
Elemental analysis for C26H29N5O5-HCl:
Calculated (%): C, 59.14; H, 5.73; N, 13.26;
Cl, 6.71.
Found (~): C, 59.56; H, 6.09; N, 13.16;
Cl, 6.21.
Example 80:
Preparation of 1,3-dimethyl-6-{4-[2-(4-benzoyl-- 2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 137):
O O
--'~ ~ HOCHzCH2CH20H ~ \/ ~
25'~CO-,/,~Cl ~ ~C~Cl _ - 253 - 2 G ~ ~ ~ 8 9 ~rCH 2 CO OCzH 5 \ / 1) HCl > ~ C- ~ CH2COOC2H5 >
NOz ~)NdOH
C ~ CHzCOOH ~ ~ C ~ CHzCH20H
HN N- ~ N-CH3 10 CH3- ~ SOzCl '' ~o (COOH)2/CH30H
CH3 >
C ~ C 2CH2N~_~N~ N-CH3 CH3 ~(COOH)2 ( Compound 137) (1) Preparation of 2-(4-chloro-3-nitrophenyl)-2-phenyl-1,3-dioxane:
10 g of 4-chloro-3-nitrobenzophenone, 15 ml of 1,3-propanediol and 0.5 g of camphorsulfonic acid were dissolved in 50 ml of benzene and while eliminating water by a molecular sieve ("Molecular Sieves 3A", trade mark; 1/16 pellets; product of Junsei Chemical Co., Ltd.), were reacted under reflux for 12 hours.
The resultant reaction mixture was allowed to cool down, washed with a 1 N aqueous solution of sodium , ~ .
Z~)1389 hydroxide, washed further with water, dried and then concentrated, thereby obtaining an oily substance.
Next, the oily substance was purified by chromatography on a silica gel column (eluent:
hexane/ethyl acetate = 4/1, by volume) to obtain 7.8 g of 2-(4-chloro-3-nitrophenyl)-2-phenyl-1,3-dioxane.
Analytical results of the compound thus obtained:
Elemental analysis for C16H13NO4Cl:
Calculated (%): C, 60.29; H, 4.11; N, 4.39;
Cl, 11.12.
Found (%): C, 60.09; H, 4.56; N, 4.01;
Cl, 11.29.
(2) Preparation of ethyl 4-(2-phenyl-1,3-dioxan-2-yl)-2-nitrophenylacetate:
lS 5.2 g of zinc powder were suspended in a mixed solution of 10 m~ of benzene and 10 m~ of trimethyl borate. In a nitrogen gas atmosphere, 9 m~ of ethyl bromoacetate were added dropwise at room temperature to the suspension to react them.
Upon an elapsed time of 1 hour, the reaction mixture was added further with a solution of 7.8 g of 2-(4-chloro-3-nitrophenyl)-2-phenyl-1,3-dioxane in 40 m~ of benzene, 0.9 m~ of dimethylformamide and 0.22 g of tris(triphenylphosphine) palladium(II) chloride. The resultant mixture was allowed to stand overnight at room temperature to react them.
Z6~1389 Insoluble matters were then filtered off and the filtrate was concentrated. The thus-obtained filtrate was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = 3/1, by volume), thereby obtaining 4.4 g of ethyl 4-(2-phenyl-1,3-dioxan-2-yl)-2-nitrophenylacetate in an oily form.
Analytical results of the ethyl phenylacetate derivative thus obtained:
NMR (CDC13), ~ppm: 7.3-8.2(m,8H), 4.15(q,2H), 3.22(s,2H), 1.40(t,3H).
(3) Preparation of 4-benzoyl-2-nitrophenylacetic acid:
4.4 g of ethyl 4-(2-phenyl-1,3-dioxan-2-yl)-2-nitrophenylacetate obtained in the above procedure (2) were dissolved in 30 m~ of methanol, followed by the addition of 15 m~ of 1 N hydrochloric acid. They were reacted under reflux for 1 hour.
After completion of the reaction, the reaction mixture was allowed to cool down and the solvent was distilled off. The residue was extracted with ether.
The organic layer obtained by the extraction was washed with water and then concentrated, whereby 3.5 g of an oily crude substance.
Next, the oily substance was dissolved in 20 m~
of ethanol. The resulting solution was added with 5 m~ of a 10% aqueous solution of sodium hydroxide, 2~3~1389 and they were reacted overnight at room temperature.
The solvent was distilled off from the reaction mixture. The residue was added with 10 m~ of water, followed by the addition of 3 N hydrochloric acid to acidify the resultant solution. Precipitated crystals were collected by filtration, thereby obtaining 2.8 g of 4-benzoyl-2-nitrophenylacetic acid.
Analytical results of the nitrophenyl acetic acid derivative thus obtained:
NMR (CDC13), ~ppm: 7.2-8.3(m,8H), 3.73(s,2H).
(4) Preparation of 2-(4-benzoyl-2-nitrophenyl)ethyl alcohol:
A solution of 2.8 g of 4-benzoyl-2-nitrophenyl-acetic acid, which had been obtained in the above procedure (3), in SO m~ of tetrahydrofuran was ice-cooled, to which 2.3 mQ of borane-methyl sulfide complex were added dropwise. The resultant mixture was left over.
Upon an elapsed time of 1 hour, water was added to terminate the reaction. The solvent was distilled off from the reaction mixture. The residue was added with ether and the resulting ether solution was washed with a dilute hydrogen peroxide solution.
After the washing, the ether solution was concentrated. The resulting syrup was added along with Z~}0~8~
17 g of activated manganese dioxide into S0 m~ of chloroform. The mixture was vigorously stirred for 30 hours.
After completion of the stirring, manganese dioxide was filtered off from the reaction mixture and the filtrate was concentrated. The concentrate was purified by chromatography on a silica gel column (eluent: hexane/ethyl acetate = 3/1, by volume), thereby obtaining 1.9 g of 2-(4-benzoyl-2-nitrophenyl)-ethyl alcohol in an oily form.Analytical results of the compound thus obtained:
NMR (CDC13), ~ppm: 7.2-8.3(m,8H), 4.05(t,2H), 3.11(t,2H).
(5) Preparation of 1,3-dimethyl-6-{4-[2-(4-benzoyl-2-nitrophenyl)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 137):
1.9 g of 2-(4-benzoyl-2-nitrophenyl)ethyl alcohol obtained in the above procedure (4), 1.5 g of p-toluenesulfonyl chloride and 1.8 m~ of pyridine were dissolved in 30 mQ of chloroform and reacted at room temperature for 24 hours. Water was then added to the reaction mixture. After vigorously stirring the reaction mixture for 3 hours, the chloroform layer was separated, washed first with a 1 N aqueous solution of hydrochloric acid and then a 1 N aqueous solution of sodium hydroxide, washed with water, concentrated over Z~ .89 sodium sulfate, and then concentrated to obtain a brown oily substance.
The brown oily substance, 0.6 g of 1,3-dimethyl~
6-(1-piperazLnyl) -2,4(lH,3H)-pyrimidinedione and 3 mQ of triethylamine were reacted for 6 hours under reflux in 20 m~ of isopropanol.
The reaction mixture was allowed to cool down, concentrated, and then dissolved in chloroform~ The resultant chloroform solution was washed with water, concentrated and then purified by chromatography on a silica gel column (eluent: chloroform/methanol ~ 40~1 by volume), thereby obtaining 0.7 g of 1,3-dime~yl~6 {4-[2-(4-benzoyl-2-nitrophenyl)ethyl]piperazin-l~yl~
2,4(lH,3H)-pyrimidinedione in an oily form.
Analytical results of the pyrimidinedione deriva~i~e thus obtained:
NMR (CDC13), ~ppm: 8.01(d,1H), 7.3-7.8(m,7H), 5.12(s,1H), 4.55(m,2H), 3.22(s,3H), 3.30(s,2H), 2.6-3.3(m,10H).
Next, the oily pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.6 g of 1,3-dimethyl-6-{4-t2-(4-benzoyl-2-nitrophenyl)ethyl]-2C~
piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 137).
Analytical results of Compound 137 thus obtained:
IR vmBax (cm 1): 2550, 1740, 1700, 1650, 1530, 1340, 1200, 1030, 830, 760, 700.
Elemental analysis for C25H27N5O5-(COOH)2-3H2O:
Calculated (~): C, 52.17; H, 5.68; N, 11.27.
Found (%): C, 52.57; H, 6.01; N, 11.30.
~0 Example 81:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-[2-(2-benzoyl-4-nitrophenyl)ethyl~piperazin-l-yl}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 133) available by the process of Example 76:
1 g of the pyrimidinedione derivative oxalate (Compound 133), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of 5 g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 82:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-t2-(2-benzoyl-4-nitroanilino)ethylamino]-2,4(1H,3H)-pyrimidinedione (Compound 131) available by the process of Example 74:
5 g of the pyrimidinedione derivative oxalate (Compound 131), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 83:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{3-[4-nitro-2-(3-pyridinecarbonyl)anilino]propylamino}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 129) available by the process of Example 72:
20 mg of the pyrimidinedione derivative oxalate (Compound 129) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 6:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 12 and obtained in the corresponding examples described above were determined. The results are summarized in Table 12.
2~ 8g Table 12 Result of Pharmacological Test 75 ( ) ERP (%) 5 Compound Dose (~g/ml)Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.0 3.0 133 - - - 6.3 6.318.8 136 11.0 14.0 - - 7.715.4 15.4 137 32.0 51.0 - 6.3 6.312.5 18.8 Toxicity Test 6:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 13 and obtained in the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 13.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table 13 Compound No.Mortality rate (%) 26~ 89 Example 84:
Preparation of 1,3-dimethyl-6-{4-[3-(3-methyl-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4~
(lH,3H)-pyrimidinedione hydroxide (Compound 138):
r-~ ~ 2 2 2 . (Compound 157) ~ ~
--/ N~o (Compound 139) ~3 O2N ~ OH Hcl/cH3oH
> >
3 ,O
2 ~ 2C~2CH2~ ~ -CH3 HCl C~3 (Compound 138) (1) Preparation of 1,3-dimethyl-6-[4-(3-hydroxypropyl)-piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139):
14.1 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157), 11.7 g of 3-2~
bromo-l-propanol and 13 g of triethylamine were reacted under reflux for 20 hours in 250 ml of ethanol. After completion of the reaction, the reaction mixture was concentrated to dryness. The residue was dissolved in 300 m~ of chloroform. The chloroform solution was washed twice with 100 m~ portions of water and the thus-washed organic layer was dried over anhydrous magnesium sulfate. The organic layer was heated under reduced pressure to distill off the solvent, whereby 20.5 g of a crude product were obtained. Ether was added to the crude product to have it crystallized.
The resultant crystals were collected, washed and then dried, thereby obtaining 12.4 g of 1,3-dimethyl-6-[4-(3-hydroxylpropyl)piperazin-1-yl]-2,4(lH,3H)-pyridine-dione ICompound 139) (yield: 69.8%).
Analytical results of crystals of Compound 139 thus obtained:
Melting point: 119-121~C.
NMR ( CDC13), ~ppm: 1.8(d,lH), 2.7(m,6H), 3.02(m,4H), 3.36(s,3H), 3.43(s,3H), 3.82(t,2H), 4.34(br.1H), 5.26(s,1H), IR vmax (cm 1): 3380, 3180, 2830, 1695, 1650, 1605, 1440, 1213, 1068, 1000, 921, 750.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(3-methyl-4-2~1389 nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 138):
1.13 g of Compound 139 obtained in the above procedure, 1.21 g of triphenylphosphine and 0.70 g of 3-methyl-4-nitrophenol were suspended and mixed in 15 m~ of anhydrous tetrahydrofuran. Into the resultant suspension, a solution of 0.8 g of diethyl azodicarboxylate in 10 m~ of anhydrous tetrahydrofuran was added at room temperature.
After stirring the resultant mixture for 10 minutes, it was concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent: methanol/ethyl acetate = 1/15 - 1/7, by volume), thereby obtaining 0.92 g of 1,3-dimethyl-6-{4-[3-(3-methyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 178.5-181~C.
Elemental analysis for C20H27N5O5:
Calculated (%): C, 57.54; H, 6.52; N, 16.78.
Found (%): C, 57.30; H, 6.56; N, 16.64.
NMR (CDC13), ~ppm: 1.9-2.3(m,2H), 2.6-2.8(m,9H), 3.0-3.2(m,4H), 3.44(s,3H), 3.54(s.3H), 4.28(t,2H), 5.44(s,1H), 7.0-7.16(m,2H), Z00~89 8.40(d,lH).
Next, 0.80 g of 1,3-dimethyl-6-{4-[3-(3-methyl-4-nitrophenyloxy)propyl~-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione was treated in an HCl/methanol solution by a method known per se in the art to obtain 0.60 g of 1,3-dimethyl-6- {4-[3-(3-methyl-4-nitrophenyloxy)-propyl]piperazin- l-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 138).
Analytical results of Compound 138 thus obtained:
Melting point: 224~C (decomposed1.
Elemental analysis for C2oH27N5O5-HCl-2H2O:
Calculated (%): C, 49.03; H, 6.58; N, 14.29;
Cl, 7.24.
Found (%): C, 48.82; H, 6.88; N, 14.18;
Cl, 7.31.
Example 85:
Preparation of 1,3-dimethyl-6-{4-[3-(4-chloro-2-nitrophenoxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 140):
C1 ~ OH+HOC~2CH2CH2N N ~ -CH3 (Compound 139 HCl/CH3OH
2~389 Cl ~ OCH2CH2CH2N~_~N ~ N--CH3 HC1 NO2 c~3 (Compound 140) 0.80 g of 4-chloro-2-nitrophenol, 1.13 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 139) and 1.21 g of triphenylphosphine were suspended in 15 mQ of anhydrous tetrahydrofuran, followed by the addition of 0.80 g of diethyl azodicarboxylate. The resultant mixture was treated in a similar manner to Example 84-(2~, thereby obtaining 1.43 g of 1,3-dimethyl-6-{4-[3-(4-chloro-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 162-163~C.
Elemental analysis for ClgH24N5O5Cl-~H2O:
Calculated (%): C, 51.07; H, 5.64; N, 15.67;
Cl, 7.93.
Eound (%): C, 51.11; H, 5.68; N, 15.64;
Cl, 7.94.
NMR (CDC13), ~ppm: 1.8-2.2(m,2H), 2.4-2.8(m,6H), 2.8-3.04(m,4H), 3.2-3.4(m,2H), z~
3.52(s.3H), 3.80(s,3H), 4.18(t,2H), 5.20(s,1H), 7.20(d,lH), 7.45(dd,lH).
7.81(d,1H).
5Next, 1.2 g of the pyrimidinedione derivative were treated in a 15% HCl/methanol solution by a method known E~ se in the art to obtain 1.13 g of 1,3-dimethyl-6-{4-[3-(4-chloro-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 140).
Analytical results of Compound 140 thus obtained:
Melting point: 271~C (decomposed).
Elemental analysis for ClgH24N5O5Cl-HCl:
Calculated (%): C, 48.11; H, 5.31; N, 14.76;
Cl, 14.95.
Found (%): C, 47.80; H, 5.33; N, 14.62;
Cl, 14.86.
Example 86:
Preparation of 1,3-dimethyl-6-{4-[3-(2-chloro-4-20nitrophenyloxy)propyl~piperazin-1-yl}-2,4-(lH,3H)-pyrimidinedione hydrochloride (Compound 141):
O2N ~ OH+HOCR2CH2C~2N N ~ O-CH3 (Compound 139) HCl/CH3OH
~00~389 2 ~ Oc~2cH2cH2N~-~N ~ -CH
(Compound 141) 2.4 g of 2-chloro-4-nitrophenol, 3.38 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 3.62 g of triphenylphosphine were suspended in 70 me of anhydrous tetrahydrofuran, followed by the addition of 2.4 g of diethyl azodicarboxylate. The resultant mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.5 g of pale yellow crystals. Those crystals were recrystallized from ethanol so that 2.07 g of 1,3-dimethyl-6-{4-t3-(2-chloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione were obtained as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 133-134~C.
Elemental analysis for ClgH24N5O5Cl:
Calculated (%): C, 52.12; H, 5.52; N, 15.99;
C1, 8.10.
Found (%): C, 51.99; H, 5.72; N, 15.70;
ZQ~89 Cl, 8.06.
NMR (CDC13), ~ppm: 1.8-2.3(m,2H), 2.3-3.1(m,10H), 3.33(s,3H), 3.41(s,3H), 4.24(t,2H), 5.26(s,1H), 7.0-8.4(m,3H).
Next, 0.5 g of the pyrimidinedione derivative was treated in a 15% HCl/methanol solution by a method known ~ se in the art to obtain 0.5 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 141).
Analytical results of Compound 141 thus obtained:
Melting point: 115-120~C.
Elemental analysis for ClgH24N5O5Cl-HCl-H2O:
Calculated (%): C, 46.35; H, 5.53; N, 14.22;
Cl, 14.40.
Found (%): C, 46.25; H, 5.29; N, 14.46;
Cl, 14.69.
IR vmaBr (cm 1): 1700, 1345, 1285, 1200, 1130, 1055, 900, 830, 750.
Example 87:
Preparation of 1,3-dimethyl-6-{4-t3-(4-methane-sulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 142~:
Z(~01389 H2N ~ OH ~CH3CONH ~ OH
(Compound 143) s BrCH2CH2CH2Br ) CH3CONH ~ 2 2 2 1) 2N HCl 2) CH3S02Cl CH3S02NH~OCH2CH2CH2C
HN N ~ N-CH
~-~ N-~o 3 CH3 HCl/CH30H
(Compound 157) CH3S02NH ~ O~H2CH2C~2N~_~N ~ N CH3 (Compound 142) (1) Preparation of 4-acetamido-2-nitrophenol (Compound 143):
Z~i1389 10.1 g of 4-amino-2-nitrophenol were dissolved in 80 m~ of acetic acid, followed by the addition of 6.7 g of acetic anhydride over 5 minutes. After stirring the resultant mixture for 1 hour, the solvent S was distilled off under reduced pressure. Water was added to the residue, whereby a solid of a dark brown color precipitated. The solid was collected by filtration. The solid was washed with water and then recrystallized from water-containing ethanol, thereby obtaining 10.2 g of 4-acetamido-2-nitrophenol (Compound 143) as crystals.
Analytical results of crystals of Compound 143 thus obtained:
Melting point: 158-159~C.
(2) Preparation of 3-(4-acetamido-2-nitrophenyloxy)-propyl bromide:
A mixture consisting of 10.2 g of 4-acetamido-2-nitrophenol (Compound 143) obtained by the above procedure, 13.9 g of potassium carbonate, 100 m~ of methyl ethyl ketone and 40.2 g of 1,3-dibromopropane was reacted under reflux for 6 hours. Insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated under reduced pressure.
The residue was dissolved in chloroform. The chloroform solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent Z~0~389 was distilled off under reduced pressure. The residue was then purified by chromatography on a silica gel column leluent: chloroform/methanol = 100/1, by volume), followed by recrystallization from dichloro-s methane-hexane to obtain 5.2 g of 3-(4-acetamido-2-nitrophenyloxy)propyl bromide as crystals.
Analytical results of crystals of the propyl bromide derivative thus obtained:
Melting point: 134~C.
Elemental analysis for CllH13N2O3Br:
Calculated (%): C, 41.66; H, 4.13; N, 8.83;
Br, 25.13.
Found (%): C, 41.84; H, 4.35; N, 8.92;
Br, 24.73.
(3) Preparation of 3-(4-methanesulfonamido-2-nitro-phenyloxy)propyl chloride:
1.0 g of 3-(4-acetamido-2-nitrophenyloxy)propyl bromide obtained by the above procedure was suspended in 15 m~ of 2N hydrochloric acid. After heating the resultant mixture under reflux for 30 minutes, 10 m~
of acetic acid were added, followed by heating under reflux for additional 4 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. Sodium carbonate was added to the resultant aqueous mixture to adjust the pH to 7-8.
The aqueous mixture was then extracted with chloroform.
~i1;389 The extract was dried over anhydrous sodium sulfate.
The drying agent was filtered off. The filtrate was added with 1 m~ of pyridine. A solution of 0.5 g of mesyl chloride in 5 m~ of chloroform was added dropwise under ice-cooling. After stirring the thus-obtained mixture for 2 hours under ice-cooling, it was stirred at room temperature for 2 hours and then extracted twice with a 2 N solution of sodium hydroxide. The resultant aqueous layer was washed with chloroform. This aqueous layer was acidified with 6 N
hydrochloric acid and then extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was recrystallized from ethanol, thereby obtaining 0.7 g of 3-(4-methanesulfon-amido-2-nitrophenyloxy)propyl chloride as crystals.
Analytical results of crystals of the propyl chloride derivative thus obtained:
Elemental analysis for CloH13ClN2O5S:
Calculated (%): C, 38.90 H, 4.24; N, 9.07;
Cl, 11.49; S, 10.38.
Found (%): C, 38.90; H, 4.30; N, 8.94;
Cl, 10.72; S, 10.03.
(4) Preparation of 1,3-dimethyl-6-{4-t3-(4-methane-sulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 142):
2~1389 0.31 g of 3-(4-methanesulfonamido-2-nitro-phenyloxy)propyl chloride, 0.22 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157) and O.S ml of triethylamine were dissolved under heat S in 10 m~ of ethanol to give a uniform solution. The solvent was distilled off under reduced pressure.
After heating the residue at 110~C for 2 hours, 10 m~
of n-butanol were added and the resulting mixture was heated under stirring at 110~C for S hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a dilute aqueous solution of sodium hydroxide. The thus-prepared solution was washed with chloroform. The water layer was then adjusted to pH 1-2 with dilute lS hydrochloric acid, washed with ethyl acetate, and then added with sodium hydrogencarbonate to raise the pH to 7-8. Precipitated insoluble matters were collected by filtration. The thus-collected substance was dried under reduced pressure and then dissolved in methanol.
15% HCl/methanol was added to convert it into the hydrochloride by a method known per se in the art, thereby obtaining 0.2 g of 1,3-dimethyl-6-{4-[3-(4-methanesulfonamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 142) as crystals.
- Z~01389 Analytical results of crystals of Compound 142 thus obtained:
Melting point: 239~C.
Elemental analysis for C20H28N607S~HCl-~H20:
Calculated (%): C, 44.32; H, 5.58; N, 15.51;
Cl, 6.54; S, 5.92.
Found (%): C, 44.30; H, 5.58; N, 15.45;
Cl, 6.96; S, 5.94.
Example 88:
Preparation of 1,3-dimethyl-6-{4-[3-(4-acetamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 144):
CH3CONH ~ OH+HOCH2CH2CH2N N ~ N-CH3 2 C~3 (Compound 143) (Compound 139) HCl/CH30H
>
CH3CONH ~ ~C~2c~'2c~'2N ~ h-C~3 (Compound 144) 2.71 g of 4-acetamido-2-nitrophenol (Compound 143) o~tained in Example 87-(1), 3.38 g of 1,3-- Z~01~89 dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl3-2,4(1H,3H)-pyrimidinedione (Compound 139) and 3.62 g of triphenylphosphine were suspended in 70 mQ of anhydrous tetrahydrofuran, followed by the addition of 2.4 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.7 g of pale yellow crystals. 2.0 g of the crystals were treated in a 15% HCl/methanol solution by a method known ~er se in the art to obtain 2.5 g of 1,3-dimethyl-6-{4-[3-(4-acetamido-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 144).
Analytical results of Compound 144 thus obtained:
Melting point: 228.5-230~C.
Elemental analysis for C21H28N6O6-HCl:
Calculated (%): C, 50.76; H, 5.88; N, 16.91;
Cl, 7.13.
Found (%): C, 50.67; H, 6.27; N, 17.07;
Cl, 6.81.
Example 89:
Preparation of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 145):
O2N ~ OH+HOCH2CH2C~2N N ~ -CH3 (Compound 139J
02N ~ OCH2CH2CH2N~ N CH3 (Compound 145 - free form) H2~ ~ ~ -C~3.
(Compound 145) 0.63 g of 2-nitrocatechol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 1.06 g of triphenylphosphine were suspended in 15 ml of anhydrous tetrahydrofuran, followed by the addition of 0.71 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 0.65 g of pale yellow crystals. The crystals were recrystallized form ethanol to obtain 0.55 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 145 - free form) as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 171-173~C.
Elemental analysis for C19H25N5O5:
Calculated (%): C, 54.40; H, 6.00; N, 16.69.
Found (%): C, 54.40; H, 6.28; N, 16.48.
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.6-3.2(m,10H), 3.2(m,10H), 3.3(s,3H), 3.4(s,3H), 4.1(t,2H), 5.24(s,1H), 6.88-7.08(m,lH), 7.60-7.80(m,2H).
IR vKBr (cm~l) 1700, 1620, lS00, 1340, 1285, max 1280, 1140, 990, 870.
Next, 0.5 g of the pyrimidinedione derivative were treated in a 20% HCl/methanol solution by a method known per se in the art to obtain 0.5 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 145) as crystals.
Analytical results of crystals of Compound 145 thus obtained:
Melting point: 246-249~C.
Elemental analysis for ClgH25N5O5-HCl-2H2O:
Calculated (%): C, 46.39; H, 6.15; N, 14.24;
Cl, 7.21.
~ - 279 - ~ a ~ 89 -Found (%): C, 46.83; H, 5.97; N, 14.55;
Cl, 7.77.
Example 90:
Preparation of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 146):
( ~0CH2CR2CH2N~N~N-C~3 (Compound 145 - free form) HCl/CH30H
> >
02N ~ OC~2C~2C~2~_JN ~ N CB3 HC
( OCH2CH=CH2 H3C
(Compound 146) 1 g of 1,3-dimethyl-6-{4-13-(2-hydroxy-5-nitro-phenyloxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidine-dione (Compound 145 - free form), 0.31 g of allyl bromide and 0.36 g of potassium carbonate were suspended in 10 ml of dry acetone and heated under reflux for 5 hours. The reaction mixture was poured , ~ .....
Z~1389 into 60 m~ of water and then extracted three times with 30 m~ portions of chloroform. The extract was washed first with a 0.5 N aqueous solution of sodium hydroxide and then with water. The chloroform solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol = 20/1, by volume).
The resulting oily substance was crystallized from ethanol, thereby obtaining 0.78 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 120-121~C.
NMR (CDC13), ~ppm: 2.08(t,2H), 2.5-3.0(m,10H), 3.3(s,3H), 3.36(s,3H), 4.16(t,2H), 4.5-4.7(m,2H), 5.2(s,1H), 5.16-5.6(m,2H), 5.8-6.24(m,1H), 6.9(d,lH), 7.68-7.92(m,2H).
IR vmaBxr (cm 1): 1690, 1630, 1510, 1330, 1280, 1000.
Next, 0.5 g of the pyrimidinedione derivative was treated in a 20~ HCl/methanol solution by a method known per se in the art to obtain 0.5 g of 1,3-dimethyl-6-{4-t3-(2-allyloxy-5-nitrophenyloxy)propyl]-2~)1389 piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydro-chloride (Compound 146) as crystals.
Analytical results of Compound 146 thus obtained:
Melting point: 161.5-180~C.
~xample 91:
Preparation of 1,3-dimethyl-6-{4-[3-(4-methylthio-2-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 147):
o CH3S ~ OH+HOCH2C~2CH2N~--J~ ~ CH3 N~2 CH3 (Compound 139) HCl/CH30H
CH3S ~ 0cH2cH2cH2N~~ C~3 HC
N~2 C/H3 (Compound 147) 1.5 g of 4-methylthio-2-nitrophenol, 2.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 2.2 g of triphenylphosphine were suspended in 30 m~ of 2~1389 anhydrous tetrahydrofuran, followed by the addition of 1.35 m~ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 2.9 g of 1,3-dimethyl-6-{4-[3-(4-methylthio-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.48(s,3H), 2.4-2.7(m,6H), 2.8-3.0(m,4H), 3.28(s,3H), 3.36(s,3H), 4.14(m,2H), 5.16(s,1H), 7.0(d,1H), 7.36(dd,1H), 7.62(d,1H).
Next, 0.5 g of the pyrimidinedione derivative were treated in a 20% HCl/methanol solution by a method known E~ se in the art to obtain 0.4 g of 1,3-dimethyl-6-{4-t3-(4-methylthio-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (Compound 147) as crystals.
Analytical results of crystals of Compound 147 thus obtained:
Melting point: 224-226~C.
Elemental analysis for C20H27N5O5S-HCl:
Calculated (%): C, 49.43; H, 5.81; N, 14.41;
Cl, 7.30; S, 6.60.
Found (%): C, 49.20; H, 5.97; N, 14.28;
2()0~389 Cl, 7.23; S, 6.84.
Example 92:
Preparation of 1,3-dimethyl-6-{4-<3-t2~
hydroxybenzyl)-4-nitrophenyloxy]propyl>pipera-zin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 148):
o2~ ~ o~+~oC~2c~2c~2~ C~3 (Compound 139) 2 ~ 2 2 ~2N~ J ~ ~ C~3 ~ C~3 (Compound 149) Oxalic acid/CH30H
02N ~ OCH2CH2CE2N~_~N ~ N CH3 ( 2 OH c~3 (Compound 148) (1) Preparation of 1,3-dimethyl-6-{4-[3-(2-benzoyl-4-nitrophenyloxy)propyllpiperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 149) 3.74 g of 2-benzoyl-4-nitrophenol, 3.5 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 3.3 g of triphenylphosphine were suspended in 50 m~ of anhydrous tetrahydrofuran, followed by the addition of 2.40 m~ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 3.9 g of 1,3-dimethyl-6-{4-t3-(2-benzoyl-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 149) as crystals.
Analytical results of crystals of the pyrimidinedione derivative (Compound 149) thus obtained:
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.4-2.7(m,6H), 2.8-3.0(m,4H), 3.26(s,3H), 3.36(s,3H), 4.14(m,2H), 5.14(s,1H), 7.0-7.8(m,8H), 8.36(d,2H).
(2) Preparation of 1,3-dimethyl-6-{4-<3-[2-(a-hydroxy-benzyl)-4-nitrophenyloxy]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 148):
0.2 g of the pyrimidinedione derivative (Compound 149) obtained in the above procedure and 15 mg of sodium borohydride were dissolved in ethanol.
The resultant solution was stirred at room temperature for 6 hours. The reaction mixture was poured into water and then extracted with chloroform. The 2~0~389 chloroform layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume), thereby obtaining 0.15 g of 1,3-dimethyl-6-{4-<3-[2-(a-hydroxy-benzyl)-4-nitrophenyloxy]propyl>piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.0(m,2H), 2.5-2.9(m,10H), 3.26(s,3H), 3.37(s,3H), 4.11(m,2H), 5.16(s,1H), 6.04(s,1H), 6.88(d,1H), 8.14(dd,lH), 8.52(d,lH).
Next, 0.15 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.15 g of 1,3-dimethyl-6-{4-<3-[2-(~-hydroxybenzyl)-4-nitrophenyloxy]-propyl>piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 148) as crystals.
Analytical results of crystals of Compound 148 thus obtained:
Melting point: 111-115~C.
Elemental analysis for C26H31N5O6 2 2 Calculated (%): C, 52.91; H, 5.87; N, 11.02.
Found (%): C, 52.74; H, 5.65; N, 10.94;
IR vKBr (cm-l) 3460, 1700, 1640, 1610, 1510, max 2~1389 1340, 760, 700.
Example 93:
Preparation of 1,3-dimethyl-6-{4-[3-(3-trifluoromethyl-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 150):
~2N ~ 2 2 2N~_~N ~ ~ C~3 CF3 c/~3 (Compound 139) Oxalic acid/CH3OH
>
O2N ~ OC~2CH2C~2U N ~ N-C~3-(COOH)2 3 C~3 (Compound 150) l.9 g of 4-nitro-3-trifluoromethylphenol, 2.25 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 2.41 g of triphenylphosphine were suspended in 60 m~ of anhydrous tetrahydrofuran, followed by the addition of 1.6 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 2~ 389 84-(2), thereby obtaining 3.50 g of pale yellow crystals. The crystals were recrystallized from ethanol to obtain 3.31 g of 1,3-dimethyl-6-{4-[3-(3-trifluoromethyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.9-2.2(m,2H), 2.5-2.75(m,6H), 2.9-3.1(m,4H), 3.3(s,3H), 3.4(s,3H), 4.15(t,2H), 5.3(s,1H), 7.1-7.4(m,2H), 8.15(d,1H).
Next, 3.2 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method ~nown Per se in the art to obtain 3.22 g of 1,3-dimethyl-6-{4-[3-(3-trifluoromethyl-4-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 150) as crystals.
Analytical results of crystals of Compound 150 thus obtained:
Melting point: 187-189~C.
Elemental analysis for C20H24F3N5O5-(COOH)2:
Calculated (%): Ct 47.06; H, 4.67; N, 12.47;
F, 10.15.
Found (~): C, 47.51; H, 5.24; N, 12.67;
F, 10.49.
- 288 - ~ O ~ ~ 3 8 ~
Example 94:
Preparation of 1,3-dimethyl-6-{4-13-(2-methoxycarbonyl-4-nitrophenyloxy)propyl~-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 151):
02N~OH ~ 02N~OH
~ ~~
2 2 2 ~ ~0 3 c~3 (Compound 139) ; >
02N ~ OC~2C~2CH2N~_~N ~ N--C~3 (Compound 151 - free form) Oxalic acid/CH30H
2 ~ OC-2CH2C22N~_~N ~ -C~3~(COOH)2 (Compound 151) (1) Preparation of methyl 5-nitrosalicylate:
,~ .
. " . . ~
Z~389 80 m~ of methanol and 10 g of concentrated sulfuric acid were added to 5 g of 5-nitrosalicylic acid. The resultant mixture was heated under stirring for 8 hours whlle distilling methanol off. The solvent was then distilled off under reduced pressure and the residue was dissolved in chloroform. The resultant chloroform solution was washed with water and then concentrated to dryness. The resultant residue was purified by chromatography on a silica gel column (eluent: chloroform), followed by recrystallization from chloroform-ether to obtain 5.1 g of methyl 5-nitrosalicylate as crystals.
Analytical results of crystals-of methyl 5-nitro-salicylate thus obtained:
Melting point: 114-116~C.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-carbonyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 151):
2.96 g of methyl 5-nitrosalicylate obtained by the above procedure, 4.23 g of 1,3-dimethyl-6-t4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidine-dione (Compound 139) and 3.93 g of triphenylphosphine were suspended in 50 m~ of anhydrous tetrahydrofuran, followed by the addition of 2.6 g of diethyl azo-dicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby -~9~ 89 obtaining 6.5 g of pale yellow crystals. The crystals were recrystallized from methanol to obtain 5.74 g of 1,3-dimethyl-6-{4-~3-(2-methoxycarbonyl-4-nitro-phenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidine-d ione (Compound 151 - free form) as crystals.
Analytical results of crystals of the pyrimidinedione derivative (Compound 151 - free form) thus obtained:
Melting point: 145-146~C.
NMR (CDC13), ~ppm: 1.8-2.2(m,2H), 2.4-3.0(m,10H), 3.27(s,3H), 3.36(s,3H), 3.87(s,3H), 4.17(t,2H), 5.24(s,1H), 7.0-8.7(m,2H).
Next, 5.5 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 5.6 g of 1,3-dimethyl-6-{4-[3-(2-methoxycarbonyl-4-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 151) as crystals.
Analytical results of crystals of Compound 151 thus obtained:
Melting point: 186-187~C (decomposed).
Y 21 27 5 7 ( )2 3 Calculated (%): C, 47.92; H, 5.86; N, 11.64.
Found (%): C, 47.74; H, 5.66; N, 11.43.
IR vmax ~cm 1): 1655, 1520, 1345, 1200, 1130, 1080, 820, 765, 750.
c~l3~9 Example 95:
Preparation of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 152):
2 ~ 0C~2C~2C~2N~_~N ~ _CH3 (Compound 151 - free form) Oxalic acid/CH30H
2 ~ 2C 2CH2~_~N ~ CH3 (Compound 152) 1.38 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-carbonyl-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione (Compound 151 - free form) were dissolved in 200 ml of methanol, followed by the addition of 100 m~ of a 1.5 N aqueous solution of sodium hydroxide. The resultant mixture was stirred at 60~C for 30 minutes. The reaction mixture was allowed to cool down, neutralized with dilute hydrochloric acid, and then concentrated to a total volume of 50 mQ
under reduced pressure. The concentrate was ice-cooled 6)1389 and precipitated crystals were collected by filtration, thereby obtaining 1.16 g of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 155-158~C.
NMR (DMSO-d6), ~ppm: 1.8-2.3(m,2H), 2.4-3.2(m,10H), 3.13(s,3H), 3.27(s,3H), 4.2(t,2H), 5.2(s,1H), 7.3-8.5(m,3H).
Next, 1.0 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per _ in the art to obtain 0.9 g of 1,3-dimethyl-6-{4-[3-(2-carboxy-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 152) as crystals.
Analytical results of crystals o~ Compound 152 thus obtained:
Melting point: 191-193~C (decomposed).
Elemental analysis for C20H25N5O7-(COOH)2-H2O:
Calculated (~): C, 47.57; H, 5.26; N, 12.61.
Found (~): C, 47.85; H, 5.32; N, 12.49.
IR vmax (cm 1): 1700, 1650, 1500, 1345, 1290, 1135, 1075, 760, 750.
Example 96:
Preparation of 1,3-dimethyl-6-{4-[3-(2-amino-4--2~01389 -nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 153):
o 2 ~ 2 2 2 ~_~ ~ 3 NH2 c~3 (Compound 139) Oxalic acid/CH30H
. o 2 ~ OC~2CH2C~2N~ N--CB3~(COOH)2 NH2 c/~3 (Compound 153) 1.54 g of 2-amino-4-nitrophenol, 2.82 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 2.88 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 1.92 g of diethyl azodicarboxylate. The thus-prepared mixture was stirred for 1 hour at room temperature and a precipitate was collected by filtration. The precipitate was washed with chloroform-ether to obtain 1.44 g of crytals. The crystals were recrystallized from ethanol-chloroform, thereby obtaining 0.6 g of 1,3-dimethyl-6-{4-[3-(2-amino-4-nitrophenyloxy)propyll-- 29i~QO1389 piperazin-l-yl}-2, 4tlH,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 188~C.
NMR (DMSO-d6), ~ppm: 1.9-2.0(m,2H), 2.4-3.0(m,10H), 3.1(s,3H), 3.24(s,3H), 4.08(m,2H), 5.15(s,1H), 5.35(br.2H), 6.8-7.5(m,3H).
Next, 0.2 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.21 g of 1,3-dimethyl-6-{4-[3-(2-amino-4-nitrophenyloxy)propyl]
piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 153) as crystals.
Analytical results of crystals of Compound 153 thus obtained:
Melting point: 145~C.
Elemental analysis for ClgH26N6O5-(COOH)2:
Calculated (~): C, 49.60; H, 5.55; N, 16.53.
Found (%): C, 49.53; H, 5.96; N, 16.49.
IR vmax (cm 1): 3430, 3340, 2940, 1690, 1650, 1510, 1435, 1340, 1290, 1235, 1075.
Example 97:
Preparation of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)propyl]--- 2~Q~3as piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 154):
Ho~CoocH3+HocH2cH2cH2N~N~ - cH3 (Compound 139) Oxalic acid/CH30H
H300C ~ OC~2CH2C~2N~_~N ~ -C~3 ~COOH)2 (Compound 154) 0.84 g of methyl 4-hydroxy-3-nitrobenzoate, 1.5 n . 8 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-l~yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 0.88 g of triphenylphosphine were suspended in 14 m~
of anhydrous tetrahydrofuran, followed by the addition of 0.54 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 1.1 g of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
ZO~)138~
NMR (CDC13), ~ppm: 2.1(m,2H), 2.3-3.0(m,10H), 3.3(s,3H), 3.4(s,3H), 3.95(s,3H), 4.3(t,2H), 5.25(s,1H), 7.25(d,1H), 8.27(dd,lH), 8.61(d,lH).
Next, 1.0 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per _ in the art to obtain 1.0 g of 1,3-dimethyl-6-{4-[3-(4-methoxycarbonyl-2-nitrophenyloxy)-propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate ~Compound 154) as crystals.
Analytical results of crystals of Compound 154 thus obtained:
Melting point: 190-193~C (decomposed).
Elemental analysis for C21H27N5O7-(COOH)2-3H2O:
Calculated (%): C, 45.62; H, 5.83; N, 11.57.
Found (%): C, 45.92; H, 5.21; N, 11.84.
IR vmax (cm 1): 2900, 2500, 1740, 1720, 1700, 1640, 1620, 1530, 1340, 800.
Example 98:
Preparation of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 155):
2~1389 02N ~ Cl+HOCX2C~2Ca2N~_~N ~ C 3 CN C~3 (Compound 139) Oxalic acid/CH30H
02N ~ OCH2CX2C~2N~_~N ~ N C~3 (C )2 (Compound 155) 0.82 g of 2-chloro-5-nitrobenzonitrile, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and O.Z2 g of sodium hydride were reacted at 0~C for 1 hour in 5 m~
of dimethylformamide. Water was then added.
Precipitated crystals were collected by filtration and washed with water. The thus-obtained crystals were dried in vacuum, thereby obtaining 0.9 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.1(m,2H), 2.6-3.0(m,10H), 3.3(s,3H), 3.35(s,3H), 4.6(t,2H), 5.1(s,1H), 7.5(d,1H), 8.6(m,2H).
2~)1389 Next, 0.9 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.87 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 155) as crystals.
Analytical results of crystals of Compound 155 thus obtained:
Melting point: 191-193~C (decomposed).
Elemental analysis for C20H24N6~5-(C~~H)2-3H2~
Calculated (%): C, 46.15; H, 5.63; N, 14.68.
Found (%): C, 45.89; H, 5.38; N, 14.29.
IR Vmax (cm ): 2200, 1680, 1630, 1600, 1580, 1520, 1340, 840.
~5 Example 99:
Preparation of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 156):
O O
BrCH2CH2CH2Br ~J~
NII ~ ~ N-CH2CH2cH2sr O O
- 2~ )1389 ~ ~4 N
(Compound 157) Hydrazine H2O
> >
H2NCH2CH2CH2N~_~N N_~N CH3 (Compound 158) Oxalic acid/CH OH
O2N ~ NHCH2C~2C~2~_~N ~ ~N-C~3 (COOH)2 (Compound 156) (1) Preparation of 1,3-dimethyl-6-t4-(3-aminopropyl)-piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione (Compound 158):
A solution in which 18.52 g of potassium phthalimide and 200 g of 1,3-dibromopropane were suspended in 100 mQ of dimethylformamide was heated under stirring at 120~C for 6 hours, so that potassium ;~;)0~L389 phthalimide and 1,3-dibromopropane were reacted. Next, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated to dryness under reduced pressure. The residue was washed with hexane and then recrystallized from ethanol-water.
Crystals-thus obtained were collected by filtration, washed and then dried, thereby obtaining 13.8 g of N-(3-bromopropyl)phthalimide.
Next, 13.0 g of N-(3-bromopropyl)phthalimide, 10.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (Compound 157) and 20 g of triethyl-amine were suspended in 200 m~ of dioxane. The suspension was thereafter heated under reflux for 6 hours.
Further, insoluble matters were filtered off from the reaction mixture and the filtrate was concentrated to dryness under reduced pressure. The residue (dry concentrate) was recrystallized from ethyl acetate/n-hexane. Resultant crystals were collected by filtration, washed and then dried, thereby obtaining 1.25 g of 1,3-dimethyl-6-[4-(3-phthaloylaminopropyl)-piperazin-l-yl]-2,4(1H,3H)-pyrimidinedione.
12.5 g of the crystals and 6.0 g of hydrazine hydrate were next suspended in 200 m~ of ethanol. The suspension was heated for 4 hours under reflux. After allowing the suspension to cool down, resultant Z~0~389 ~ - 301 -insoluble matters were filtered off. The filtrate was concentrated to dryness under reduced pressure. Then, the residue (dry concentrate) was dissolved in water, to which dilute hydrochloric acid was added to adjust the pH to about 3. Insoluble matters formed upon the pH adjustment were filtered off. The filtrate was added with a large amount of potassium carbonate and then extracted with chloroform. After completion of the extraction, the resultant organic layer was dried over anhydrous sodium sulfate and then heated under reduced pressure to distill the solvent off, whereby 6.80 g of 1,3-dimethyl-6-[4-(3-aminopropyl)piperazin-l-yl]-2,4(lH,3H)-pyrimidinedione (Compound 158) were obtained as a colorless syrupy substance. The syrupy substance was crystallized when allowed to stand overnight.
Analytical results of crystals of Compound 158 thus obtained:
Melting point: 85-88~C.
NMR (CDC13), ~ppm: 1.58(br.2H), 1.66(m,2H), 2.48(t,2H), 2.59(m,4H), 2.78(t,2H), 2.97(m,4H), 3.32(s,3H), 3.38(s,3H), 5.24(s,1H).
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 156):
0.3 g of Compound 158 obtained beforehand, 0.3 g of 2-chloro-5-nitrobenzonitrile and 0.31 m~ of triethylamine were stirred at 80~C for 1 hour in 5 m~
of dimethylformamide. The reaction mixture was concell~dLed under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume), thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-t3-(2-cyano-4-nitroanilino)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.0(m,2H), 2.6-3.3(m,12H), 3.35(s,3H), 3.45(s,3H), 5.33(s,1H), 7.28(m,1H), 8.4-8.6(m,2H).
Next, 0.4 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per _ in the art to obtain 0.41 g of 1,3-dimethyl-6-{4-[3-(2-cyano-4-nitroanilino)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 156) as crystals.
Analytical results of crystals of Compound 156 thus obtained:
Melting point: 156-158~C (decomposed).
Elemental analysis for C20H25N7O4 2 2 Calculated (%): C, 49.41; H, 5.43; N, 17.94.
Z~
Found (~): C, 49.34; H, 5.46; N, 18.31.
IR vmax (cm 1): 3300, 2250, 2200, 1530, 1340, 1160, 800, 750, 700.
Example 100:
Preparation of 1,3-dimethyl-6-{4-t3-(2-chloro-4-nitroanilino)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 159):
10 0 N~Cl+H2NCH2 CH2CE~2N~N~N--CH3 (Compound 158) Oxalic acid/CH30H
>
O2N ~ NHCH2CH2CH2N~_~N ~ C~3 (C )2 (Compound 159) A mixture consisting of 0.4 g of Compound 158 obtained in Example 99-(1), 0.4 g of 3,4-dichloro-nitrobenzene, 0.43 ml of triethylamine and 6 ml of dimethylformamide was treated in a manner similar to Example 99-(2), thereby obtaining 0.55 g of 1,3-Z~1389 dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.0(m,2H), 2.5-3.3(m,10H), 3.28(s,3H), 3.39(s,3H), 5.23(s,1H), 6.77(m,1H), 8.11(m,1H), 8.20(m,1H).
Next, 0.5 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.53 g of 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitroanilino)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 159) as crystals.
Analytical results of crystals of Compound 159 thus obtained:
Melting point: 153-155~C (decomposed).
Y 19 2sC 6 4 (C )2 ~ 2 Calculated (%): C, 44.10; H, 5.64; N, 14.69;
Cl, 6.20.
Found (%): C, 44.14; H, 5.20; N, 14.63;
Cl, 6.13.
IR vmBax (cm 1): 2250, 1690, 1640, 1630, 1590, 1530, 1330, 800, 740.
Example 101:
Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-200138~
2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 160) OH~HOC~2CH2CH2N~_J~ ~ -CH3 (Compound 139) HCl/CH30H
02N ~ ~
OC~2C~2C~2N~ N Ca3 H
~ (Compound 160) 0.9 g of 2-methoxy-5-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 1.1 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 0.67 m~ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a simila-r manner to Example 84-(2), thereby obtaining 1.2 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-5-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione derivative thus obtained:
2~
NMR (CDC13), ~ppm: 2.15(m,2H), 2.5-3.2(m,10H), 3.3(s,3H), 3.4(s,3H), 3.97(s,3H), 4.23(t,2H), 5.26(s,1H), 6.96(d,1H), 7.86(m,2H).
Next, 1.1 g of the pyrimidinedione derivative was treated in a 10% HCl/methanol solution by a method known per se in the art to obtain 1.17 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-5-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydro-chloride (Compound 160) as crystals.
Analytical results of crystals of Compound 160 thus obtained:
Melting point: 158-162~C (decomposed).
Elemental analysis for C20H27N5O6-HCl-H2O:
Calculated (%): C, 49.23; H, 6.20; N, 14.35;
Cl, 7.27.
Found (%): C, 49.04; H, 6.28; N, 14.26;
Cl, 7.54.
IR vKBr (cm~l) 3400, 2950, 1660, 1620, 1540, max 1350, 1260, 1010, 810, 770.
Example 102:
Preparation of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 161):
~ 307 ~ ~ O ~ ~ ~ 89 02N ~ OH + H~CH2CH=CH2 2 ~
OH OCH2CH=cH2 HOCH2CH2CH2N N ~ N-CH3 (Compound 139) 3 02N ~ OCH2CH2CH2N~_~N ~ C~3 OCH2CH=CH2 c~3 (Compound 161 - free form) HCl/CH30H
( 2 ~ 2C~2c~2~ N ~ N-C~3 HC1 OCH2CH=CH2 CH~
(Compound 161) (1) Preparation of 2-allyloxy-4-nitrophenol:
1.7 g of 4-nitrocatechol, 0.74 ml of allyl alcohol and 2.4 g of triphenylphosphine were suspended in 40 ml of anhydrous tetrahydrofuran, followed by the addition of 1.5 m~ of diethyl azodicarboxylate. The resultant mixture was stirred at room temperature for B
2Q~1389 11 hours, followed by the addition of 5 g of silica gel. The thus-prepared mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent:
hexane/ethyl acetate = 3/1, by volume), thereby obtaining 1.5 g of 2-allyloxy-4-nitrophenol as an oily substance.
Analytical results of the phenol derivative thus obtained:
NMR (CDC13), ~ppm: 4.76(m,2H), 5.22(m,lH), 5.35(m,1H), 5.96(m,1H), 6.99(d,1H), 7.91(m,2H).
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 161):
1.5 g of 2-allyloxy-4-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 1.1 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 0.67 mQ of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 1.1 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 161 - free form) as an oily substance.
0~389 Analytical results of the pyrimidinedione derivative (Compound 161 - free form) thus obtained:
NMR (CDC13), ~ppm: 2.1(m,2H), 2.5-3.3(m,10H), 3.35(s,3H), 3.43(s,3H), 4.76(m,2H), 5.3(s,lH), 5.6(m,2H), 6.15(m,lH), 7.0(m,1H), 7.8(m,2H).
Next, 0.5 g of the pyrimidinedione derivative was treated in a 10% HCl/methanol solution by a method known E~ se in the art to obtain 0.4 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (Compound 161) as crystals.
Analytical results of crystals of Compound 161 thus obtained:
Melting point: 134-136~C (decomposed).
Elemental analysis for C22H29N5O6-HCl-2~H2O:
Calculated (%): C, 48.84; H, 6.52; N, 12.95;
Cl, 6.55.
Found (%): C, 48.97; H, 6.27; N, 12.74;
Cl, 6.75.
IR vmax (cm 1): -~3350, 2900, 1700, 1640, 1510, 1340, 1280, 1090, 810, 760.
Example 103:
Preparation of 1,3-dimethyl-6-{4-t3-(2-hydroxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride 2~01389 (Compound 162):
2 ~ OCH2CH2CH2N N ~ N-CH
OCH2CH=CH2 C/H3 (Compound 161 - free form) HCl/CH30H
~
02N ~ oc~2c~2c 2N N ~ -C~3 HC
(Compound 162) 0.6 g of 1,3-dimethyl-6-~4-[3-(2-allyloxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione (Compound 161 - free form) was dissolved in 10 ml of methanol, followed by the addition of 0.1 g of 10~ Pd/activated carbon, 0.1 g of p-toluenesulfonic acid monohydrate and 2 ml of water.
The resultant mixture was heated for 15 hours under stirring and reflux. After allowing the reaction mixture to cool down, insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by chromatography on a silica gel column 2 ~3Q~ ~ 8 9 (eluent: chloroform/methanol = 50/1, by volume), thereby thereby obtaining 0.4 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.15(m,2H), 2.7-3.3(m,10H), 3.34(s,3H), 3.43(s,3H), 4.13(t,2H), 5.34(s,1H), 7.0(m,1H), 8.03(m,2H).
Next, 0.4 g of the pyrimidinedione derivative was treated in a 10% HCl/methanol solution by a method known ~ se in the art to obtain 0.33 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride (Compound 162) as amorphous powder.
Analytical results of amorphous powder of Compound 162 thus obtained:
Elemental analysis for ClgH25N5O6-HCl-l~H2O:
Calculated (%): C, 47.26; H, 6.05; N, 14.05;
Cl, 7.34.
Found (%): C, 47.53; H, 6.21; N, 13.75;
Cl, 7.59.
IR Vmax (cm ) 3350, 1680, 1630, 1530, 1340, 1220, 1000, 750, 710.
Example 104:
Preparation of 1,3-dimethyl-6-{4-[3-(2-benzyl-2n ~ ~ 3 8 9 ~i amino-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 163):
02N ~ OH + ~ CHO ~ 02N ~ OH
NH2 HCH2 ~
o (, IOCH2C~2CF12 ~ N~N--cH3 c~3 (Compound 139) Oxalic acid/CH30H
02N ~ OC~2C zCH2N~ CH3~(COOH)2 (Compound 163) (1) Preparation of 2-benzylamino-4-nitrophenol:
4.4 g of 2-amino-4-nitrophenol, 5.2 g of benzaldehyde and 0.4 g of p-toluenesulfonic acid monohydrate were dissolved in 300 ml of benzene. The resultant mixture was heated under reflux for 5 hours while removing water. The solvent was distilled off under reduced pressure and hexane is added to the residue. Precipitated crystals were collected by filtration to obtain 6.6 g of crystals. The crystals were dissolved in S5 ml of dimethylformamide, followed ~....
. ~ , - Z~1~)138~
by the addition of 2.2 g of sodium borohydride under ice-cooling. The resultant mixture was stirred at the same temperature for 2 hours. Ether was added to the reaction mixture. The resultant ether solution was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 4-.2 g of 2-benzylamino-4-nitrophenol. This product was provided for the subsequent reaction without purification.
Analytical results of 2-benzylamino-4-nitrophenol thus obtained:
NMR (CDC13), ~ppm: 4.5(s,2H), 6.8-7.0(d,1H), 7.3-7.6(m,2H), 7.4(s,1H).
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 163):
0.7 g of 2-benzylamino-4-nitrophenol, 0.8 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(lH,3H)-pyrimidinedione (Compound 139) and 0.9 g of triphenylphosphine were suspended in 20 m~ of anhydrous tetrahydrofuran, followed by the addition of 0.65 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), thereby obtaining 0.93 g of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy~propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione as crystals.
2Q~ 8~
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 2.05(m,2H), 2.6(m,6H), 2.95(m,4H), 3.3(s,3H), 3.35(s,3H), 4.15(t,2H), 4.35(d,2H), 4.8(m,1H), 5.25(s,1H), 6.75(d,1H), 7.2-7.45(m,1H), 7.35(s,5H), 7.6(m,1H).
Next, 0.8 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 0.81 g of 1,3-dimethyl-6-{4-[3-(2-benzylamino-4-nitrophenyloxy)-propyl~piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 163) as crystals.
Analytical results of crystals of Compound 163 thus obtained:
Y 26 32N6 5 (COO )2 ~ 2~
Calculated (%): C, 55.35; H, 5.81; N, 13.83.
Found (%): C, 55.73; H, 5.78; N, 13.87.
Example 105:
Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 164):
~01389 . - 315-~ 2 N ~ OH
\-- N~~o c~3 (Compound 139) HCl/CH30H
~2N ~ 2C''2C~2N~_J~ ~ C 3 HCl (Compound 164) (1) Preparation of 2-methoxy-4-nitrophenol:
50 g of 2-amino-5-nitroanisole, 50 g of sodium hydroxide were dissolved in 450 ml of water. The resultant mixture was heated under reflux for 3 hours and then ice-cooled. Precipitated crystals were collected by filtration, followed by dissolution in water. The thus-prepared solution was neutralized with 6 N hydrochloric acid and crystals thus precipitated were collected by filtration. The crystals were dissolved in chloroform. The resultant solution was washed with water and dried over anhydrous sodium - 316 2 ~ ~ 1 3 8 9 sulfate. By concentrating the chloroform layer under reduced pressure, 4.5 g of 2-methoxy-4-nitrophenol were obtained as crystals.
Analytical results of 2-methoxy-4-nitrophenol thus 5 obtained: -Melting point: 102-103~C.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2-methoxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 164):
0.68 g of 2-methoxy-4-nitrophenol, 1.0 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 1.1 g of triphenylphosphine were suspended in 20 mQ of anhydrous tetrahydrofuran, followed by the addition of 0.71 g of diethyl azodicarboxylate. The thus-prepared mixture was treated in a similar manner to Example 84-(2), followed by recrystallization from methanol, whereby 1.35 g of 1,3-dimethyl-6-{4-[3-(2-methoxy-4-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.9-3.3(m,12H), 3.43(s,3H), 3.5(s,3H), 4.06(s,3H), 4.26(t,2H), 5.35(s,1H), 7.05(d,1H), 7.8-8.15(m,2H).
Next, 1.3 g of the pyrimidinedione derivative was treated in a lO~HCl/methanol solution by a method known per se in the art to obtain 1.17 g of 1,3-dimethyl-6-{4-t3-(2-methoxy-4-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 164) as crystals.
Analytical results of crystals of Compound 164 thus obtained:
Melting point: 135-138~C.
Elemental analysis for C20H27N5O6-HCl-l~H2O
Calculated (%): C, 48.34; H, 6.29; N, 14.09;
Cl, 7.13.
Found (%): C, 48.20; H, 6.61; N, 14.27;
Cl, 7.38.
Example 106:
Preparation of 1,3-dimethyl-6-{4-[3-(2,6-dichloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 165):
02N~OH + BrCH2CH2CH2Br Cl 02N~OCH2CH2CH2Br ~1389 ~0 HCl/CH30H
(Compound 157) ~C , / 11~
(Compound 165) (1) Preparation of l-bromo-3-(2,6-dichloro-4-nitro-phenyloxy)propane:
A mixture of 4.16 g of 2,6-dichloro-4-nitrophenol, 40.4 g of 1,3-dibromopropane, 2.76 g of potassium carbonate and 2.46 ~-of potassium t-butoxide was heated under reflux for 4 hours in 50 ml of methyl ethyl ketone. The reaction mixture was allowed to cool down and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform. The thus-prepared chloroform solution was washed with water, and the chloroform was then distilled off. The residue was purified by chromatography on a silica gel column (eluent: chloroform/hexane = 4/1, by volume) to obtain 6.24 g of 1-bromo-3-(2,6-dichloro-4-nitrophenyloxy)-propane. This compound was employed in the nextreaction without any further purification.
(2) Preparation of 1,3-dimethyl-6-{4-[3-(2,6-dichloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 165):
4.94 g of 1-bromo-3-(2,6-dichloro-4-nitro-phenyloxy)propane obtained by the above procedure, 3.36 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(lH,3H)-pyrimidinedione (Compound 157) and 4 ml of triethyl-amine were dissolved in 100 m~ of dioxane. The thus-prepared mixture was heated for 2 hours under stirring and reflux. The reaction mixture was allowed to cool down and then filtered to remove insoluble matters. ~he filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in chloroform. The resultant chloroform solution was washed with water and the solvent was distilled off.
The residue was purified by chromatography on a silica gel column (eluent: chloro~orm/methanol = 100/0-2, by volume), followed by recrystallization from ethanol, whereby 3.57 g of 1,3-dimethyl-6-{4-[3-(2,6-dichloro-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ppm: 1.95-2.25(m,2H), 2.5-2.8(m,6H), 2.9-3.1(m,4H), 3.3(s,3H), 3.4(s,3H), 4.2(t,2H), 5.35(s,1H), 8.25(s,2H).
Next, 0.5 g of the pyrimidinedione derivative was treated in a 10%HCl/methanol solution by a method known ~ se in the art to obtain 0.45 g of 1,3-dimethyl-6-{4-t3-(2,6-dichloro-4-nitrophenyloxy)propyl]-piperazin-1-yl}-2,4(lH,3H)-pyrimidinedione hydro-chloride (Compound 165) as crystals.
Analytical results of crystals of Compound 165 thus obtained:
Melting point: 200-202~C.
~0 Elemental analysis for ClgH23cl2N5O5-Hcl-4H2o:
Calculated (%): C, 44.46; H, 4.81; N, 13.64;
Cl, 20.72.
Found (%): C, 44.47; H, 4.87; N, 13.55;
Cl, 20.73.
~5 Example 107:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{4-[3-t4-chloro-2-nitrophenyloxy)propyl]piperazin-l-yl}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 140) available by the process of Example 85:
1 g of the pyrimidinedione derivative hydrochloride (Compound 140), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of 5 g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant -particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 108:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{4-[3-(2-chloro-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione hydro-chloride ~Compound 141) available by the process of Example 86:
5 g of the pyrimidinedione derivative hydro-chloride ~Compound 141), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Bxample 109:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{4-[3-~4-methanesulfonamido-2-nitrophenyloxy)propyl]-piperazin-l-yl}-2,4~lH,3H)-pyrimidinedione hydrochloride ~Compound 142) available by the process of Example 87:
20 mg of the pyrimidinedione derivative hydro-25 chloride (Compound 142) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water Z~ 389 for injection to give a total volume of 100 m~, thereby preparing a formulation suitable for injection.
Pharmacological Test 7:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 14 and obtained in the corresponding examples described above were determined. The results are summarized in Table 14.
Table 14 Result of Pharmacological Test Effects to duration Effects to refractory time of myocardinal period of ventricular action potential muscle Compound75 t ) ERP (%) ~Dose (~g/m~) Dose (mg/kg, i.v.) 1.0 3.0 10.0 0.1 0.3 1.0 3.0 140 6 17 29 0 3.55 3.55 141 27 41 - 0 2.1 2.1 15 145 7 16 23 0 6.7 6.7 20 150 - 16 - 0 0 6.3 6.3 153 20 25 - 6.1 9.1 18.3 154 9 12 20 0 0 5.9 11.8 161 26 39 - 0 6.7 6.7 6.7 164 - 8 12 0 7.7 15.4 15.4 2(~1389 Toxicity Test 7:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 15 and obtained in the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 15.-Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
Table 15 Results of Toxicity Test on Novel Pyrimidine Derivative Compounds Compound No. Mortality rate (%) .
~0 Example 110:
Preparation of 1,3-dimethyl-6-{2-[N-methoxy-carbonylmethyl-3-(4-nitroanilino)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 166):
-o o ~C:~3 HocH2cH2NH2 CH3 ~ 2 ~ N~C~3 cl N~o ~ ~ CH3~S03CH2cH2NH N~o c~3 CH3 > C ¢N~o CH3 ~ ~ -CH
(Compound a) N ~ 3 N02-0-F T NH2-CH2CH2CH2NH2 ~I N~2-~- NHCH2CH2CH2NH2 N~2 ~ 2 2 2NHcH2cH2NH ~ CH Cl-CH2COOCH3 HCl/MeOH
(Compound b) CH3 ~
N~2 ~ CH2coocH3 ~ 3 HCl (Compound 166) CH3 ~
(1) Preparation of 1,3-dimethyl-6-[2-(p-toluene-sulfonyloxy)ethylamino]-2,4(1H,3H)-pyrimidinedione:
35.0 g of 2-aminoethanol were heated to 90~C
and then removed from an oil bath. 50.0 g of 6-chloro-1,3-dimethyl-2,4-(lH,3H)-pyrimidinedione were then added to react them to each other. The addition was conducted at such a rate that the reaction temperature was maintained within the range of 90-110~C. After completion of the addition, the reaction mixture was stirred for 10 minutes, followed by the addition of 300 m~ of dioxane/methanol (= 10/1, by volume). The resultant mixture was allowed to stand overnight.
2~:)1389 Crystals thus obtained were washed with a small amount of dioxane and then dried to obtain 49.0 g of 1,3-dimethyl-6-(2-hydroxyethylamino)-2,4-(lH,3H)-pyrimidinedione as white crystals.
Next, a suspension of 49.0 g of the white crystals in 200 ml of pyridine was chilled to -5~C, to which 40.0 g of p-toluenesulfonyl chloride were added at a rate slow enough to maintain the reaction temperature below 5~C. To eliminate cloudiness from the reaction mixture, 51.0 g of p-toluenesulfonyl chloride were used additionally.
The reaction mixture was poured into 1.5 1 of ice water in which 70 g of K2CO3 were contained.
The thus-obtained mixture was allowed to stand overnight. Resulting crystals were collected by filtration, washed with water, and then dried under reduced pressure, thereby obtaining 50.5 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(lH,3H)-pyrimidinedione as pale yellow crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 146.0-149.0~C.
IR vmax (cm ): 3270, 1682, 1615, 1550, 1480, 1435, 1360, 1190, 1178, 1010, 903, 780.
(2) Preparation of 6-(1-aziridinyl)-1,3-dimethyl-ZC~01389 _ 326 -2,4(lH,3H)-pyrimidinedione (Compound a):
To a solution of 47.2 g of 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]-2,4(lH,3H)-pyrimidinedione, which had been obtained in the above procedure, in 150 mQ of anhydrous dimethylsulfoxide, 6.24 g of 60% oil-base sodium hydride were gradually added at room temperature. The resultant mixture was vigorously stirred at room temperature for 5 hours and then cooled. A small amount of water was added to terminate the reaction. The thus-obtained mixture was poured into 1 ~ of water which contained 70 g of potassium carbonate. The resultant mixture was extracted 3 times with 200 m~ portions of chloroform.
The extracts were combined into an organic layer. The lS organic layer was dried over anhydrous sodium sulfate and then concentrated. The concentrate thus prepared was added with 300 m~ of ether and the resulting solution was allowed to stand overnight.
Pale yellow crystals which had precipitated by while the solution was allowed to stand overnight were collected by filtration, washed with ether and then dried under reduced pressure, whereby 15.2 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione (Compound a) were obtained.
Analytical results of crystals of Compound a thus obtained:
- 327 - a o Q 1 3 8 9 Melting point: 126.0-126.5~C.
I~ vmBax (cm 1): 1705, 1650, 1612, 1470, 1440, 1305, 1160, 783, 490.
lH-NMR (CDC13), ~ ppm: 2.34(s,4H), 3.35(s,3H), 3.56(s,3H), 5.25(s,1H).
(3) Preparation of 1,3-dimethyl-6-{2-[3-(4-nitro-anilino)propylamino]ethylamino}-2,4(lH,3H)-pyrimidine-dione (Compound b):
2.8 g of 4-nitrofluorobenzene were heated to 80~C in 29.6 g of propylenediamine and then stirred for 1 hour at the same temperature. The reaction mixture was poured into water and precipitated crystals were collected by filtration, thereby obtaining 3.6 g of N-(4-nitrophenyl)propylenediamine as crystals.
After dissolving 1.2 g of N-(4-nitrophenyl)-propylenediamine and 1.1 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione (Compound a), which were obtained in the above procedure (2), in 5 ml of chloroform, the resultant mixture was concentrated under reduced pressure. The residue was added with 10 mg of "Amberlist 15" (trade mark; product of Rohm & Hass Co.) and stirred at 80~C for 1 hour.
The thus-obtained mixture was dissolved in 20 ml of chloroform and "Amberlist 15" was filtered off. The filtrate was washed with water and dried over anhydrous sodium salfate. The solvent was then distilled off -under reduced pressure to obtain 1,3-dimethyl-6-{2-[3-(4-nitroanilino)propylamino~ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound b) in a crude form. Although the reaction product obtained by the above procedure contained impurities, it was provided for the next reaction without purification.
(4) Synthesis of 1,3-dimethyl-6-{2-~N-methoxycarbonyl-methyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 166):
1.5 g of 1,3-dimethyl-6-{2-[3-(4-nitroanilino)-propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound b) obtained in the above procedure (3) were dissolved in 12 m~ of DMSO, followed by the addition of 1.2 g of methyl chloroacetate and 1.5 m~ of triethylamine. The resultant mixture was stirred at 50~C for 2 hours, dissolved in chloroform, washed with water and then dried over anhydrous sodium sulfate.
The solvent was thereafter distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol =
30/1, by volume), thereby obtaining 1.8 g of 1,3-dimethyl-6-{2-[N-methoxycarbonylmethyl-3-(4-nitro-anilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
- 2~0138~
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (DMSO-d6), ~ ppm: 1.70(m,2H), 2.6-2.9(m,4H), 2.95-3.4(m,4H), 3.25(s,3H), 3.3(s,3H), 3.45(s,2H), 3.65(s,3H), 4.6(s,1H), 6.45(m,1H), 6.6(d,2H), 7.2(m,1H), 7.95(d,2H).
Further, 1.5 g of the pyrimidinedione derivative were treated in an HCl/methanol solution by a method known ~ se in the art to obtain 1.4 g of 1,3-dimethyl-6-{2-[N-methoxycarbonylmethyl-3-(4-nitroanilino)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 166) as amorphous powder.
Elemental analysis for C20H28N6O6-HCl-H2O:
Calculated (%): C, 47.76; H, 6.21; N, 16.71;
Cl, 7.05.
Found (%): C, 47.06; H, 5.91; N, 16.05;
Cl, 7.58.
Example 111:
Preparation of 1,3-dimethyl-6-{2-[N-(2-acetoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 167~:
;~0~3~9 N02 ~ CH2CH2C~~H > ' N02 ~ cH2CH2coNHcH2CH20H
> N02 ~ CH2CH2CH2NHCH2CH20H
O O
~C%3 NH2CH2~H2~H CH35~2Cl ~N~CH3 K2C03 cl I ~o > CH3502-ocH2cH2NH N~o >
CH3 (Compound c) c~3 No2~CH2CH2cH2NHcH2cH20 CH2CH20H ,~11~
No2~cH2cH2cH2N-cH2cH2 N~o (Compound dJ C~3 o (CH3CO)20 (COOH)2/MeOH ¦ ~ N,CH3 > ~ N02~CH2CH2CH2NCH2cH2NH N~o ~ ( COOH)2 (Compound 167) CH3 (1) Preparation of N-(2-hydroxyethyl)-3-(4-nitro-phenyl)propionamide:
60 g of 3-(4-nitrophenyl)propionic acid were suspended in 360 m~ of chloroform, followed by the addition of 2.25 g of dimethylformamide. The thus-prepared reaction mixture was heated at 50-60~C, to which 33.5 m~ of thionyl chloride were gradually added dropwise. After the dropwise addition, the resultant mixture was heated under reflux for 1 hour, the solvent was distilled off under reduced pressure, and the resultant oily substance was dissolved in 150 m~ of chloroform. The chloroform solution was added dropwise Z~)0~38~3 under ice cooling into a solution which had been formed by dissolving 28.2 g of ethanolamine and 42.5 g of potassium carbonate in 450 m~ of water. After completion of the dropwise addition, the resultant mixture was stirred for 1 hour. Precipitated crystals were collected by filtration and then recrystallized from 1 ~ of ethyl acetate, thereby obtaining 56.1 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propionamide as - crystals.
Melting point: 122-125~C.
(2) Preparation of N-(2-hydroxyethyl)-3-(4-nitro-phenyl)propylamine:
50 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propionamide obtained in the above procedure and 31.8 g of sodium borohydride were suspended in 500 m~ of tetrahydrofuran, followed by the dropwise addition of 50.5 g of acetic acid under ice-cooling. After completion of the dropwise addition, the resultant mixture was heated under reflux for 2 hours. It was again ice-cooled, followed by the dropwise addition of 500 m~ of water. 4 N hydrochloric acid was added to adjust the pH to 5-6 and tetrahydrofuran was distilled off under reduced pressure. The resultant aqueous solution was added with 425 m~ of 4 N hydrochloric acid and the mixture thus prepared was heated at 60-70~C for 1 hour under stirring. The reaction ~ 9 mixture was allowed to cool down to room temperature and washed with chloroform. The resultant aqueous solution was adjusted to pH 11 with a 16% aqueous solution of sodium hydroxide and then extracted twice with 500 mQ portions of chloroform. The chloroform extracts were combined together and then concentrated under reduced pressure. The residue was crystallized from 900 mQ of toluene, thereby obtaining 38.6 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine as crystals.
Melting point: 82.5-84.5~C.
(3) Preparation of 1,3-dimethyl-6-(2-methanesulfonyl-oxyethylamino)-2,4(1H,3H)-pyrimidinedione (Compound c):
52.4 g of 6-chloro-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione were dissolved in 280 mQ of pyridine, followed by the addition of 45.5 g of triethylamine and 21.3 g of aminoethanol. The thus-prepared mixture was heated under reflux at 90~C for 4 hours. The reaction mixture was ice-cooled and while maintaining the internal temperature at 0-4~C, 55.8 g of methane-sulfonyl chloride were added dropwise. The resultant mixture was stirred for 3 hours at the same tempera-ture. 1.2 Q of methanol were added, followed by stirring for additional 2 hours. Crytals precipitated in the reaction mixture were collected by filtration and then recrystallized from 3.5 ~ of methanol, thereby obtaining 70.0 g of 1,3-dimethyl-6-(2-methane-sulfonyloxyethylamino)-2,4(lH,3H)-pyrimidinedione (Compound c) as crystals.
Melting point: 169-170~C.
(4) Preparation of 1,3-dimethyl-6-{2-tN-(2-hydroxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound d):
20.2 g of 1,3-dimethyl-6-(2-methanesulfonyloxy-ethylamino)-2,4(1H,3H)-pyrimidinedione (Compound c), which had been synthesized in the above procedure (3), and 15.1 g of potassium carbonate were suspended in 300 m~ of acetonitrile. The resultant mixture was heated under reflux for 4 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure to the total volume of about 60 m~, followed by the addition of 18 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine obtained in the above procedure (2), 36 m~ of DMF and 0.69 g of p-toluenesulfonic acid monohydrate. Under reduced pressure, acetonitrile was distilled off. The residue was heated under stirring at 80~C for 2 hours. The reaction mixture was cooled to room temperature, to which 900 m~ of 0.1 N hydrochloric acid were added to dissolve insoluble matters. Thereafter, a 0.5 M
aqueous solution of potassium carbonate was added to ~1389 render the mixture alkaline. The thus-prepared mixture was stirred at room temperature for 3 hours.
Precipitated crystals were collected by filtration, dried and then recrystallized from ethanol, thereby obtaining 26.6 g of 1,3-dimethyl-6-{2-[N-(2-hydroxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound d) as crystals.
Melting point: 125-126~C.
(5) Preparation of 1,3-dimethyl-6-{2-[N-(2-acetoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 167):
1.6 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione (Compound d) and 0.8 g of acetic anhydride were dissolved in 5 m~ of pyridine. The resultant mixture was stirred at room temperature for 24 hours and then at 60~C for 1 hour. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with water and then concentrated. The residue was purified by chromato-graphy on a silica gel column (eluent: chloroform/
methanol = 25/1-10/1, by volume), thereby obtaining 1.65 g of 1,3-dimethyl-6-{2-[N-(2-acetoxyethyl~-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione as crystals.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 90.5-92.0~C.
NMR (CDC13), ~ ppm: 1.85 (m,2H), 2.15(s,3H), 2.5-3.3(m,10H), 3.26(s,3H), 3.37(s,3H), 4.3(t,2H), 4.78(s,1H), 7.2-8.2(m,4H).
- Further, 1.5 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 1.6 g of 1,3-dimethyl-6-{2-tN-(2-acetoxyethyl)-3-(4-nitrophenyl)-propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 167) as crystals.
Analytical results of crytals of Compound 167 thus obtained:
Y 21 29N5~6 (COOH)2 H2O
Calculated (%): C, 49.73; H, 5.99; N, 12.61.
Found (%): C, 50.22; H, 5.75; N, 12.98.
Example 112:
Preparation of 1,3-dimethyl-6-{2-[N-(2-benzoyl-oxyethyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 168):
2~1389 CH2c~20~ ~( ~ CO)2o HCl/MeOH
No2~cH2cH2cH2N-cH2cH2 N~o >
(Compound d) CH3 C~12CH20C~
o N~2 ~ CH2CH2CH2NCH2cH2NH ~N ~ .(COOH)2 (Compound 168) c~3 In a similar manner to Example 111-(5) except for the use of 1.6 g of benzoic anhydride in place of acetic anhydride, 1.85 g of 1,3-dimethyl-6-{2-[N-(2-benzoyloxyethyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(1H,3H)-pyrimidinedione were obtained.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.93 (m,2H), 2.5-3.4(m,10H), 3.29(s,3H), 3.38(s,3H), 4.45(t,2H), 4.77(s,1H), 7.0-8.2(m,9H).
Further, 1.5 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 1.4 g of 1,3-dimethyl-6-{2-[N-(2-benzoyloxyethyl)-3-(4-nitro phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 168) as crystals.
Analytical results of crytals of Compound 168 thus obtained:
ement na ysis for C26 31N5~6 (C ~ )2 2 Calculated (%): C, 54.45; H, 5.71; N, 11.34.
Found (%): C, 54.90; H, 5.55; N, 11.55.
Example 113:
Preparation of 1,3-dimethyl-6-{2-<N-[2-(4-fluorobenzoyloxy)ethyl]-3-(4-nitrophenyl)propyl-amino>ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 169):
I NH ~ N_CH
N02~CH2CH2cH2NcH2cH2 N~o CH2cH2oc ~ F
(COOH)2/MeOH ~ N_CH3 N02~CH2CH2CH2N-cH2cH2 I~N~O ~ ( COOH)2 (Compound 169) CH3 1.0 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound d), which had been obtained in Example 111-(4), and 0.8 g of p-fluorobenzoyl chloride were dissolved in 5 ml of pyridine. The resultant mixture was stirred at room temperature for 12 hours, poured into water, and then extracted with Z~1389 chloroform. The extract was washed with water and then concentrated. The residue was purified by chromato-graphy on a silica gel column (eluent: chloroform/
methanol = 40/1, by volume), thereby obtaining 1.0 g of S 1,3-dimethyl-6-{2-<N-[2-(4-fluorobenzoyloxy)ethyl]-3-(4-nitrophenyl)propylamino>ethylamino}-2,4(lH,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.9-3.1(m,12H), 3.29(s,1H), 3.38(s,3H), 4.59(t,2H), 4.78(s,1H), 7.1-8.0(m,8H).
Further, 0.95 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known per se in the art to obtain 1.07 g of 1,3-dimethyl-6-{2-<N-[2-(4-fluorobenzoyloxy)ethyl]-3-(4-nitrophenyl)propylamino>ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 169) as crystals.
Analytical results of crytals of Compound 169 thus obtained:
Melting point: 96-99~C (decomposed).
Y 26 30 5~6 (COO )2 2H2o Calculated (%): C, 51.45; H, 5.55; N, 10.71.
Found (%): C, 51.82; H, 5.40; N, 10.82.
IR vmax (cm 1): 3350, 2950, 1740, 1700, 1620, 1530, 1330, 1000, 850, 760.
200~389 Example 114:
Preparation of 1,3-dimethyl-6-{2-<N-[2-(4-methoxybenzoyloxy)ethyl]-3-(4-nitrophenyl)-propylamino>ethylamino}-2,4(lH,3H)-pyrimidine-dione oxalate (Compound 170):
CH2CH2OH l~U~ CH3O~COCl No2~cH2cH2cH2NcH2cH2 N~o CH2CH20C ~ oCH3 ( COOH ) 2 /MeOH ¢I~N~CH 3 N02~CH2CH2CH2NcH2cH2NH N~o ~ ~ COOH ) 2 ( C~ ~und 170 ) C~3 In a similar manner to Example 113 except for the use of 0.63 g of p-methoxybenzoyl chloride instead of p-fluorobenzoyl chloride, 1.1 g of 1,3-dimethyl-6-{2-<N-[2-(4-methoxybenzoyloxy)ethyl]-3-(4-nitrophenyl)-propylamino>ethylamino}-2,4(lH,3H)-pyrimidinedione were obtained.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.4-3.0(m,10H), 3.31(s,3H), 3.42(s,3H), 3.50(s,3H), 4.4(t,2H), 4.77(s,1H), 5.31(br,1H), 2~01389 7.18(m,4H~, 8.0(m,4H).
Further, 1.0 g of the pyrimidinedione derivative were treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 1.05 g of 1,3-dimethyl-6-{2-<N-[2-(4-methoxybenzoyloxy)ethyl]-3-(4-nitrophenyl)propylamino>ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate ~Compound 170) as crystals.
Analytical results of crytals of Compound 170 thus obtained:
Elemental analysis for C27H33N5O7-(COOH)2-~H2O:
Calculated (%): C, 54.54; H, 5.68; N, 10.97.
Found (%): C, 54.21; H, 5.99; N, 10.92.
IR vmBx (cm 1): 3300, 2950, 1690, 1600, 1520, 1350, 1250, 1020, 850, 760.
Example 115:
Preparation of 1,3-dimethyl-6-{2-[N-(2-methoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 171):
O
¢)~N--CH3 3 2 2 2 CH3 ( Compound a ) No2~cH2cH2cH2oso2~ 3 >
( COOH ) 2/MeCH fH2CH2~CH~
~, NO 2 ~ CH 2 CH 2 CH 2 NCH 2 C 2 N~o ~ ( COOH ) 2 ( Compound 171 ) CH3 200~389 A mixture consisting of 1 g of 3-(4-nitro-phenyl)propyl p-toluenesulfonate, 6.5 ml of 2-methoxy-ethylamine and 5 m~ of dioxane was heated under reflux for 3 hours, followed by the addition of 100 m~ of chloroform. The resultant mixture was washed with water and then dried over anhydrous sodium sulfate.
The thus-prepared chloroform solution was added with 10 mg of p-toluenesulfonic acid and 0.54 g of 6-(1-- aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (Compound a) obtained in Example 110-~2), followed by the distillation of the solvent under reduced pressure.
The mixture was then heated at 80~C for 2 hours and then cooled down to the room temperature. The thus-obtained mixture was directly subjected to chromato-graphic purification on a silica gel column (eluent:chloroform/methanol = 40/1, by volume), thereby obtaining 0.82 g of 1,3-dimethyl-6-{2-[N-(2-methoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione as an oily substance.
Analytical results of the pyrimidinedione thus obtained:
NMR (CDC13), ~ ppm: l.9(m,2H), 2.4-3.6(m,12H), 3.23(s,3H), 3.30(s,3H), 3.33(s,3H), 4.71(s,1H), 5.74(br,1H), 7.19(d,2H), 8.03(d,2H).
Further, 0.80 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.85 g of 1,3-dimethyl-6-{2-[N-(2-methoxyethyl)-3-(4-nitrophenyl)-propylamino~ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 171) as crystals.
Analytical results of crytals of Compound 171 thus obtained:
Elemental analysis for C20H29N5O5-(COOH)2-H2O:
Calculated (~): C, 50.09; H, 6.31; N, 13.28.
Found (%): C, 50.14; H, 6.39; N, 13.30.
IR vmax (cm 1): 3300, 3000, 1680, 1630, 1510, 1430, 1350, 1200, 770, 700.
Example 116:
Preparation of 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 172):
2 0 ~ 2 2 ¢U'N~CH3 No2~CHzCH2CH20502~CH3 > >
O
( COOH ) 2 /MeOH ICH2 ~N~CH 3 > N02~CH2CH2cH2N-cH2cH2 ~N~o ~(COOH)2 ( Compound 172 ) CH3 In a similar manner to Example 115 except for the use of 0.36 m~ of benzylamine instead of 2-methoxyethylamine and the addition of 1 ml of tri-ethylamine, 1.6 g of 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione were obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.4-3.3(m,8H), 3.21(s,3H), 3.25(s,3H), 3.58(s,2H), 4.67(s,1H), 5.22(br,1H), 7.22(d,2H), 7.30(s,5H), 8.03(d,2H).
Further, 1.50 g of the pyrimidinedione deriva-tive were treated in an oxalic acid/methanol solutionby a method known E~ se in the art to obtain 1.55 g of 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 172) as crystals.
Analytical results of crytals of Compound 172 thus obtained:
Y 24 29 5 4 (C ~ )2 ~ 2~
Calculated t%): C, 56.72; H, 5.86; N, 12.72.
Found (%): C, 56.41; H, 5.82; N, 12.24.
IR vmax (cm 1): 3300, 2950, 1680, 1630, 1540, 1340, 1200, 770, 700.
- 344 - ~ 3 8 9 Example 117:
Preparation of 1,3-dimethyl-6-{2-[N-(t-butoxy-carbonyl)-3-(4-nitrophenyl)propylamino~ethyl-amino}-2,4(1H,3H)-pyrimidinedione (Compound 173):
~ NH4OH/H O N~ElH
N02~3CH2CH2CC1 2 ~ N02~CH2CH2CH2NH2 C ~N
l O O
C~3 ~(CH3)3Coc0120 1 ~Y3 ~N~ 3 ~,~ NC2~CH2CH2C~2N-cH2cH2NH I~N~O
(C~ 173)CS~3 (1) Preparation of 3-(4-nitrophenyl)propylamine:
A solution of 21 g of 3-~4-nitrophenyl)propionyl chloride in 30 ml of chloroform was added dropwise into a mixture of 75 ml of concentrated aqueous ammonia and 75 ml of ice water. The resultant mixture was then stirred for 2 hours under ice-cooling. The resultant precipitate was collected by filtration, dried in air and recrystallized from ethyl acetate, thereby obtaining 13.7 g of 3-(4-nitrophenyl)propan-amide.
10.0 g of the amide compound and 9.S g of sodium borohydride were suspended in 250 ml of dioxane, followed by the dropwise addition of 15 ml of acetic acid. The resultant mixture was stirred for 10 hours under reflux. The reaction mixture was added with B
~r, .
10 mQ of methanol and then concentrated to dryness.
The residue was dissolved in chloroform. The solution thus obtained was washed with water and then concentrated to dryness, thereby obtaining 6.0 g of 3-(4-nitrophenyl)propylamine as an oily substance.
This compound was provided for the next reaction without any further purification.
NMR (CDC13), ~ ppm: l.9(m,2H), 2.4-3.0(m,4H), - 6.70(br,2H), 8.31(d,2H), 8.10(d,2H).
(2) Preparation of 1,3-dimethyl-6-{2-[N-(t-butoxy-carbonyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione (Compound 173):
6.0 g of 3-(4-nitrophenyl)propylamine obtained in the above procedure (1) and 3.98 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (Compound a) obtained in Example 110-(2) were dissolved in 50 ml of chloroform, and the resultant mixture was concentrated to dryness under reduced pressure. The residue was added with 50 mg of p-toluenesulfonic acid monohydrate and the mixture thus prepared was stirred at 90~C for 2 hours. The mixture was dissolved in 60 ml of tetrahydrofuran, followed by the addition of 3.0 g of di-tert-butyldicarbonate. The thus-obtained mixture was stirred at room temperature ~or 1 hour and then concentrated. The residue was 26:~1389 purified by chromatography on a silica gel column (eluent: chloroform/methanol = 40/1, by volume), thereby obtaining 5.0 g of 1,3-dimethyl-6-{2-[N-(t-butoxycarbonyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(lH,3H)-pyrimidinedione (Compound 173) as crystals.
A~alytical results of Compound 173 thus obtained:
Melting point: 111-112~C.
NMR (CDC13), ~ ppm: 1.51(s,9H), l.9(m,2H), 2.5-3.0(m,6H), 3.3-3.4(m,2H), 3.28(s,3H), 3.36(s,3H), 4.68(s,1H), 6.54(br,1H), 7.39(d,2H), 8.20(d,2H).
Elemental analysis for C22H31N5O6:
Calculated (%): C, 57.25; H, 6.77; N, 15.17.
Found (%): C, 57.29; H, 6.76; N, 15.13.
Example 118:
Preparation of 1,3-dimethyl-6-{2-[N-(4-methoxy-benzyl)-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 174):
COOC~ CH3 ) 3 ~
N02~ 2CH2CH2N-CH2CH2NH-~,~ 3 HCl/O/--\O
( Compound 173 ) - 2~1~1389- - 347 -Z~CH2cH2cH2NH-cH2cH2NH~
(Compound e)~HCl ~H3 O
1 ~ CH2Br (COOH)2/MeOH NO2 ~ CH2CH2CH2N-CH2cH2NH ~ ~ ~(COOH) (Compound 174) CH3 (1) Preparation of 1,3-dimethyl-6-{2-[3-(4-nitro-phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione hydrochloride (Compound e):
30 m~ of 0.-5 N HCl/dioxane were added to 4.9 g of 1,3-dimethyl-6-{2-[N-(t-butoxycarbonyl~-3-(4-nitro-phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione (Compound 173). The resultant mixture was stirred at room temperature for 24 hours. Precipitated crystals were collected by filtration and then washed with a chilled solvent consisting of a 1:2 mixture (by volume) of ethanol and ether, thereby obtaining 3.9 g of 1,3-dimethyl-6-{2-[3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e).
Analytical results of crystals of Compound e thus obtained:
Melting point: 230-231~C (decomposed).
Elemental analysis for C17H23N5O4-2HCl-H2O:
Calculated (%): C, 45.14; H, 6.02; N, 15.48;
26~389 Cl, 15.68.
Found (%): C, 45.31; H, 5.87; N, 15.54;
Cl, 15.67.
(2) Preparation of 1,3-dimethyl-6-{2-[N-(4-methoxy-benzyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 174):
1.4 g of 1,3-dimethyl-6-{2-[3-~4-nitrophenyl)-propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e) were dissolved in 5 m~ of water, followed by the addition of potassium carbonate to render the solution alkaline. The solution was then extracted with chloroform. The thus-obtained chloro-form solution was concentrated to dryness, followed by the addition of 0.6 g of p-methoxybenzyl bromide, 3 m~
of triethylamine and 20 m~ of isopropanol. The resultant mixture was heated for 8 hours under reflux.
The solvent was distilled off under reduced pressure and the residue was directly subjected to chromato-graphic purification on a silica gel (eluent: chloro-form/methanol = 40/1, by volume), thereby obtaining0.55 g of 1,3-dimethyl-6-{2-[N-(4-methoxybenzyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.5-3.1(m,8H), 3.24(s,3H), 3.30(s,3H), 3.64(s,2H), 4.59(s,1H), 5.16(m,1H), 7.16(m,4H), 7.94(m,4H).
Further, 0.52 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.54 g of 1,3-dimethyl-6-{2-[N-(4-methoxybenzyl)-3-(4-nitro-phenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidine-dione oxalate (Compound 174) as crystals.
Analytical results of crytals of Compound 174 thus obtained:
Melting point: 104-106~C (decomposed).
IR vmax (cm 1): 3300, 2950, 1710, 1700, 1630, 1520, 1340, 1250, 1070, 770, 700.
Y 25 31 5 5 ( )2 2 Calculated (%): C, 54.18; H, 6.06; N, 11.70.
Found (%): C, 54.74; H, 5.97; N, 11.37.
Example 119:
Preparation of 1,3-dimethyl-6-{2-tN-ethoxy-carbonylmethyl-3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 175):
N02 ~ CH2CH2CH2NHCH2cH2NH ~N
(Compound e) HCl C 3 Br-CH COOC H (COOH) /MeOH CH2cooc2H5 ~
2 2 5 2 > NO2 ~ C~2cH2cH2NcH2cH2NH ~N~ ~ (COOHJ
(Compound 175) 1~3~ 2 In a similar manner to Example 118-(2) except for the use of 0.4 m~ of ethyl bromoacetate in place of p-methoxybenzyl bromide, 0.77 g of 1,3-dimethyl-6-~2-[N-(2-ethoxycarbonylmethyl-3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.30(t,3H), l.9(m,2H), 2.4-3.0(m,6H), 3.0-3.4(m,4H), 3.3(s,3H), 3.5(s,3H), 4.22(q,2H), 4.74(s,1H), 7.31(d,2H), 8.12(d,2H).
Further, 0.7 g of the pyrimidinedione derivative was treated in an oxalic acid/methanol solution by a method known ~ se in the art to obtain 0.72 g of 1,3-dimethyl-6-{2-[N-ethoxycarbonylmethyl-3-(4-nitro-phenyl)propylamino]ethylamino~-2,4(lH,3H)-pyrimidine-26~389 dione oxalate (Compound 175) as crystals.
Analytical results of crytals of Compound 175 thus obtained:
Melting point: 148-149~C (decomposed).
IR Vmax (cm ): 2930, 2450, 1730, 1700, 1600, 1540, 1340, 1250, 1200, 850, 750.
Element ana ys s r 21 29N5O6 ( )2 ~ 2 Calculated (%): C, 50.55; H, 5.90; N, 12.81.
- Found (%): C, 50.89; H, 5.81; N, 12.62.
Example 120:
Preparation of 1,3-dimethyl-6-{N-(2-phenyl-ethyl)-2-[3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 176):
o Cl ~¢DN~o CH 2CH2-~
NH2CH2 2 CH3 HocH2cH2N~
~>-cH2cH2-Br ~ 3 O
(COc1)2-DMso 02N~CH2CH2CH2NH2 HCl/MeOH
? ~ >
o 02N~CH2CH2CH2NHcH2cH2N -~N~ ~ HCl (Compound 176) CH3 (1) Preparation of 1,3-dimethyl-6-[N-(2-hydroxyethyl)-2-phenylethylamino]-2,4(1H,3H)-pyrimidinedione:
A mixture consisting of 3 mO of phenethyl bromide, 13 m~ of ethanolamine and 15 m~ of isopropanol was heated for 2 hours under reflux. After allowing the reaction mixture to cool down, 50 mQ of chloroform were added. The thus-prepared mixture was washed with water and then concentrated to obtain an oily substance. To the oily substance, 3.5 g of 6-chloro-1,3-dimethyl-2,4(lH,3H)-pyrimidinedione and 3.3 m~ of triethylamine were added. The resultant mixture was dissolved in 15 m~ of dimethylformamide and stirred at 110~C for 4 hours. The solution was cooled down to room temperature, followed by the addition of 150 mQ of chloroform. The resultant chloroform solution was washed with water and then concentrated to obtain an oily substance. By crystallizing the oily substance from ether, 4.1 g of 1,3-dimethyl-6-[N-(2-hydroxyethyl)-2-phenyl-ethylamino]-2,4(lH,3H)-pyrimidinedione were obtained as crystals.
~nalytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 77-78~C.
NMR (CDC13), ~ ppm: 2.4-3.2(m,6H), 3.18(s,3H), 3.22(s,3H), 3.50(t,2H), 5.28(s,1H), 7.18(br,5H).
Elemental analysis for C16H21N3O3:
Calculated (%): C, 63.35; H, 6.98; N, 13.85.
Found (%): C, 63.01; H, 6.78; N, 13.91.
(2) Preparation of 1,3-dimethyl-6-{N-(2-phenylethyl)-2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound 176):
0.26 m~ of oxalyl chloride was dissolved in 5 m~ of dichloromethane. The resultant mixture was - chilled to -78~C, followed by the dropwise addition of a solution of 0.21 m~ of dimethylsulfoxide in 5 m~ of dichloromethane. The thus-prepared mixture was stirred for 15 minutes at the same temperature, followed by the dropwise addition of a solution of 0.6 g of 1,3-dimethyl-6-[N-(2-hydroxyethyl)-2-phenylethylamino]-2,4(1H,3H)-pyrimidinedione in 10 m~ of dichloro-methane. The mixture was stirred for further 15 minutes. After adding 0.84 ml of triethylamine, the mixture was gradually cooled to room temperature and then stirred for 5 minutes. 30 m~ of chloroform were added. The mixture thus obtained was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.51 g of an oily substance.
The oily substance was dissolved in 10 m~ of methanol, followed by the addition of 0.72 g of 3-(4-nitrophenyl)propylamine obtained in Example 117-(1) and 0.5 mQ of 4 N-HCl/dioxane. The resulting mixture was stirred at room temperature for 30 minutes and 1 g of sodium cyanoborohydride was added in several small portions. After stirring the mixture at room temperature for 12 hours, 1 N hydrochloric acid was added to acidify the reaction mixture. Methanol was distilled off and potassium carbonate was added to neutralize the residue. The thus-prepared solution was extracted with chloroform and the chloroform layer was concentrated to dryness. The residue was purified by chromatography on a silica gel column (eluent:
chloroform/methanol = 40/1, by volume), thereby obtaining 0.2 g of 1,3-dimethyl-6-{N-(2-phenylethyl)-2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: l.9(m,2H), 2.6-3.6(m,12H), 3.18(s,3H), 3.26(s,3H), 5.28(s,1H), 7.18(br,5H), 7.30(d,2H), 8.09(d,2H).
Further, 0.19 g of the pyrimidinedione deriva-tive was treated in a 1 N-HCl/methanol solution by a method known ~ se in the art to obtain 0.12 g of 1,3-dimethyl-6-{N-(2-phenylethyl)-2-[3-(4-nitrophenyl)-26~C)1389 propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione hydrochloride (Compound 176) as crystals.
Analytical results of crystals of Compound 176 thus obtained:
Elemental analysis for C25H31N5O4-HC1-3H2O:
Calculated (%): C, 54.00; H, 6.89; N, 12.59;
Cl, 6.38.
Found (%): C, 53.81; H, 6.74; N, 12.11;
- Cl, 5.91.
10IR vKBr (cm~l) 3420, 2610, 1700, 1650, 1620, 1550, max 1320, 1010, 820, 780, 750.
Example 121:
Preparation of 1,3-dimethyl-6-{2-tN-allyl-3-(4-nitrophenyl)propylamino]ethylamino}-15 2,4(lH,3H)-pyrimidinedione oxalate (Compound 177):
~ N_CH3 ~\" Br (COOH)2/MeOH
N02~CH2CH2cH2NHcH2cH2NHJ~N~o (Compound e) HCl CH3 N02~ CH2-CH-CH2~
~Compound 177) CH3 In a similar manner to Example 118-(2) except Eor the use of 0.38 m2 of allyl bromide in place of p-methoxybenzyl bromide, 0.9 g of 1,3-dimethyl-6-{2-2~1389 [N-allyl-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(lH,3H)-pyrimidinedione was obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 109-111~C.
NMR (CDC13), ~ ppm: 2.0(m,2H), 2.5-3.1(m,10H), 3.26(s,3H), 3.34(s,3H), 4.75(s,1H), 5.16(m,2H), 5.63(m,1H), 7.25(d,2H), 8.04(d,2H).
Further, 0.80 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by a method known E~ se in the art to obtain 0.75 g of 1,3-dimethyl-6-{2-[N-allyl-3-(4-nitrophenyl)propylamino]-ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 177) as crystals.
Analytical results of crytals of Compound 177 thus obtained:
Melting point: 85-90~C.
Elemental analysis for C20H27N5O4-(COOH)2-l~H2O:
Calculated (%): C, 50.96; H, 6.22; N, 13.51.
Found (%): C, 51.30; H, 6.26; N, 13.24.
IR vmax (cm 1): 3250, 2940, 1690, 1620, 1540, 1340, 1160, 990, 850, 770, 700.
Example 122:
Preparation of 1,3-dimethyl-6-{2-[N-propargyl-3-~ 357 ~ 2~Q~38g (4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 178):
~ N_cH3 ~r-CH2-C~CH (COOH)2/MeOH
N02~C~2CH2c~2NHcH2c~2NH N~o (C. ,-~nd e) CH3 ~HCl C~12-C-CH ~
N02 ~ CH2cH2cH2NcH2cH2NH ~ ~COOH~
(C~ , ~ 178~ CN3 In a similar manner to Example 118-(2) except for the use of 0.37 ml of propargyl bromide in place of p-methoxybenzyl bromide, 0.85 g of 1,3-dimethyl-6-{2-tN-propargyl-3-(4-nitrophenyl)propylamino]ethyl-amino}-2,4(1H,3H)-pyrimidinedione was obtained.
Analytical results of crystals of the pyrimidinedione derivative thus obtained:
Melting point: 156-157~C.
NMR (CDC13), ~ ppm: l.9(m,2H), 2.23(m,1H), 2.4-3.1(m,10H), 3.25(s,3H), 3.34(s,3H), 4.73(s,1H), 5.22(br,1H), 7.27(d,2H), 8.04(d,2H).
Further, 0.80 g of the pyrimidinedione deriva-tive was treated in an oxalic acid/methanol solution by ~=
2~ 389 a method known per se in the art to obtain 0.75 g of 1,3-dimethyl-6-{2-[N-propargyl-3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(lH,3H)-pyrimidinedione oxalate (Compound 178) as crystals.
Analytical results of crytals of Compound 178 thus obtained:
Melting point: 170-172~C.
Element n y 20 25 5 4 ( 2 ~ 2 Calculated (%): C, 53.01; H, 5.66; N, 14.05.
Found (%): C, 53.31; H, 5.63; N, 14.18.
IR vmax (cm 1): 3250, 2600, 1640, 1620, 1530, 1340, 770, 700.
Example 123:
Production of tablets containing as an effective ingredient 1,3-dimethyl-6-{2-[N-(2-acetoxy-ethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4-(lH,3H)-pyrimidinedione oxalate (Compound 167) available by the process of Example 111:
1 g of the pyrimidinedione derivative oxalate (Compound 167), 123 g of lactose and 20 g of corn starch were finely mixed. Using a solution of 5 g of hydroxypropylcellulose in 100 m~ of water, the resultant mixture was granulated. The resultant particles were dried at 50~C for 4 hours and then mixed thoroughly with 1 g of magnesium stearate. The 2~1389 thus-prepared mixture was then compressed into tablets, each containing 150 mg, by a tablet machine.
Example 124:
Production of capsules containing as an effective ingredient 1,3-dimethyl-6-{2-[N-benzyl-3-(4-nitrophenyl)propyl-amino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (Compound 172) available by the process of Example 116:
5 g of the pyrimidinedione derivative oxalate (Compound 172), 120 g of lactose and 25 g of corn starch were finely mixed. The resulting mixture was filled into hard capsules, each containing 150 mg, by a capsule filling machine.
Example 125:
Production of injection containing as an effective ingredient 1,3-dimethyl-6-{2-[N-ethoxycarbonylmethyl-3-(4-nitrophenyl)propyl-amino]ethyl-2,4~1H,3H)-pyrimidinedione oxalate (Compound 175) available by the process of Example 119:
20 mg of the pyrimidinedione derivative oxalate (Compound 175) and 0.85 g of sodium chloride were weighed. They were dissolved in distilled water for injection to give a total volume of 100 mQ, thereby preparing a formulation suitable for injection.
Z~01389 Pharmacological Test 8:
Similarly to Pharmacological Test 1, the ADP75 and ERP of each of the compounds shown in Table 16 and obtained in the corresponding examples described above were determined. The results are summarized in Table 16.
Table 16 Results of Pharmacological Test 75 ( ) ERP (%) CompoundDose (~g/m~)Dose (mg/kg, i.v.) No.
1.0 3.0 10.0 0.1 0.3 1.0 3.0 166 8 18 - 6.7 6.7 6.7 6.7 Toxicity Test 8:
Similarly to Toxicity Test 1, the toxicity of each of the compounds shown in Table 17 and obtained in the corresponding examples described above was tested to determine the mortality rate of mice. The results are summarized in Table 17.
Incidentally, the administration of each compound was conducted orally (p.o.) at a dose of 300 mg/Kg.
2~)01389 Table 17 Compound No.Mortality rate (%) 165 ~
166 ~
167 ~
23~1389 Example 126 Preparation of 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl) propylaminoJethylamino}-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedlone hydrochloride Cl N ~ HOCHzCHzNH N ~
CH CH3 CH3 1l 'CH3 CH3SO2-OCHzCHzN N ~
> ~
CH3 o CH3 NOz ~ CH2CH2CH2NHCH2CH20H HCI/CH30H
> >
NOz ~ CH2CH2CHzNCH2CH2NH ~ NCH3 HCl CH3 0 (Compound 179) (1) Preparation of 6-~2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1~,3H)-pyrimidinedione 6-chloro-1,3,5-trimethyl-2,4(1H,3H~-pyrimidinedione (3.4g) was suspended in 30 ml of isopropanol, and the suspension was added with 1.26 ml of ethanolamine and 3.8 ml of triethylamine and then the resultant mixture was refluxed fvr 3 hours. The reaction mixture was allowed to stand overnight at room temperature, and thereafter crystals formed were collected by filtration, washed with water and then recryst~llized l}sing a water-ethanol solution (1:1, vJv~, thereby 2.9g of 5-(2-hydroxyethylamino)~ ,5-trimethyl-2,4(1H,3H)-pyrimidinedione being obtained.
Results of analysis of the pyrimidinedione derivative thus obtained:
Melting point: ]59-160~C
N'MR (CDCI3), ~ ppm: 4.71 (t,2H), 3.55 (m, 2H), 3.21 (s, 3H), 3.39 (s, 3H), 1 93 (s, 3H) Elemental analysis: CgH15N303 Calculated (X): C, 50.69; H, 7.09: N, 19.71 10- Analyzed (x): C, 50.89; H, 7.11: H, 19.90 (2) Preparation of 6-(2-methanesulfonyloxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione 6-(2-hydroxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (2.9g) was dissolved in 20 ml of pyridine and added with 1.20 ml of methanesulfonyl chloride drop by drop at 0~C. After the reaction at 0~C for 4 hours, the reaction mixture was poured into lO ml of ice water and then subjected to chloroform extraction. The extract was washed with water, dried over sodium sulfate anhydrous, concentrated ln vacuo. The resultant oily substance was subjected to silica gel column chromatograph (chloroform/methanol = 30:1, v/v) for purification. Thus, 3.0 g of 6-(2-methanesulfonyloxyethylamino~-1,3,5-trimethyl-2,4~1H,3H)-pyrimidinedione was obtained.
Results of analysis of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 5.02 (t,2H), 3.~ (m, 2H), 3.30 (s, 3H), 3.41 (s, 3H), 2.14 (s, 3H), 1.99(s, 3H) Elemental analYSiS C10~17N3~5S
Calculated ~): C, 41.23; H, 5.88: N, 14.42;S, 11.01 Analy7.ed (x~: C, 40.97; H, 5.91: N, 14.65; S, 11.07 (3) Preparation of 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-1,3,5-trimethyl-2,4~1H,3H)-pyrimidinedione hydrochloride ~compound 179) 6-(2-methanesulfonyloxyethylamino)-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione (3.0 g)-was dissolved in 3~ ml of acetonitrile, added with 2.1 g potassium carbonate and then allowed to react under heating with reflux for 6 hours.
After the reaction, the reaction mixture was allowed to stand overnight at room temperature. Insoluble materials were removed by filtration and the filtrate was made to 100 ml by addition of acetonitrile. A portion of 10 ml was taken, and 0.23 g of N-~2-hydroxyethyl)-3-t4-nitrophenyl~propylamine and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in this portion. The solution was concentrated in vacuo and the resultant oily substance was allowed to react at 80~C for 6 hours. The reaction mixture was then subjected to silica gel column chromatograph (chloroform/methanol = 40:1, v/v~ for purification. Thus, 0.29 g of 6-{2-~N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-1,3,5-trimethyl-2,4(1~,3~)-pyrimidinedione was obtained.
Results of the analysis of the pyrimidinedivne derivative thus obtained:
NMR (CDCl~ ppm: 8.05 (d, 2H), 7.30 (d, 2H), 4.32 (m, 2H), 3.25 ~s, 3H), 3.31 (s, 3H), 2.6-3.1(m, lOH), 2.06 (S, 3H), 1.9 (m, 2H) Next, this pyrimidlnedione derivative was treated with HCl/methanol in an ordinary method and thereby 0.12 g o~ a hygroscopic amorphous compound, 6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-1,3,5-trimethyl-10- 2,4(1H,3H?-pyrimidinedione hydrochloride (compound 179), was obtained.
Results of the analysis of the compound 179 thus obtained:
IR ~ KBr max (cm 1): 3300, 2640, 1690? 1590, 1550, 1340, 1220, 930, 750, 700 Elemental analysis: C20H2~N505 HCl H20 Calculated (x): C, 50.68; H, 6.81: N, 14.78; Cl, 7.48 Analyzed (x): C, 51.22; H, 6.94: N, 14.29; Cl, 7.73 Example 127 Preparation of 1,3-dimethyl-6-~2-~N-(2-hydroxyethyl~-3-(4-nitrophenyl)propylamino~ethylamino~-5-nitro-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 180) Cl ~ O CH3SO2-OCH2CH2N ~ O
NO2 CH3 NO 'CH
2~01389 ,0 No2~CH2CH2CH2NHcH2CH20H
N0 \CH
N02~CH2CH2CH2NCH2CH2NH~NCH3 ~HCl (Compound 180) (1) Preparation of 6-~2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione 6-chloro-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione (4.0 g) was dissolved in a solution of 13 ml of dichloromethane and added to a solution of 1.26 ml of ethanolamine and 3.8 ml of triethylamine in dichloromethane (13 ml) gradually drop by drop at 0~C. The reaction was carried out at 0~C for 1 hour; the reaction mixture was allowed to stand at room temperature for 5 hours.
The reaction mixture was again cooled down to 0~C and added with 3.8 ml of triethylamine and with 2.28 ml of methanesulfonyl chloride drop by drop. After the reaction at 0~C for 5 hours, 30 ml of ice water was added, and the mixture was stirred vigorously for 30 minutes. The dichloromethane layer fraction was removed, and the water layer fraction was subiected to extraction with chloroform.
The extract combined with the organic layer fraction was washed with water. dried over sodium sulfate anhydrous and X~1389 then concentrated in _a~uo. The resultant oily substance was subjected to silica gel column chromatograph (chloroform/methanol = 30:1 (v/v)~ for purification. Thus, 5.8 g of 6-(2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidlnedione was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 5.12 (t, 2~, 3.44 (s, 3H), 3.22 (m, 2H~, 3.16 (s, 3H) (2) Preparation of 6-(aziridin-1-yl)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione 6-(2-methanesulfonyloxyethylamino)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione ~5.8 g) was dissolved in 70 ml of acetonitrile and added with 3.8 g of potassium carbonate. The reaction was carried out under heating with reflux for 3 hours. The reaction mixture was cooled down to room temperature; insoluble materials were removed by filtration. The filtrate was concentrated to a volume of 20 ml, added with 100 ml of ether and then stored refrigerated for 2 days. Crystals formed were collected by filtration and washed with hexane, thus 1.0 g of a powdery compound, 6-(aziridin-l-yl)-1,3-dimethyl-5-nitro-2,4(1H,3H)-pyrimidinedione, was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR C~C13, ~ ppm: 3.37 (s, 3H), 3.18 (s, 3H), 2.1-2 2 (m, ~lH) ~3) Preparation of 1,3-dimethYl-6-~2-~N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-5-nitro-2,4(lH,3H)-pyrimidinedione hydrochloride (compound 180) An oily substance obtained by dissolving 1.0 g of 6-(aziridin -l-yl)-1,3-dimethyl-5-nitro-2,4~1H,3H)-pyrimidinedione, 0.99 g of N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamine and 50 mg of p-toluenesulfonic acid in l.V ml of dimethylformamide was allowed to react at 90~C
for 3 hours. The reaction mixture was cooled down to room temperature, added with 10 ml of water and then vigorously stirred. Crystals formed were collected by filtration, dissolved in chloroform and then subjected to silica gel chromatograph (chloroform/methanol = 40:1 (v/v)) for purification. Thus, 0.44 g of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino~-5-nitro-2,4(1H,3H)-pyrimidinedione (a free form of compound 180) was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 8.01 (d, 2H), 7.31 (d, 2H), 3.66 (t,2H) 3.45 (5, 3H), 3.35 (s, 3H), 2.6-3.6 (m, lOH), 2.0(m, 2H) Next, this pyrimidinedione derivative was treated with HCI/methanol in an ordinary method; thus 0.11 g o~ a hygroscopic amorphous compound, 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenYl)propylamino]ethylamino}-5-2(~01389 nitro-2,4(1H,3H)-pyrimidinedione hydrochloride ~compound 180), was obtained.
Results of the analysis of the compound 180 thus obtained:
IR ~ KBr max (cm 1): 3300, 2550, 1700, 1650, 1530, 1350, 1110, 930, 750 Elemental analysis: C1gH26N607 HCl 3H20 Calculated (x): C, 42.19; H, 6.15: N, 15.54; Cl, 6.55 Analyzed ~X): C, 41.79; H, 6.41: N, 14.83; CI, 6.02 Example 128 Preparation of tablets containing, as an active ingredient, 1,~-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-5-nitro-2,4(1H,3H)-pyrimidinedione (free form of compollnd 180), which can be obtained by the method of Example 127.
Said pyrimidinedione derivative (free form of compound 180) ~1 g), 123 g of lactose and 20 g of corn starch were thoroughly mixed. The mixture was mixed in an aqueous solution of 5 g of hydroxypropylcellulose (100 ml) was granulated and dried at 50~C for 4 hours. The granules were 20 thoroughly blended with 1 g of magnesium stearate and then compressed into tablets using a tablet machine with a pressure of 150 mg/tablet.
Example 129 Production of capsules containing, as an active ingredient, 6-~2-[N-(2-hydroxyethyl~-3-(4-nitrophenyl)propylamino]
ethylamino}-1,3,5-trimethyl-2,4(1H,3H)-pyrimidinedione ZQ~1389 hydrochloride (compound 179), which can be obtained by the method of Example 12~
Said pyrimidinedione hydrochloride derivative (compound 179) (5 g), 120 g of lactose and 25 g of corn starch were thoroughly mixed, and the resultant mixture was formulated into hard capsules (150 mg per capsule~ using a capsule filling machine.
Example 130 Production of an injection containing, as an active ingredient, 1,~-dimethyl-6-~2-~N-(2-hydroxyethyl)-3-(4-nitrophenyl)propylamino~ethylamino}-5-nitro-2,4(1H,3H)-pyrimidinedione hydrochloride (compound 180) which can be obtained by the method of Example 127.
Said pyrimidinedione derivative hydrochloride (compound 180) (20 mg) and 0.85 g of sodium chloride were dissolved in an appropriate amount of distilled water for injection to total the volume 100 ml and thus formulated into an injection.
Pharmacological test example 9:
A pharmacological tests with the compound 180 obtained by the method of Example 127 was carried out in the same manner as described in Pharmacological test 1. As a result, the ADP75 values as shown in Table 18 were obtained.
- 371 - ~ 3 8 9 Table 18 ADP75 (~) Compound No.Concentration (Jug/ml ) 0.3 1.0 3.0 10.0 Examele 131 Preparation of 1,3-dimethyl-6-~4-<3-~2-nitro-4-(2-pyridinecarbonyl)phenoxy]propyl>piperazin-l-yl~-2~4~1H,3H~-pyrimidinedione oxalate (compound 181) Cl 'o~ C
CN
15z z ~ ~N~ (COOH)2/cH3oH
(Compound 36) CH3 >
<~C~-OCHzCH2CHzN N ~NCH3 (COOH) 2 (Com~ound 181) ... ... . ..
2~11389 (1~ Preparation of 2-chloro-5-(2-pyridinecarbonyl) nitrobenzene 2-bromopyridine ~3.3 ml) was dissolved in 30 ml of ether and added with 22.1 ml of butyllithium (1.6M, in hexane~ drop by drop at -30~C. To this mixture were added a solution of 5.0 g of 4- chlorobenzonitrile in ether (10 ml) drop by drop at the same temperatllre. The reaction mixture was stirred for 1 hour and then poured into ice water.
Ether was removed In vacuo. The resultant water-layer fraction was acidified by adding 6N HCl, stirred at 100~C
for 1 hour, cooled, alkalized by adding sodium hydroxide and then extracted with ether. The resultant ether-layer fraction was concentrated and the oil thus obtained was dissolved in 10 ml of fuming sul~uric acid at 0~C. To this solution, added 1.2 ml of fuming nitric acid drop by drop and the resultant solution was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water and crystals formed were collected by filtration. The crystals were further recrystallized using ethanol, and 3.6 g of crystalline 2-chloro-5-(2-pyridinecarbonyl)nitrobenzene was thus obtained.
(2) Preparation of 1,3-dimethyl-6-~4-<3-[2-nitro-4-(2-pyridinecarbonYl)PhenoXy]propyl>piperazin-l-yl}-2~4(lH~3H) pyrimidinedione oxalate (compound 181) Sodium hydride (60 ~ dispersion in mineral oil) (0 17 g) was washed with hexane to remove oil and added with 8 ml of DMF.
200:~389 The mixture was cooled down to V~C, added with 1.0 g of 1,3-dimethyl-6-[4-~3-hydroxypropyl>piperazin-1-yl]-2,4~lH,3H)-pyrimidinedione (compound 36) and stirred for 30 minutes. To this mixture was added 1.1 g of 2-chloro-5-(2-pyridinecarbonyl)nitrobenzene, and the resultant mixture wasstirred for 1 hour. The reaction mixture was poured into ice water and crystals formed were collected by filtration, washed with water, dried and 1.0 g of 1,3-dimethyl-6-{4-<3-t2-nitro-4-(2-pyridinecarbonyl)phenoxy]propyl>piperazin-1-yl~-2,4~1H,3H)-pyrimidinedione in an amorphous powder form was thus obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR ~CDCI3~, ~ ppm: 2.1 (m, 2H), 2.4-3.1 (m, lOH), 3.25 (s, 3H), 3.34 (s, 3H), 4.28(t, 2H), 5.14 (s, lH), 7.1-8.9 (m, 7H) Next, this pyrimidinedione deri~ative (0.98 g) was treated with an oxalic acid/methanol solution in the ordinary method; thus 0.76 g of crystals of 1,3-dimethyl-6-{4-<3-t2-nitro-4-(2-pyridinecarbonyl)phenoxy~propyl>
piperazin-l-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 181) was obtained.
Results of the analysis of the compound 181 thus obtained:
lR ~ KBr max (cm 1): 3450, 2500, 1700, 1650, 1600, 1520, 1310, 1280, 800, 740, 700 Elemental analYSis: C2~H28~6~6 (C~~~)2 2 - 374 - ~ ~ Q~ 389 -Calculated (X): C, Sl.10; H, 5.40: N, 13.24;
Analyzed (X): C, 51.32; H, 5.40: N, 13.15 Example 132 Preparation of 1,3-dimethyl-6-~2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino~ 2,4(1H,3H)-pyrimidinedione oxalate (compound 182) N02 ~ CH2CH2CH20S- ~ CH 3 ~ ~o N02 ~ ~ CH2CH2CH2NHCH2CH2CH20H >
(Compound 6) (COOH)/~OH
S CH2CH2CHz0H o N02 ~ CH2CH2CH2NCH2CHzNH- ~ CH3 CH 3 ' (C 00H) 2 (Compound 182) ( (1) Preparation of N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamine 3-(4-nitrophenyl)propyl p-toluenesulfonate (1 g) and 4.1 ml of 3-hydroxypropylamine were dissolved in 10 ml of dioxane and the solution was stirred at 80~C for 30 minutes.
To the solution was added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for separation. The chloroform-layer fraction was taken. washed , ., .~
_ - 375 -with water and then dried over sodium snlfate anhydrous.
The solvent was removed in _acuo and 0.7 g of an oil of N-~3-hydroxypropyl)-3-(4-nitrophenyl)propy1amine was vbtained.
Results of the analysis of the amine derivative thus obtained:
NMR (CDC13), ~ ppm: 1.9-2.1 (m, 4H), 2.8-3.2 (m, 6H), 4.18 (t, 2~), 7.62 (d, 2H), 8.01 (d, 2H) (2) Preparation of 1,3-dimethyl-6-{2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H~-pyrimidinedione oxalate (compound 182) N-(3-hydroxypropyl~-3-(4-nitrophenyl)propylamine ~0.7 g), 0.53 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4~1H,3H)-pyrimidinedi.one (compound 6) and 50 m~ of p-toluenesul.fonic acid monohydrate were dissolved in 30 ml acetonitrile, and then the solvent was removed ln vacuo. The resultant oil was allowed to react at 80~C for 3 hours and subjected to silica gel column chromatograph (chloroform/ methanol = 40:1 (vJv)) for purification: 0.68 g of 1,3-dimethyl-6-~2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1.H,3H)-pyrimidinedione was thus obtained.
Results of the analysis of the pyrimidinedione derivative . .
thus obtained:
NMR (CDCl~ ppm: 1.7 (m, 4H}, 2.4-3.1 (m, 8H), 3.21 (s, 3H~, 3.34 (s, 3~), 3.70 (br, 2H), 4.0 (m, 2H), 4.71 (s, IH), 5.81 (br, lH~, 7.25 (d, 2H), 8.06 (d, 2H) Next, this pyrimidinedione derivative (0.65 g) was 376 - ~ 0 0 ~ 3 8 9 ~
treated with an oxalic acid/methanol solution in the ordinary method; thus 0.62 g of crystalline 1,3-dimethyl-6-{2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl~propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate ~compound 182) was obtained.
Results of the analysis o~ the compound 182 thus obtained:
IR ~ KBr max (cm 1): 3300, 1690, 1620, 1540, ~410, 1330, 1050, 850, 770, 740, 690 Elemental analysis: C20H29N5o5 (C~~~)2 H20 Calculated (%): C, 50.09; H, 6.31: N, 13.28 Analyzed (%): C, 50.37; H, 6.25: N, 12.79 Example 133 Preparation of 1,3-dimethyl-6-~2-~N-(l-methylethyl~-3-(4-nitrophenyl)propylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione oxalate (compound 183) N0z ~ CH2CH2CHIoll ~ CH3 ~N- ~ NCH3 ,N~o N0z ~ CHzCHzCH2NHCH2(CH3~2 CH3 (Compound 6) (COOH)2/CH3oH
) CH(CH3~2 0 N02- ~ CH2CH2CHzNCH2CH2NH ~ NCH3 IN~o CH3 ~(C00H~ 2 (C~mpound 183) - Z~01389 (1) Preparation of N-(1-methylethyl)-3-(4-nitr()phenyl)propylamine 3-(4-nitrophenyl~propyl p-toluenesulfonate (1 g) and 5 ml of isopropylamine were dissolved in 15 ml of dioxane, and the solutlon was stirred under heating with reflux for 4 hours. To the solution were added 100 ml of water and 100 ml of chloroform, and the mixture was thoroughly mixed for extraction. The chloroform-layer fraction was taken, washed with water and dried over sodium sulfate anhydrous. The solvent was removed in vacuo, and thus 0.61 g of an oil of N~ methylethyl)-3-~4-nitrophenyl)propylamine was obtained.
Results of the analysis of the amine derivative thus obtained:
NMR ~CDC13), ~ ppm: 1.22 (d, 6H), 2.0 (m, 2H), 2.9-3.3 (m, i5 5H), 7.28(d. 2H), 8.0g (d, 2~) (2~ Preparation of 1,3-dimethyl-6-{2-[N-(l-methylethyl)-3-(4 nitrophenyl)propylamino~ethylamino}-2,4(1H,3H)-Pyrimidinedione oxalate (compound 183) N-~l-methylethyl~-3-(4-nitrophenyl)propylamine (0.6 g), 0.5 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3~)-pyrimidinedione (compound 6) and 50 mg of p-toluenesulfonic acid monohydrate was dissolved in 30 ml acetonitrile, and then the solvent was removed in vacuo. The resultant oil was alLowed to react at 80~C for 3 hours and subiected to silica gel column chromatograph (chloroform/ methanol = 40:1 (v/v)~ for purification. Thus, 1 0 g of 1,3-dimethyl-6-12-~)1389 [N-~1-methylethyl)-3-~4-nitrophenyl)propylamino]ethyl~mino~-2,4(1H,3H)-pyrimidinedione was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR ~GDCl3), ~ ppm: I.45~d, 6~), 2.0 ~m, 2H), 3.29 (s, 3H), 3.40 (s, 3H), 2.5-3.1 (m, ~H), 3.8-4.1 ~m, 4H), 4.80 (s, lH), 5.5 (m, lH), 7.31 (d, 2H), 8.00 (d, 2H) This pyrlmidinedione derivative ~0.95 g) was treated with an oxalic acid/methanol solution in the ordinary method; thus 0.88 g of crystals of 1,3-dimethyl-6-~2-[N-(1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 183) was obtained.
Results of the analysis of the compound 183 thus obtained:
IR ~ KBr max ~cm 1) 3250, 2600, 1700, 1640, 1590, 1510, 1~30, 1220, 760, 750, 700 Elemental analysis: C20ff29N50~ 1.5~COOH)2 0.5H20 Calculated (X): C, 50.45; H, 6.08: N, 12.79 Analy~ed (X): C, 50.25; H, 5.81: N, 12.52 Example 134 Preparation of 1,3-dimethyl-6-{2-rN-(2-hydroxy-1-methylethyl~-3-(4-nitrophenyl)propylamino]ethylamino~-2,4~1H,3H)-pyrimidinedione hydrochloride (compound 187) _ - 379 ~ a 0 n ~ ~ 8 9 NOz ~ CHzCHzCOzH ~NO2 ~ CHzCHzCNHCHCHzOH >
C ~J
r~ I CH3 NOz- ~ CH2CH2CHzNHCHCHzOH
(Compound 6) HCl /CH30H
> CH(CH3)cH2oH O
NO2 ~ CHzCHzCHzNCHzCHzN~ ~ NC~3 ~HCl (Compound 187) (1) Preparation of N-(2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propionamide 3-(4-nitrophenyl)propionic acid (5 g) was suspended in 40 ml of thionylchloride, and the suspension was stirred under heating with reflux for 2 hours. Excessive thionylchloride was removed in vacuo and the oil thus ( obtained was dissolved in 15 ml of chloroform.
Separately, 3.8 g of 2-amino-1-propanol and 3.5 g of potassium carbonate were dissolved in 35 ml water, and the resultant solution was cooled down to 0~C and added drop by drop with the chloroform solution which had been obtained previously. The mixture was stirred maintaining at ~~C for 1 hour. Crystals formed were collected by filtration and washed with water. Furthermore, the crystals were , ~ .. .
2~)1389 recrystallized using an ethyl acetate/chloroform ~1:1 (v/v)~, and thus 3.46 g of crystalline N-(~-hydroxy-l-methylethyl)-3-(4-nitrophenyl)prupionamide was obtained.
Results of the analysis of the amine derivative thus obtained:
Melting point: 174~C
(2) Preparation of N-(2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamine N-(2-hydroxy-1-methylethyl)-~-(4-nitrophenyl) propionamide obtained in (1) above (3.4 g) and sodium borohydride (2.1 g) was suspended in 32 ml of THF. To the mixture was added drop by drop with a solution of 3.3 g acetic acid in THF ~32 ml~. The mixture was stirred under heating with reflux for 10 hours. The reaction mixture was then cooled down to 5~C, added with 20 ml of methanol, stirred for 30 minutes and then concentrated by drying. To the resultant residue was added 50 ml of lN-HCl and 50 ml of chloroform, and the mixture was vigorously stirred. The mixture was allowed to stand for extraction then fractionated. The water-layer fraction was alkalinized with sodium hydroxide and extracted with chloroform. The chloroform-layer fraction was washed with water, dried over sodium sulfate anhydrous and then concentrated by drying;
thus, 2.96 g of an oily compound, N-(2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamine, was obtained.
This was used for the following reaction without further 2C~1389 purification.
~3) Preparation of 1,3-dimethyl-6-{2-[N-(3-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamino]ethylamino}-?~4(lH~3H)-pyrimidinedione hydr-ochloride (compound 187) N-(2-hydroxy-1-methylethyll-3-~4-nitrophenyl) propylamine (2.2 g) obtained in ~2~ above, 1.6 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3HS-pyrimidinedione (compound 6) and 0.1 g of p-toluenesulfonic acid mono-hydrate were dissolved in 100 ml of acetonitrile, and then the solvent was removed n vacuo. The resultant oil was allowed to react at 80~C for 3 hours and subjected to silica gel column chromatograph tchloroform/ methanol = 40:1 ~v/v)) for purification; thus, 3.0 g of 1,~-dimethyl-6-{2-~N-(2-hydroxy-l-methylethyl~-3-(4-nitrophenyl)propylamino~
ethylamino}-2,4(1H,3H)-pyrimidinedione was obtained.
Results of the analysis o~ the pyrimidinedione derivative thus obtained:
NMR (CDC13), ~ ppm: 1.04 (d, 3H), 1.9 (m, 2H), 2.5-3.0 (m, 9H), 3.28 (s, 3H), 3.40 (s, 3H), 4.13 (m, 2H), 4.69 (s, lH), 6.47 (m, lH), 7.29 (d, 2H), 8.0fi (d, 2H) This pyrimidinedione derivative (2.95 g) was treated with a HCI/methanol solution in the ordinary method; thus 3.02 g of crystalline 1,3-dimethyl-fi-~2-rN-~2-hydroxy-1-methylethyl)-3-(4-nitrophenyl)propylamlno]ethylamino}-2,~(lH,3H)-pyrimidinedione hydrochloride (compound 187) was obtained.
200~389 Resul ts of the analysis of the compound 187 thus obtained:
Melting point: 154 - 155~C
IR ~ KBr max (cm 1) 3250, 2~00, 1690, 1600, 1550, 1340, 1240, 1060, 840, 760, 700 Example 135 Preparation of 1,3-dimethyl-6-~4-(3-methyl-4-nitrobenzylpiperazin-1-yl~-2,4~1H,3H)-pyrimidinedione hydrochloride ~compound 188) HN N~CH3 - ~ N~o N02~CH20H > NO~CHzCl CH3 CH3 CH3(Compound 2) HCl /CH30H
> N02- ~ CH2N ~ - ~NCH3 ~ HCl (Compound 188 ~1) Preparation of 3-methyl-4-nitrobenzyl chloride 3-methyl-4-nitrobenzylalcoho~ (2 g) and 0.2 ml of DMF
were dissolved in 20 ml of toluene. The solution was added with 1 ml of thionyl chloride and stirred under heating with reflux for 3 hours. The reaction mi~ture was concentrated and thus 2.2 g of an oil, 3-methyl-4-nitrobenzyl chloride, 281)1389 was obtained. This compound was used for the following reaction without further purification.
(2~ Preparation of 1,3-dimethyl-6-t4-(3-methyl-4-nitrobenZYl)piperazin-l-yl~-2,4~1H,3H~-pyrimidinedione S chloride (compound 188) 3-methyl-4-nitrobenzyl chloride (2.2 g) obtained in ~1 above, 2.2 g of 1,3-dimethyl-6-(piperazin-1-yl3-2,4(1H,3H)-pyrimidinedione (compound 2) and 4.1 ml of triethylamine were dissolved in 40 ml of isopropanol, and the solution was stirred under heating with reflux for 2.5 hours. After the reaction, the solvent was removed in vacuo, and the residue was dissolved in 50 ml of chloroform. The chloroform solution was washed with water and dried over sodium sulfate anhydrous and then the solvent was removed in vacuo; thereby 2.76 g ~f crystalline 1,3-dimethyl-6- r 4-(3-methyl-4-nitrobenzyl)Piperazin-l-yl]-2~4(lH~3H)-pyrimidinedione was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
Melting point: 162 -164~C
NMR (CDC13~, ~ ppm: 2.5-3.3 (m, 8H). 2.61 (s, 3H), 3.26 ~s, 3H~, 3.36 (s, 3H), 3.61 ~br, 2H), 5.15 (s, lH~, 7.35 (m, 2H), 7.87 (d, LH) This pyrimidinedione derivative (2.4 g) was treated with a hydrochloric acid/methanol solution by the ordinary method; thus 2.34 g of crystalline 1,3-dimethyl-6-[4-(3-- 384 - 2 ~ 0 1 3 8 9 methyl-4-nitrobenzyl)piperazin-l-yl]-2~4(lH~3H)-pyrimidinedione hydrochloride (compound 188) was obtained.
Results of the analysis of the comPound 188 thus obtained:
lR ~ KBr max (cm 1~ 3360, 25~0, 1690, 1640, 1520, 1440, 1340, 1200, 980, 840, 760, 700 Elemental analYsis: C18H23N504 HCI H20 Calculated (X): C, 50.52; H, 6.12: N, 16.36; Cl, 8.28 Analyzed (X): C, 50.87; H, 6.64: N, 16.44; Cl, 7.68 Example 136 Preparation of 1,3-dimethyl-6-{2-~N-(2-hydro~yethyl~-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate ~compound 189) ~N ~CH3 ~ HOCH2CH2NHCH2CH2NH ~ CH3 (Compound 6) ~ >
~ C ~ OH ~ ~ -C ~ OCH2CH2CHzBr ( O 02 0 NOz (COOH)2/CH30H
> CH2CH20H o C, ~ OCH2CHzCH2NCHzCH2NH- ~ CH3 CH3 ~(COOH) 2 (Compound 189) (1) Preparation o~ 1,3-dimethyl-6-{2-(2-hydroxyethylamino) B
.. . .
2~01389 ethylamino~-2,~(1H,3H)-pyrimidinedione 6-(1-aziridinyl)-1,3-dimethyl-2-4(1H,3H~-pyrimidinedione (compound 6) ~0.81 g)~ 1 ml of ethanolamine and 50 mg of p-toluenesulfonic acid monohydrate were dissolved in 200 ml of acetonitrile and then the solvent was removed in vacuo. The resultant oil was allowed to react at 90~C for 3 hours. The reaction mixture was cooled down to room temperature and then dissolved by adding ethanol.
Ether was added to this soiution for crystallization. The crystals formed were collected by filtration and further recrystallized using an ethanol/ether mixed solvent; thereby 1.02 g of crystalline 1,3-dimethyl-6-~2-(2-hydroxyethylamino)ethylamino~-2,4(1~,3H)-pyrimidinedione was obtained.
Results of the analysis of the crystals of pyrimidinedione derivative Melting point: 146-148~C
~2) Preparation of 4-(3-bromopropyloxy)-3-nitrobenzophenone 4-hydroxy-3-nitrobenzophenone (2.5 g) and 7.1 g of potassium carbonate were suspended in 15 ml methylethylketone. The suspension was stirred under heating with reflux for 30 minutes, added with 1,3-dibromopropane and then heated with reflux for 6 hours. The reaction mixture was cooled down to room temperature, and insoluble substances were removed by filtration. The filtrate was then concentrated, and the resultant precipitate was - 2C~01389 subjected to silica ~el column chromatograph (hexane/ethyl acetate =3:1 (v/v)~ for purification; thereby 2.08 g of an oil, 4-(3-bromopropyloxy)-3-nitrobenzophenone, was obtained NMR ~CDC13~, ~ ppm: 2.40(m, 2H), 3.66 ~t, 2H), 4.39 (t, 2H), 7.13-8.34 (m, 8H) (3) Preparation of 1,3-dimethyl-6-~2-[N-(2-hydroxyethyl)-3-(4-benzoyl-2-nitrophenoxy~propylamino]ethylamino~-2,4(1H,3H)-pyrimidinedione oxalate (compound 189) A mixture of 0.67 g of 1,3-dimethyl-6-{2-(2-hydroxyethylamino)ethylamino}-2,4(1H,3H)-pyrimidinedione obtained in (1) above, 1.0 g of 4-(3-bromopropyloxy)-3-nitrobenzophenone obtained in (2) above, 1.5 ml of triethylamine and 3 ml of D~F were stirred under heating at 100~C for 1 hour. The mixture was cooled down to room temperature, added with 50 ml chloroform, washed with water and then dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was crystallized using an ethanol/ether mixed solvent; 0.59 g of crystalline 1,3-dimethyl-6-~2-~N-(2-hydroxyethyl)-3-(4-benzoyl-2-nitrophenoxy)propylamino]ethylamino}-2,4(1H,3H~-pyrimidinedione was thus obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
Melting point: 180 -181~C
NMR ~CDC13/DMSO-d6=1/1, v/v~, ~ ppm: 2.0 (m, 2H), 2.fi-3.1 (m, 8H~, 3.21 (s, 3H), 3.34 (s, 3H?, 3.67 (t, 2H~, 4.39 (t, 38 72~1389 2H), 4~58 (s, lH), 6.25 (br, lH~, 7.31 (d, lH), 7.5-8.1 (m, 6H), 8.26 (d, lH) This pyrimidinedione derivative (0.55 g) was treated with an oxalic acid/methanol solution in the ordinary method; 0.62 g of crystalline 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-benzoyl-2-nitrophenoxy) propylamino~ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 189) was thus obtained.
Results of the analysis of the compound 189 thus obtained:
Melting point: 144 - 147~C (Decomposed~
IR ~> KBr max ~cm 1): 3300, 2590, 1720, 1680, 1630, 1530, 1340, 1280, 1070, 7B0, 7tO
Elemental analysis: C26H31N507 (COOH)~ 2 Calculated (X): C, 53.84; H, 5.49: N, 11.21;
Analyzed ~x): C, 53.~8; H, 5.?6: N, 11.27 Example 1~7 Preparation of 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-~3-methoxy-4-nitrophenyl~propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione oxalate (compound 1~0 N0z ~ CH=CHC02H , N02 ~ CH2CHzCOzH
> N02 ~ CH2CH2CNHCH2CH20H
¦ N- ~ CH3 > N02 ~ CHzCH2CH2NHCHzCHzOII CH3 CH30 / (Compound 6) - 388 - 20 n ~ 3 8 9 !
(COOH)2/CH30H
CH2CHzOH o --~ NOz ~ -CHzCHzCHzNCHzCH2NH- ~ NCH3 N o (COOH) 2 (Compound 190) (1) Preparation of 3-(3-metho~y-4-nitrophenyl)propionic acid 3-methoxy-4-nitrocinna~ic acid (6.2 g) and 12.3 g of hydroxyamine sulfate were dissolved in 250 ml of water. To the solution was added 7.1 g of sodium hydroxide, and further alternately added a solution of 18 g of sodium hydroxide in water (27 ml) and 19.2 g of hydroxyamine-o-sulfonic acid little by little, maintaining the p~ at 9.
The mixture was stirred at 5~C for 6 hours and then insoluble substances were removed by filtration. The resultant filtrate was cooled on ice and was added with 6N
sulfuric acid to adjust the pH to 2. Crystals formed were collected by filtration, washed with water and dried; 1.~7 g of crystalline 3-(3-methoxy-4-nitrophenyl)propionic acid was thus obtained.
Results of the analysis of the crystalline propionic acid derivative thus obtained:
Melting point: 137-139~C
(2) Preparation of N-(2-hydrnxyethyl)-3-~3-methoxy-4-nitrophenyl)propanamide 3-(3-methoxy-4-nitrophenyl~propionic acid obtained in ' , , r- .i 2~01389 (1) above (1 2 g) was suspended in 20 ml of thionyl chloride. The suspension was stirred for 2 hours under heating with reflux and then the solvent was removed. The resultant residue was dissolved in 3 ml of chloroform.
Separately, 0.51 g of ethanolamine and 0.78 g of potassium carbonate were dissolved in 8 ml of water, and the resultant solution was cooled down to 0~C and added drop by drop with the chloroform solutinn which had been obtained previously. The mixture ~as vigorously for 1 hour at the temperature maintained at 0~C. Crystals formed were collected by filtration, washed with water and dried.
Furthermore, the crystals were recrystallized using an ethyl acetate solution and thus l.14 g of crystalline N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl~propanamide was obtained.
Results of the analysis of the crystalline amide thus obtained:
Melting point: 155~C (Decomposed) (3) Preparation of N-t2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamine Sodium borohydride (0.78 g) was suspended in 12 ml ofTHF. To this suspension were added ~.1 g of N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propanamide obtained in (2~ above, and further added little by little 1.2 ml of acetic acid. The mixture was stirred until bubbling stopped and then stirred under heating with reflux 2(~01389 for 10 hours. The mixture was cooled down to room temperature and added with lO ml of methanol little by little. The solvent was removed in vacuo. The residue was added with 20 ml of chloroform and then extracted with a lN-HCI solution. The extracted acidic water phase wasalkalinized by adding sodium hydroxide on ice and extracted with chloroform. The chloroform-layer fraction was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, and chloroform was removed;
thereby V.72 g of an oily compound, N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl~propylamine, was obtained. This compound was used for the following reaction without further purification.
(4) Preparation of 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamino~ethylamino}-2,4(1H,3H~-pyrimidinedione oxalate (compound 190) 6-(1-aziridinyl~-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6~ (0.45 g), 0.7 g of N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamine and 50 mg of p-toluenesulfonic acid monohydrate were dissolved in 25 ml of acetonitrile and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80~C for 3 hours and then subjected to silica gel column chromatograph (chloroform~methanol = 40/1, v/v~ for purification; thereby 0.38 g of an oil, 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamino]ethylamino}-2,4~1H,3H)-200138~
pyrimidinedjone, was obtained.
Results of the analysis of the pyrimidinedione derivative thus obtained:
NMR (CDCl3) ~~ ppm: 1.9 (m, 2H), 2.4-3.8 (m, 12H), 3.20 (s, 3H), 3.33 (s, 3H), 3.83 (s, 3H), 4.63 (s, lH), 6.11 (m, lH), 6.75 (m, 2H), 7.26 (m, lH~
This pyrimidinedione derivative (0.33 g) was treated with an oxalic acid/methanol solution in the ordinary method; 0.22 g of an amorphous powder of 1,3-dimethyl-6-{2-~N-(2-hydroxyethyl)-3-(3-methoxy-4-nitrophenyl)propylamino]ethylamino}-2,4(1H,~H)-pyrimidinedione oxalate (compound 1gO~ was thus obtained.
Results of the analysis of the compound 190 thus obtained:
IR ~ KBr max (cm 1): 3300, 2550, 1690, 1640, 1540, 1350, 1280, 760, 700 Elemental analysis: C20H29N5O6 2(COOH)2 2H20 Calculated (x): C, 44.24; H, 5.72: N, 10.75 Analyzed (X): C, 43.93; H, 5.85; N, 11.10 - 392 - 20 ~ ~ 3 89 ~
Example 138 Production of 1,3-dimethyl-6-l2-[N- (2-dieth amino) ethyl-3-(4-nitrophenyl)propylamino]ethylaminoJ-2,4(1H,3H)-pyrimidinedione oxalate (Compound 191) o N~2- ~ -CH2CH2CH2NHCH2CH2NH- ~ -CH3 CH ~
(Compound e) 3 ( ClCH2CH2N(C2H5)2 HCl (COOH)2/CH30H
CH2CH2N(C2H5)2 0 N~2- ~_CH2CH2 CH2N_CH2CH2NH_~N-CH3 (CompOund 191) CH3 ~ (C~2 )2 First, 1.4g of 1,3-dimethyl-6-l2-[3-(4-nitro-phenyl) propylamino]ethylamino~-2,4(1H,3H)-pyrimidine-dione hydrochloride (Compound e) was dissolved with 5 ml of water, followed by the addition of K2C03 to render the solution alkaline.
The resulting solution was then extracted with CHCl3. The combined layers were concentrated in vacuo, followed by the addition of 1.0 g of 2-d;ethylamino ethyl-chloride, 3 ml of triethylamine and 20 ml of isopropanol.
The reaction mixture was refluxed for 10 hours.
Solvent was removed in vacuo, and then the resulting residue was directly purified by a silica gel chromatography (eluent: CHCl3/CH30H=20/1, by volume) thereby obtaining 0.6 g -,~
2g~ 89 of 1,3-dimethyl-6-t2-[N-diethylamino)ethyl-3-(4-nitro-phenyl)propylamino~-2,4(1 H,3H)-pyrimidinedione.
Further, 0.6 g of the pyrimidinedione derivative was treated with an oxalic acid/methanol solution by a method known per se in the art to obtain 0.52 g of 1,3-dimethyl-6-t2-[N-(2-diethylamino)ethyl-3-(4-nitrophenyl)-propylamino] ethylamino~-2,4(1 H,3H)-pyrimidinedione (Compound 191) as pale yellow crystals.
Analytical results of crystals of compound 191 thus obtained:
Melting point: 197 - 199~C
IR vKBr(cm 1 ); 3000, 2950, 1720, 1700, 1600, 1340 max 852, 700
Claims (19)
1. A pyrimidinedione derivative of the general formula (1) (1) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, or ;
B represents an oxygen or a sulfur atom, , or ;
D represents , or ;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group or a lower alkyl group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected.
from the group consisting of a hydroxy group; a lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group;
a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl group, a carboxy group, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring selected from pyridyl, pyrazolyl, 395a pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and I represents an integral number, 0, 1, 2. 3 or 4.
B represents an oxygen or a sulfur atom, , or ;
D represents , or ;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl group, an unsaturated lower alkyl group or a lower alkyl group, any one of the hydrogen atoms of said alkyl groups may be substituted by a group selected.
from the group consisting of a hydroxy group; a lower monoalkylamino group; a lower dialkylamino group; a lower alkyloxy group; a lower alkanoyloxy group; a benzoyloxy group;
a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group, or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a hydroxy group, a lower alkyloxy group, a lower alkylthio group, a lower alkyloxycarbonyl group, a carboxy group, a cyano group, an amino group, a lower alkanoyloxy group, a lower alkanoylamino group, a lower alkylsulfonamido group, a lower mono- or di-alkylamino group, a phenyl-substituted lower alkylamino group or an unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, a nitro group, a methyl group or a cyano group; R5 represents a hydrogen atom, a lower alkanoyl group, a lower alkylsulfonyl group or a lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl group, a cycloalkyl group or a phenyl group, said phenyl group may be substituted by either one or two of groups selected from the group consisting of a halogen atom, a lower alkyl group, a hydroxy group and a lower alkyloxy group, or a heterocyclic ring selected from pyridyl, pyrazolyl, 395a pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and I represents an integral number, 0, 1, 2. 3 or 4.
2. A pyrimidinedione derivative as set forth in claim 1, of the general formula (2) (2) in which R1" and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1" and R2 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carhoxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number 2 or 3; and k represents an integral number, 2, 3 or 4.
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carhoxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number 2 or 3; and k represents an integral number, 2, 3 or 4.
3. The pyrimidinedione derivative as set forth in claim 1, of the general formula (3) (3) in which A represents -(CH2)m-, -B'-(CH2)k- or , wherein B' represents an oxygen or sulfur atom, or ;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 2, 3 or 4; and k represents an integral number, 2, 3 or 4.
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 2, 3 or 4; and k represents an integral number, 2, 3 or 4.
4. The pyrimidinedione derivative as set forth in claim 1, of the general formula (4) (4) in which A" represents -B"-(CH2)k-, or .
wherein B" represents an oxygen or sulfur atom or , R1 and R2 2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a 400a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; and k represents an integral number, 2, 3 or 4.
wherein B" represents an oxygen or sulfur atom or , R1 and R2 2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a 400a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; and k represents an integral number, 2, 3 or 4.
5. The pyrimidinedione derivative as set forth in claim 1, of the general formula (5) (5) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, or , wherein B represents an oxygen or sulfur atom, , or , D represents , or ;
R1' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1' and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
R1' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1' and R5 may be so linked as to make an alkylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
6. The pyrimidinedione derivative as set forth in claim 1, of the general formula (6) (6) in which R1" and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group;
a phenyl group substituted by a halogen atom or a lower alkyloxy group, and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
403a n represents an integral number, 2 or 3; and m represents an integral number, 0, 1, 2, 3 or 4.
a phenyl group substituted by a halogen atom or a lower alkyloxy group, and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
403a n represents an integral number, 2 or 3; and m represents an integral number, 0, 1, 2, 3 or 4.
7. The pyrimidinedione derivative as set forth in claim 1, of the general formula (7) (7) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, or , wherein B represents an oxygen or sulfur atom, , or , D represents , or ;
R1' and R2' each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each inAependently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1' and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
R1' and R2' each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each inAependently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1' and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
8. The pyrimidinedione derivative as set forth in 405a claim 1, of the general formula (8) (8) in which A"' represents -(CH2)m-, - B'"-(CH2)k-, -D-(CH2)1-, or , wherein B"' represents an oxygen or sulfur atom, , or , D represents , or ;
R1"' and R2' each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups: a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoyloxy, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
R1"' and R2' each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups: a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoyloxy, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4.
9. A pharmaceutically acceptable acid addition salt of the pyrimidinedione derivative as set forth in any one of claims 1 - 8.
10. A process for the production of the pyrimidinedione derivative as set forth in claim 2, in which a compound of the general formula (9) (9) in which X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl, is allowed to react, in the presence of a dehydrate condensing agent, with a compound of the general formula (10) (10) R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1" and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
n represents an integral number, 2 or 3; and k represents an integral number, 2, 3 or 4.
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl, is allowed to react, in the presence of a dehydrate condensing agent, with a compound of the general formula (10) (10) R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1" and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
n represents an integral number, 2 or 3; and k represents an integral number, 2, 3 or 4.
11. A process for the production of the pyrimidinedione derivative as set forth in claim 4, in which a compound of the general formula (11) (11) in which X1 and X2 each independently represent a hydrogen atom -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl; and Y2 represents a halogen atom, is allowed to react with a compound of the general formula (12) (12) in which A represents -Bn-(CH2)k- or , wherein B" represents an oxygen or sulfur atom or ;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
n represents an integral number, 2 or 3; and k represents an integral number, 2, 3 or 4.
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl; and Y2 represents a halogen atom, is allowed to react with a compound of the general formula (12) (12) in which A represents -Bn-(CH2)k- or , wherein B" represents an oxygen or sulfur atom or ;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
n represents an integral number, 2 or 3; and k represents an integral number, 2, 3 or 4.
12. A process for the production of the compound as set forth in claim 3, in which the compound represented by the following general formula (13) (13) in which A' represents -(CH2)m-, -B'-(CH2)k- or , wherein B' represents an oxygen or sulfur atom or ;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
Y1 represents a halogen atom or a substituting group that can be eliminated in the reaction with a compound of the following general formula (14);
m represents an integral number, 0, 1, 2, 3 or 4; and k represents an integral number, 2, 3 or 4, is allowed to react with a compound represented by the general formula (14) (14) in which R1" and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group;
a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1" and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom or nitro, methyl or cyano group;
n represents an integral number, 2 or 3.
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
Y1 represents a halogen atom or a substituting group that can be eliminated in the reaction with a compound of the following general formula (14);
m represents an integral number, 0, 1, 2, 3 or 4; and k represents an integral number, 2, 3 or 4, is allowed to react with a compound represented by the general formula (14) (14) in which R1" and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group;
a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1" and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom or nitro, methyl or cyano group;
n represents an integral number, 2 or 3.
13. A process for the production of the pyrimidinedione derivative as set forth in claim 1, in which a compound represented by the general formula (15) (15) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)]-, or , wherein B represents an oxygen or sulfur atom, , or , D represents , or ;
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents 415a an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and l represents an integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (16) (16) in which R3 and R4 each independently represent a hydrogen atom or lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group; and Y3 represents a halogen atom or a substituting group that can make an eliminating group in the reaction with a compound of the general formula (15) above.
R1 and R2 each independently represent a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group), or R1 and R2 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents 415a an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and l represents an integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (16) (16) in which R3 and R4 each independently represent a hydrogen atom or lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group; and Y3 represents a halogen atom or a substituting group that can make an eliminating group in the reaction with a compound of the general formula (15) above.
14. A process for the production of a pyrimidinedione derivative as set forth in claim 5, in which a compound represented by the general formula (17) (17) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, or , wherein B represents an oxygen or sulfur atom, , or , D represents , or ;
R1' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents a n integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (18) (18) 417a in which R3 and R4 each independently represent a hydrogen atom or lower alkyl group; and X3 represents a hydrogen atom, nitro, methyl or cyano group.
R1' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1 and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents a n integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (18) (18) 417a in which R3 and R4 each independently represent a hydrogen atom or lower alkyl group; and X3 represents a hydrogen atom, nitro, methyl or cyano group.
15. A process for the production of the pyrimidinedione derivative as set forth in claim 7, in which a compound represented by the general formula (17) (17) in which A represents -(CH2)m-, -B-(CH2)k-, -D-(CH2)1-, or , wherein B represents an oxygen or sulfur atom, , or , and D represents , or ;
R1' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1' and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and l represents an integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (19) (19) 419a in which R2 represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the groue consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
n represents an integral number, 2 or 3; and Y4 represents a halogen atom or a substituting group that can make an eliminating group in the reaction with the compound of the general formula (17) above.
R1' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
R5 represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group, or R1' and R5 may be so linked as to make an ethylene or propylene chain and thus form a heterocyclic structure;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and l represents an integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (19) (19) 419a in which R2 represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the groue consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X3 represents a hydrogen atom, nitro, methyl or cyano group;
n represents an integral number, 2 or 3; and Y4 represents a halogen atom or a substituting group that can make an eliminating group in the reaction with the compound of the general formula (17) above.
16. A process for the production of the pyrimidinedione derivative as set forth in claim 8, in which a compound represented by the general formula (20) (20) in which A"' represents -(CH2)m-. B"'-(CH2)k-, -D-(CH2)1-, or , wherein B"' represents an oxygen or sulfur atom, , or , and D represents , or ;
R2' represents a hydrogen atom. a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino. lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom or a nitro, methyl or cyano group;
R5' represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (21) R1"' - Y4 (21) in which R1"' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
Y4 represents a halogen atom or a substituting group that can be eliminated in the reaction with a compound of the general formula (20) above.
R2' represents a hydrogen atom. a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino. lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
R3 and R4 each independently represent a hydrogen atom or a lower alkyl group;
X1 and X2 each independently represent a hydrogen atom, -CO-R6, a halogen atom, a lower alkyl, halogen-substituted lower alkyl, hydroxy, lower alkyloxy, lower alkylthio, lower alkyloxycarbonyl, carboxyl, cyano, amino, lower alkanoyloxy, lower alkanoylamino, lower alkylsulfonamido, lower mono- or di-alkylamino, phenyl-substituted lower alkylamino or unsaturated lower alkyloxy group;
X3 represents a hydrogen atom or a nitro, methyl or cyano group;
R5' represents a hydrogen atom, a lower alkanoyl, lower alkylsulfonyl or lower alkyl group;
R6 represents a lower alkyl, cycloalkyl, phenyl group (said phenyl group may be substituted by either one or two of substituting groups selected from the group consisting of a halogen atom, a lower alkyl group, hydroxy group and lower alkyloxy group), or a heterocyclic ring selected from pyridyl, pyrazolyl, pyrimidinyl, thienyl, furyl and pyrrolyl;
n represents an integral number, 2 or 3; m represents an integral number, 0, 1, 2, 3 or 4; k represents an integral number, 2, 3 or 4; and 1 represents an integral number, 0, 1, 2, 3 or 4, is allowed to react with a compound represented by the general formula (21) R1"' - Y4 (21) in which R1"' represents a hydrogen atom, a lower alkyloxycarbonyl, unsaturated lower alkyl or lower alkyl group (any one of the hydrogen atoms of said alkyl groups may be substituted by a substituting group selected from the group consisting of a hydroxy, lower monoalkylamino, lower dialkylamino, lower alkyloxy, lower alkanoyloxy and benzoyloxy groups; a benzoyloxy group substituted by a halogen atom or a lower alkyloxy group; a phenyl group; a phenyl group substituted by a halogen atom or a lower alkyloxy group; and a lower alkyloxycarbonyl group);
Y4 represents a halogen atom or a substituting group that can be eliminated in the reaction with a compound of the general formula (20) above.
17. A process for the production of a pharmaceutically acceptable acid addition salt of a pyrimidinedione derivative, which comprises a step of allowing the pyrimidinedione derivative obtained by the method as set forth in any one of claims 10 - 16 to react with an acid so as to obtain said pharmaceutically acceptable acid addition salt.
18. An antiarrythmic agent containing, as an effective ingredient, the pyrimidinedione derivative as set forth in any one of claims 1 - 8.
19. An antiarrythmic agent containing, as an effective ingredient, the pharmaceutically acceptable acid addition salt of the pyrimidinedione derivative as set forth in any one of claims 1 - 8.
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP271992/1988 | 1988-10-29 | ||
| JP27199288 | 1988-10-29 | ||
| JP30684188 | 1988-12-06 | ||
| JP306841/1988 | 1988-12-06 | ||
| JP306840/1988 | 1988-12-06 | ||
| JP30684088 | 1988-12-06 | ||
| JP9641889 | 1989-04-18 | ||
| JP9641789 | 1989-04-18 | ||
| JP9641689 | 1989-04-18 | ||
| JP096416/1989 | 1989-04-18 | ||
| JP096417/1989 | 1989-04-18 | ||
| JP096418/1989 | 1989-04-18 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2001389A1 CA2001389A1 (en) | 1990-04-29 |
| CA2001389C true CA2001389C (en) | 1998-02-10 |
Family
ID=27551984
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2001389 Expired - Lifetime CA2001389C (en) | 1988-10-29 | 1989-10-24 | Pyrimidinedione derivative compounds, method of producing the same and antiarrythmic agents containing the same |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2001389C (en) |
-
1989
- 1989-10-24 CA CA 2001389 patent/CA2001389C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2001389A1 (en) | 1990-04-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0369627B1 (en) | Pyrimidinedione derivative compounds, method of producing the same and antiarrythmic agents containing the same | |
| KR900004693B1 (en) | 4,5,6 - substituted - n - (substituted phenyl) -2- pyrimidinamins their preparation and composition of matter | |
| KR880000968B1 (en) | 1,2-diaminocyclobutene-3,4-diones and its preparation process | |
| DE69815008T2 (en) | Alpha-substituted phenylpropionic acid derivatives and medicaments containing them | |
| EP0877744B1 (en) | Substituted aza- and diazacycloheptane and cyclooctane compounds and their use | |
| CH662562A5 (en) | 1,2,4-TRIAZOL-3-ON COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THE SAME. | |
| CH649539A5 (en) | ANTIDEPRESSIVE EFFECTIVE PIPERAZINYLALKYL-1,2,4-TRIAZOL-3-ONE. | |
| EP0524146A1 (en) | Aminosubstituted Piperazinederivatives | |
| EP0772603A1 (en) | Substituted pyrimidine compounds and their use | |
| DE19728996A1 (en) | Triazole compounds and their use | |
| GB2177395A (en) | Thiazole derivatives | |
| CN101679308A (en) | inhibitors of the hedgehog pathway | |
| EP0772604A1 (en) | Triazole compounds and their use as dopamine-d 3?-ligands | |
| ES2218439T3 (en) | INDOLOQUINAZOLINONES. | |
| JPH01249769A (en) | Psychotropic heterobicycloalkyl piperadine derivative | |
| US6380229B1 (en) | 2-(N-cyanoimino)thiazolidin-4-one derivatives | |
| US5135931A (en) | Pyridinylpiperazine derivatives | |
| US4613601A (en) | (1-benzodioxin-6-ylmethyl)-4-substituted piperazines having antipsychotic activity | |
| CA2001389C (en) | Pyrimidinedione derivative compounds, method of producing the same and antiarrythmic agents containing the same | |
| EP0093252B1 (en) | Thiomethylpyridine derivatives, process for their preparation and medicaments containing them | |
| DE69827233T2 (en) | DIAMIDE DERIVATIVES AND MEDICAMENTS CONTAINING THEREOF | |
| DD218362A5 (en) | PROCESS FOR PREPARING NEW 1H, 3H-PYRROLO (1,2-C) THIASOL DERIVATIVES | |
| US5332739A (en) | Pyrimidinedione derivatives and antiarrhythmic agents containing same | |
| CN106008506B (en) | Substituted purin analog derivative and preparation method and application | |
| EP0430693B1 (en) | Pyrimidinedione derivative compounds, method for preparing same, and antiarrhythmic agents containing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |