CA2053475A1 - Quinazoline derivatives and their preparation - Google Patents
Quinazoline derivatives and their preparationInfo
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- CA2053475A1 CA2053475A1 CA002053475A CA2053475A CA2053475A1 CA 2053475 A1 CA2053475 A1 CA 2053475A1 CA 002053475 A CA002053475 A CA 002053475A CA 2053475 A CA2053475 A CA 2053475A CA 2053475 A1 CA2053475 A1 CA 2053475A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
- C07D239/96—Two oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
ABSTRACT
Compounds of the formula:
in which R1 and R2 are each hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substituent(s), A is lower alkylene, and the formula: is N-containing heterocyclic group, or pharmaceutically acceptable salts thereof. These compounds display effects on the periperal or central nervous system, in particular the peripheral nervous system. These compounds are also useful as dopamine receptor agonists. They are particularly useful for treating hypertension, cardiovascular disorders (e.g.
angina pectoris, myocardial infarction, etc.), Parkinsonism and the like. The preparation of these compounds is also disclosed as well as pharmaceutical compositions containing them and medical treatments using them.
Compounds of the formula:
in which R1 and R2 are each hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substituent(s), A is lower alkylene, and the formula: is N-containing heterocyclic group, or pharmaceutically acceptable salts thereof. These compounds display effects on the periperal or central nervous system, in particular the peripheral nervous system. These compounds are also useful as dopamine receptor agonists. They are particularly useful for treating hypertension, cardiovascular disorders (e.g.
angina pectoris, myocardial infarction, etc.), Parkinsonism and the like. The preparation of these compounds is also disclosed as well as pharmaceutical compositions containing them and medical treatments using them.
Description
- 1 2~.5~
QIJI~A30LINE DERI~ATIVES AND THEIR PREPARATION
The present invention relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to novel ~uinazoline derivatives and pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, to processes for the preparation thereof~ to a pharmaceutical composition comprlsing the same, to a use of the same as a medicament and to a method of the therapeutic tre~tment of diseases in a human being or animal.
Accordingly, one object of the present invention is to provide novel quinazoline derivatives and pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, in particular on the peripheral nervous system.
QIJI~A30LINE DERI~ATIVES AND THEIR PREPARATION
The present invention relates to novel quinazoline derivatives and pharmaceutically acceptable salts thereof.
More particularly, it relates to novel ~uinazoline derivatives and pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, to processes for the preparation thereof~ to a pharmaceutical composition comprlsing the same, to a use of the same as a medicament and to a method of the therapeutic tre~tment of diseases in a human being or animal.
Accordingly, one object of the present invention is to provide novel quinazoline derivatives and pharmaceutically acceptable salts thereof, which display effects on the peripheral or central nervous system, in particular on the peripheral nervous system.
- 2 - 2~J~.~7~
.~nocher object of the present invention is to provide processes for the preparation of novel quinazoline derivatives and salts thereof.
~ further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinazoline derivatives and pharmaceutically acceptable salts thereof.
Still further object of the present invention is to provide a use of said quinazoline derivatives and pharmaceutically acceptable salts thereof as a dopamine receptor agonist and a metho~ of the therapeutic treatment of dopamine receptor mediated diseases, particularly hypertension, cardiovascular disorder (e.g. angina pectoris, myocardial infarction, etc.), Parkinsonism, and the like, in a human being or animal.
The object quinazoline derivatives are novel and can be represented by the following general formula:
Rl o 2 5 ~il`~ ~N ~o --R I (I) in which Rl and R2 are each hydrogen, halogen, nitro, amino, ~rotected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substit~ent(s), A is lowe~ alkylene, and the formula: NJ is N-containing heterocyclic grou~, and pharmaceutically acceptable salts thereoE.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g.
calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt ~e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g.
hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid , glutamic acid, etc.~; and the like. ---According to the present invention, the objectcompound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
_ _ 4 ~ 7~
Process 1 : ~
~N --7L R
R1 O (III) R1 O
~ ~ ~NH ~ ~ NH
~ or salts R? ~ ~ N ~\~thereof ~ ~ N~o A - OH A-~ ~ - R
(II) (I) ~~~~
10 or its reactive derivative or salts thereof at the hydroxy group, or salts thereof Process 2 :
Reduction of Rl O the amido R1 O
20 R ~1 ~ O glO~p ~^ ¢ J NH
A1-co_N ~ R3 A-N ~ R3 (IV) (I) or salts thereof or salts thereof Process 3 :
Reduction of R1 O the nitro R1 O
~ g~L ~Up in R~ ~ ~ N~
R ~ N ~ R~ ~ I ~ 3 A-N ~ Ra A-N ~ -- R~
~I-a) (I-b) or salts thereof or salts thereo-f ~ ~53 ~7 ~
P~ocess 4 :
RZ~ R4 3 -/~Nl\o A-N~ R A-N~- R
~V) ( I ) or salts thereof or salts thereof Process 5 :
H Rydrolysis \ ~ NH
A-N~ R3 (I-c) (I-d) ~r salts thereof or salts thereof 25 Process 6 : -Reduction of Rl O nitro group(s) Rd c I Rd ~ ~ I r A-N~ R A-N~- R
(I-e) (I-f) 35 or salts thereof or salts thereof - 2~5~
o Process 7 :
R O xl Rl O
~ ~ x2 ~ ~ N~
R2 ~ N~ (Xl) ~ N ~o A-N ~ R A-N ~ R3 10(VIII) !I!
or salts thereof or salts thereof Process 8 :
Introduction of Re ` amino-protective Rf o J ~ ~I~\N~l R A-~ ~ R3 Rf A-N ~ R3 ~I-g) (I-h) or salts thereof or salts thereof wherein Rl, R2, R3, A and the formula :
- N ~ are each a~ defined above, one of Ra and Ra is lower alkoxy while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imida~olyl, one of Rb and Rb is hydroxy while the other is hydrogen, halogen, nitro, ami.no, protected 2 ~ ~ 3 ~ 7 3 am.ino, hydroxyamino, lower alkoxy, lower alXyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of Rc and Rc is nitro while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylth.io or imidazolyl, one of R1 and Rd is hydroxyamino or amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of Re and Re is amino while the other is hydrog~n, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, s.ulfamoyl, carboxy, protected carboxy, carbamoyl, mercap~o, lower alkylthio or imidazolyl, one of R1 and R2 is protected amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazoly', Ra is aryl substituted by nitro, 3Q Rb is aryl substituted by amino, R4 is esterified carboxy, A1 is Cl-C5 alkylene, and X and X are each a leaving group.
The starting compounds used in the Processes may be - ~- 2~3~7~
new and can be prepared, for example, by the following methods or a conventional manner.
Method A :
Rl O Rl O
Reduction ~ ~ N
A -COOH A-OH
(VI) (II) or salts thereof or salts thereof Method B :
~- ~ 3 HN ~ R
Rl O ~_~ Rl O
~ ~ ~III) ~ ~ NH
2 ~ N ~ O or salts 2 ~ N~o R ~ thereof R
A -COOH A -CO-N ~ R3 (VI) (IV) or its react.ive derivativeor salts thereof at the carboxy group, or salts thereof g 2853~5 Method C :
R \ O R1 0 2 ~ N R ~nide.tion ~ N42 A-N ~ R A-N~ R3 (VII ) ~~ ~v~ ~J
or its reactive derivative or salts thereof at the carboxy group, or salts thereof Method D :
"/ N-R ~IX) ~J ` -~
2 R2 ! ~-~ R2 A-N ~ R A-N -~ R3 (VII) ~x) ~
or its reactive derivative at or salts thereof the carboxy group, or salts thereof Method E :
; or its reactive ~ ~ NH2 2 ~N~o equivalent, 2 ~ NH
R ~ or its salt R
A-N ~ R A-N--~- R3 (X) (VIII ~
35or salts thereof or salts ihereof o 2~ 7~
i hi h R1 R2 R3 R4 A, A1 and the formula : -N
are each as defined above, and X is a leaving group.
Some of the starting materials of the above Methods are new and can be prepared, for example, according to the method of Preparation as mentioned below, or by a conventional manner.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
The term "lower" is intended to me~n 1 to 6, preferably 1 to 4 carbon atom(s~, unless otherwise indicated.
Suitable "lower alkyl" may include straight or branched one such as me~hyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which the most preferable example may be methyl.
Suitable "lower alkoxy" may include straight-or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, and the like, in which the most preferable example may be methoxy and ethoxy for Rl and/or R2 and methoxy, ethoxy and propoxy for the subs~ituent(s) in R3.
Suitable "aryl wh.ich may have suitable substi-tuent(s)" may include phenyl, tolyl, xylyl, cumenyl, mesithyl, naphthyl, and the like, each of which may be substituted by one or more, preferably one to three, more 2 ~ 7 ~
. 1 preferably one or two substituent(s) such as halogen (e.g.
fluorine, chlorine, bromine, iodine), lower alkyl as mentioned above (e.g. methyl, etc.), lower alkoxy as mentioned above (e.g. methoxy, ethoxy, propoxy, etc.), amino, nitro, and the like, in which more preferred example may be phenyl which is subs~ituted or unsubstituted by a group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro and amino, and the most preferred one may be phenyl, 2-(or 4-)tolyl, 2-(or 4-)-chlorophenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2-nitrophenyl and 2-aminophenyl.
Suitable "aryl substituted by nitro" and "aryl substituted by amino" means a~orementioned "aryl which may have suitable substituent(s)", in which said aryl is substituted by nitro and amino res~ectively.
Suitable "protected carboxy" may include esterified carboxy wherein "esterified carboxy" can be referred to the ones as mentioned below.
Suitable examples of the ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-~or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryl-oxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-~or 2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl 2~3 -~7~
- 1? -ester. isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-~or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower~alkyl ester te.g. 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g.
2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc~);
lower alkoxycarbonyloxy(lower)alkyl ester [e.g.
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxy-carbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-~or 2-)ethoxycarbonyloxyethyl ester, 1-~or 2-) isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene-(lower)alkyl ester, or (5-lower alkyl-2-oxo-1,3-di-oxol-4-yl)~lower)alkyl ester [e.g. (5-methyl-2-oxo-1,3-di-oxol-4-yl)methyl ester, ~5-ethyl-2 oxo-1,3-dioxol-4-yl)-methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower al~enyl ester (e.g. vinyl ester, allyl es~er, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester ~e.g. mono- or di- or triphenyl(lower)alkyl ester, etc.] which may have at least one suitable substituent(s) (e.g. lower alkoxy, nitro, hydroxy, lower al~yl, etc.), for example, mono- or di- or triphenyl~C1-C4)alkyl ester which may have (C1-C4)alkoxy [e.g. benzyl ester, benzhydryl ester, trityl ester, phenethyl ester, 4-methoxybenzyl ester, --3,4-dimethoxybenzyl ester, bis(methoxyphenyl)methyl ester, etc.], nitrophenyl(Cl-C4)alkyl ester (e.g. 4-nitrobenzyl ester, etc.), [hydroxy]-(C1-C4)alkylphenyl(C1-C~)alkyl ester (e.g. 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);
aryl ester which may have at least one suitable sub~tituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
3~ More preferable example of the protected carboxy thus 2~3~73 ue~ined may ~e C1-C4 alkoxycarbonyl and the most pre~erable one may be methoxycarbonyl.
Suitable "esteri~ied carboxy" may be the same one as mentioned in the explanation of "protected carbox~" in which the most preferred example may be ethoxycarbonyl.
Suitable "protected amino" may include amino protected by a conventional amino-protective group as mentioned below.
Suitable "amino-protective group" may include acyl such as carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.
The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, bu~y~sulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.
vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
The aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, -~ - 14 - 2~5~7~
phenethyloxycarbonyl, etc.), and the like.
These acyl groups may be further substituted with one or more suitable substituent(s) such as nitro, and the like, and preferable acyl having such substituent(s) may be nitroar(lower)alkoxycarbonyl~e.g.
nitrobenzyloxycarbonyl, etc.), and the like.
More preFerable example of amino-protective group may be aliphatic acyl such as lower alkylsulfcnyl and the most preferable one may be methanesulfonyl.
More preferable example of protected amino thus defined may be aliphatic acylamino such as lower alkylsulfonylamino and the most preferable one may be methanesulfonylamino.
Suitable '7halogen" may be fluorine, chlorine, bromine, iodine, and more preferred example may be chlorine and fluorine.
Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene~ ethylethylene, propylene, and the like, in which more preferred example may be Cl-C4 alkylene and the most preferred one may be tetramethylene.
Suitable "Cl-C5 alkylene" means aforementioned "lower alkylene" except for C6 alkylene, in which more preferred example may be Cl-C4 alkylene and the most preferred one may be trimethylene.
Suitable "leaving group" may include imidazole, lower alkylimidazole (e.g. 2-methylimidazole, etc.), an acid residue such as halogen as mentioned above (e.g. chlorine, _ - - 15 - 2 ~ i 3 !~ 7 ~
etc.), sulfonyloxy (e.g. m~sy:oxy, tosyloxy, etc.), trihalo(lower)alkyloxy (e.g. trichloromethoxy, etc.) and ~he like.
Suitable 'lower alkylthio" may include straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio, hexylthio, and the like.
Suitable "N-containing heterocyclic group'l means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom and optionally other hetero-atom(s) such as an oxygen, sulfur, nitrogen atom and the like, and said heterocyclic group is attached to A at the ring nitrogen atom.
Preferable N-containing heterocyclic group may be :
-unsaturated 3 to 8-membered, prefercbly 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrol-1-yl, pyrrolin-1-yl, imidazol-1-yl, pyrazol-1-yl, tetrahydropyridyl (e.g.
1,~,3,6-tetrahydropyridin-1-yl, etc.), triazolyl, (e.g.
4H-1,2,4-triazol-4-yl, lH-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, etc.), tetrazolyl (e.g.
lH-tetrazol-1-yl, 2H-tetrazol-2-yl, etc.), dihydrotriazinyl (e.g. 4,5-dihydro-1,2, -t ~zin-4-yl, 2,5 dihydro-1,2,4-triazin-2-yl, etc.), etc.;
-saturated 3 to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azetidin-1-yl, pyrrolidin-1-yl, imidazolidin-1-(or 3-)yl, piperidin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, etc.;
-unsaturated 3 to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and l to 3 nitrogen atom(s), for example, oxazinyl (e.g. 4H-1,4-oxazin-4-yl, etc.), oxadiazinyl (e.g. 4H-1,2,4-oxadiazin-4-yl, etc.), ~ 16 - 2~47~
-saturated 3 to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing l to 2 oxygen atom(s) and l to 3 nitrogen atom(s), for example, morpholin-4-yl, etc.;
-unsaturated 3 to 8-membered, preferably ;- or 6-membered heteromonocyclic ~ntaining l to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolinyl (e.g. 1,3-thiazolin-3-yl, 1,2-thiazolin-2-yl, etc ), ~tc.
-saturated 3 to 3-membered, preferably 5- ~r 6-membered heteromonocyclic group containing l to 2 sulfur atom(s) and l to 3 nitrogen atoms(s), for example, ,hiazolidinyl e.g. 1,3-thiazolidin-1,2-thiazolidin-2-yl, etc.l, etc.;
wherein more preferred example may be saturated or unsaturated 5- or 6-mem~ered heteromonocyclic group containing l to 4 nitrogen atom(s), and the most preferable one may be piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl.
2~
Preferable embodiments of R1, R2, R3, ~ and the formula -N~ are as follows :
Rl and R2 are each hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto or ower alkylthio, R3 is aryl which may have suitable substituent(s), r~
A is lower alkylene, and the formula : -N ~ is N-containing heterocyclic group.
Further, preferable embodiments of R1, R2, R3, A and the formula -N ~ are as follows :
- 2 ~ ~ 3 ~
R1 and R2 are each hydrogen, halogen, nitro, amino, acylamino such as lower alkylsulfonyl (e.g.
methylsulfonyl, ethylsulfonyl, etc.), hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, esterified carboxy such as lower alkoxycarbonyl, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is phenyl which is substituted or unsubstituted by one to three substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro and amino, A is lower alkylene, and the formula -N ~ is saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) such as piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl, and the like.
The processes for the prepa ation of the object compound (I) of the present invention are explained in detail in the following.
(1) Process 1 :
The compound (I) or salts thereof can be prepared by reacting the compound (II) or its reactive derivative at 2~ the hydroxy group, or salts thereof with the compound (III).
Suitable salts of the compound (II) may be the same as those for the compound (I).
Suitable salts of the compound (III) may be the same acid addition salts such as those given for the compound ~I).
Suitable reactive derivative at the hydroxy group of the compound (II) may include halide (e.g. chloride, ~ - 18 ~ 3~7~
bromide, iodide, etc.), sulfonate (e.g. methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), and the like.
This reaction is usually carried out in the presence s of an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.~. magnesium hy~roxide, calcium hydroxide, etc.~, alkali metal hydride (e.g.
sodium hydride, potassium hydride, etc.), alkaliTIe earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.~, etc; an organic base such as trimethylamine, triethylamine, dicyclohe~ylamine, pyridine, picoline, lutidine, N-ethyl-N,N-diisopropylamine, etc.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof. -The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(2) Process 2 :
The compound (I) or salts thereof can be prepared by reducing the amido mo:iety of the compound ~IV) or salts thereof.
- 19 - 2 ~
Suitable salts of the eompound (IV) may be the same as those for the compound (I).
The reduetion method applieable for this removal reaction may inelude a eonventional one whieh is eapable of eonverting the amido group into the aminomethyl group, for example, reduetion by using a eombination of a metal (e.g. zine, zine amalgam, etc.) or a salt of chrome compound (e.g. ehromous ehloride, ehromous aeetate, ete.) and an organic or inorganie acid te.g. aeetie acid, propionie aeid, hydroehlorie aeid, sulfurie aeid, etc.); a conventional catalytic reduetion in the presenee of a eonventional metallie eatalyst sueh as palladium eatalysts (e.g. spon~y palladium, palladium blaek, palladium oxide, palladium on earbon, eolloidal palladium, palladium on barium sulfate, palladium on barium earbonate, palladium hydroxide on earbon, ete.), nickel c2talysts (e.g. redueed nickel, nickel oxide, Raney niekel, ete.), platinum eatalysts (e.g. platinum plate, spongy platinum, platinum blaek, eolloidal platinum, platinum oxide, platinum wire, ete.); lithium aluminum hydride; sodium borohydride, a combination of tri(lower)alkylborane and sodium borohydride; borane, diborane, a eombination of sodium borohydride and borone trifluoride; and the like, in whieh more preferable method is lithium aluminum hydride, borane, diborane, and a eombination of sodium borohydride and borone trifluoride.
This reaetion is usually carried out in a eonventional solvent whieh does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, aeetate buffer, ete.), and the like, or a mixture thereof.
- 20 2~3~
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
(3) Process 3 :
The compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to a reduction of the nitro group in R3.
Suitable salts of the compounds ~I-a) and (I-b) may be the same as those for the compound (I).
'The present reaction is usually carried out by a conventional method as mentioned below.
Reduction method:
The reduction method applicable for this reaction may include convantional ones which are capable of converting a nitro group to a hydrox~amino or amino group, for example, reduction using tin(II) chloride or zinc powder;
reduction using a combination of a metal ~e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); conventional catalytic reduction in the presence of a conventional metallic cataly~st such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.);
reduction using aluminum am,?lgam; electrolytic reduction;
-- - 2 ~3 ~ 7 ~
and the like.
In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral condition.
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(4) Process 4 :
The compound (I) or salts thereof can be prepared by reacting the compound ~V) or salts thereof with a base.
Suitable salts of the compound (~II) may be the same as those for the compound (I).
Suitable base used in this reaction may be the-same ones as mentioned in Process 5.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as alcohol (e.g. methanol, ethanol, etc.), dichloromethane, pyridine, N,N~dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereo~.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
~ 22 - 2 ~ 7 ~
~) Process 5 :
The compoun~ ~I-d) or salts thereof can be prepared by hydrolyzing the compound (I-c) or salts thereof.
5Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I).
The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.
sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal car~onate le.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and the like.
Suitable acid may include an organic acid (e.g.
~ormic acid, acetic acid, propionic acid, trifluoroacetic acid, ~enzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.~. The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g.
phenol, anisole, etc.).
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g.
methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquid base or acid _ - - 23 - 2~3-~7~
can be also used as the solvent.
- The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
(6) Process 6 :
The compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to a reduction of the nitro group(s) of Rc and/or Rc.
Suitable salts of the compounds (I-e) and ~I-f) may be the same as those for the compound (I).
The method of reduction and the reaction conditions (eOg. reaction temperature, solvent, etc.) are substantially the same as those illustrated in Process 3, and thexefore are to be referred to said explanation.
(7) Proce~s 7 :
The compound (I) or salts thereof can be prepared by reacting the compound (VIII) or salts thereof with the compound (XI).
Suitable salts of the compound (VIII) may be the same as those for the compound tI).
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g.
methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried Ollt under from warming to heating.
~~ ~ - 24 - 2 ~ ~ 3 ~ 7 t3 In this reaction, when at least one of R and R is halogen and the compound ~XI) is carbonyldiimidazole, at least one of R1 and R2 may be converted into imidazol-l~yl group in the ob~ect compound (I~ during the reaction.
(8) Process 8 :
The compound (I-h) or salts thereof can be prepared by introducing an amino-protective group into the compound (I-g) or salts thereof.
Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I).
Suitable introducing agent of an amino-protective group is a conventional one such as an acylating agent of an amino group such as an organic carboxylic, carbonic, sulfonic and carbamic acid or its conver.tional reactive derivatives.
This reaction is usually carried out in the presence of an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide) potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g.
sodium hydride, potassium hydride, etc.), alkaline-earth metal hydride te.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc ), an alkali metal caxbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicaxbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), etc; an organic base such as trimethylamine, triethylamine, dicyclohexylamine, pyridine, picoline, lutidine, N-ethyl-N,N-diisopropylamine, etc.
~ ` ` ~5 2 ~
Further, this reaction can be carried out in the presence of a conventional condensing agent used for a so-called "acylation", when the introducing agent of an amino-protective group is in a free acid form.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warmlng The object compounds obtained according to the above Processes can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
Methods for preparing the new starting compound or salts thereof used in the above processes are explained in detail in the following.
(A) Method A :
The compound (II~ or salts thereof can be prepared by reducing the compound (VI) or salts thereof.
Suitable salts of the compound (VI) may be the same as those for the compound (I).
The method of reduction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated in Process 2, 2 ~ ~ 3 ~ ~ ~
- _6 which are capable o converting the carboxy group into the hydroxymethyl group, and therefore are to be referred to said explanation.
(B) Method B :
The compound (IV) or salts thereof can be prepared by reacting the compound (VI) or its reactive derivative at the carboxy group, or salts thereof with the compound (III).
Suitable reactive derivative at the carboxy group of the compound (VI) may include acid halide (e.g. acid chloride, acid bromlde, acid iodide, etc.), an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with acid such as substituted phosphoric acid Ee.g.
dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.~, dialkyiphosphorous acid, sulfurous acid; thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e~g. succinimido ester, cyanomethyl ester, methoxymethyl ester, dimethyliminiomethyl r(CH3)2~=CH_]
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl _ - - 27 - 2~ 7 S
thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.~, or an ester with a N-hydroxy comp~und ~e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-lH-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected among them according to the kind of the compound (VI) to be used.
This reaction is usually carried out in the presence of an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide, pGtassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g.
sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide ~e.g. sodium methoxide, sQdium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbon~te, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), etc; an organic base such as trimethylamine, triethylamine, dicyclohexylamine, pyridine, picoline, lutidine, N ethyl-N,N-diisopropylamine; etc.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
~ 8 - 2 Q ~ 3 ~ '7 a (C) Method C :
The compound (V) or salts thereof can be prepared by amidating the compound (VII) or its reactive derivative at the carboxy group, or salts thereof.
Suitable reactive derivative at the carboxy group of the compound ~VII) may be the same ones as mentioned in Method B.
Suitable amidating agent used in this reaction may include a conventional one which is capable of converting the carboxy group into the amido group such as ammonia or acid addition salts thereof (e.g. ammonium chloride, etc.), and the like.
This reaction can be carried out in the presence of a such base as mentioned in Method C.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, acetonitrile, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
(D) Method D :
The compound (X) or salts thereof can be prepared by reacting the compound (VII) or its reactive derivative at the carboxy group, or salts thereof with the compound (IX).
Suitable salts of the compound (X) may be the same as those for the compo~md (I).
~ 29 - ~ ~ 3 ~
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamlde, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture 5 thereof.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(E) Method E :
The compound (VIII) or salts thereof can be prepared by reacting the compound (X) or salts thereof with ~nonia or its reactive equivalent, or its salt.
Suitable reactive equivalent of ammonia may be a conventional one and include ammonium hydroxide, and the like.
Suitable salt of ammonia may be acid addition salt such as ammonium chloride, and the like.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, acetonitrile, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
The object ~uinazoline derivatives (I) stimulate presynaptic(neuronal) and/or postsynaptic(vascular) dopamine receptors that mediate inhibition of neurogenic release of catecholamine and~or dilatation of rena vasculature and remission of parkinsonism, respectively.
Quinazoline derivatives (I) effect on the cardiovascular _ - 30 _ 2 0 ~ ~ 1 7 ~
system as a consequence of its interaction with dopaminergic and adrener~ic receptors.
The object compound (I) and pharmaceutically acceptable salts thereof of the present invention are novel and display dopamine receptor stimulating effects;
5-HT receptor antagonism, especially 5-HT2 receptor antagonism; a1 receptor antagonism; and the like, and are useful as a dopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT2 receptor antagonist;
a1 receptor antagonist; and the like, for treating or preventing hypertension such as renal hypertension and other cardiovascular disorders (e.g. angina pectoris, congestive heart failure, myocardial infarction, etc.);
Parkinsonism; hyperprolactinemia; disorders of peripheral perfusion such as Raynaud's phenomenon, Burger's diseases, and intermittent claudicatio~; thrombotic and/or smooth muscle cell p~oliferative disease such as restenosis after percutaneous transluminal coronary angioplasty;
hypercholesterolemia, hyperlipemia; urinary disturvance;
and the like.
The compound (I) and pharmaceutically acceptable salts thereof may be also useful as an adrenolytic, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, hypoglycemic anti-viral, or blood flow increasing agent.
Now in order to show the utility of the object compound (I) and pharmaceutically acceptable salts, the test data on dopamine receptor stimulating effects of the representative compound of the compound (I) of this invention are shown in the following.
~ - 31 - 2~3-~7~
Test 1 ~Dopamine receptor (DA2 receptor) binding assay]
Test Method l :
The afflnity for DA2 receptor of a Test Compound was determined following in vitro receptor binding assays.
Male rats weighing 150-300g were decapitated and the stratum were dissected from their brains. The tissue was homogenized in 30 volumes of buffer which consisted of 50 mM Tris-HCl (pH 7.4 at 25C), 120 mM sodium-chloride, 5 mM
potassium chloride, l mM calcium chloride, l mM magnesium chloride, lO ~M pargirine, and 0.1% ascorbic acid. The homogenate was centrifuged at 50,000 g for 15 minutes.
The pellet was resuspended in 30 volumes of the buffer.
The tissue suspension was centrifugPd and suspended again in the same way.
Incubation tubes received 100 ~l of [phenyl-4- H~spiperone, lO0 ~l of the Test Compound and 0.8 ml of tissue suspension during binding assays. The concentration of rphenyl-4- H]spiperone was 0.2 nM. The final tissue concentration of rat striatum was 160 ~g/ml.
The tubes were incubated at 37C for lO minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times with 3 ml of ice-cold buffer. The filters were counted by liquid scintillation counter.
Specific binding of the ~3H]spiperone was determined in the presence of 1 ~M butacl~mol. The IC50 value of the Test Compound was calculated from the data of [3H]spiperone binding in the presence of lO 9M, lO 8M, lO 7M and lO 6M Test Compound.
Test Compound Compound A ~The product of Example 6]
- ~2 - 2~17~
Test Result 1 :
~ Test Compound IC50 (M) . . . _ Compound A 7.4 x 10 9 Test 2 [Inhibition of reserpine-induced DOPA
accumulation]
Test Method 2 :
Male SD rats weighing 300-400 g were used in this test. Rats were pretreated with reserpine (1 mg/kg, S.C.) 17-19 hours before sacrifice and then fasted. Test Compound was given orally to the rats 2 hours before sacrifice. ~m-Hydro~ybenzylhydrazine (100 mg/kg, i.p.) was given 30 minutes before sacrifice.] Each rat was exposed to microwaves using a head-focus microwave applicator for 1.5 seconds. The whole brain was removed and further separated into the striatum.
DOPA was determined as follows; the striatum was homogenized in 9 volumes of 0.lN perchloric acid solution t0.4% EDTA-2Na). The homogenate was centrifuged at 10,000 rpm for 1 minutes. The supernatant was applied to high performance liquid chromatography.
Test Result 2 ~Test Compound ¦ dose ~ Inhibition (~) .
Test 3 [Hypotensive effect on spontaneous hypertensive rats]
~ - 33 2 ~ 3~ ' 7 ~
Test Method 3 :
15 to 25-Week-old male spontaneous hypertensive rats with mean arterial blood pressure of about 160-200 m~Hg, weighing 300-350 g, were used. The animals were 5 cannulated in the left femoral artery and the mean blood pressure and heart rate were measured with a pressure-transducer. The animals were deprived of food for about 18 hours before oral dosing. The Test Compound was suspended in 0.5% methylcellulosP, and given orally.
Test Result 3 :
The maximum decrease of blood pressure (%) is shown in Table.
15~ p ~ (mg/kg) blood pressure (~) 20For therapeutic administration, the object compound (I~ and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or li~uid excipient which is suitable for oral, parenteral and external administration.
The pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid Form suc~
as solution, suspension, syrup, emulsion, lemonade, and the like.
If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as -2 ~ 7 ~
lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between about O.OOl mg and about 300 mg, preferably about O.l mg to about 50 mg per day may be administered to a patient. An average single dose of about O.OOl mg, O.Ol mg, 0.03 mg, O.l mg, 0.3 mg, 0.6 mg, l.0 mg, 3.0 mg, lO.0 mg, 50.0 mg, lO0.0 mg, of the object compound (I) of the present invention may be used as adrenolytic, hypotensive, cardiovascular, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, and anti-viral agents.
The following Preparations and Examples are given for the purpose of illustrating this invention i~ more detail.
Preparation l l) A mixture of 2,4(lH,3H)-quinazolinedione (l.62 g), 1,1,1,3,3,3-hexamethyldisilazane (3.54 g) and ammonium sul~ate (160 mg) in toluene (5 ml) was refluxed for 3 hours. Af~er toluene and excess l,l,l,3,3,3-hexamethyl-disilazane were evaporated in vacuo, ethyl 4-bromocrotonate (3.84 g) was added thereto. The mixture was heated to 120C. After 3 hours, the reaction mixture was cooled below 100C, and ethanol was added.
Crystallized materials were collected and washed with ethanol to give l-(3-ethoxycarbonyl-2-propenyl)-2,4-(lH,3H)-quinazolinedione (l.95 g).
NMR (CDCl3, ~) : 1.25 (3H, t, J=6Hz), 4.20 (2H, q, J=6Hz), 4.90 (2H, dd, J=2, 3Hz), 5.90 (lH, td, - 35 - 2 ~
J=1.5, 13Hz), 6.95-7.10 (2H, m), 7.Z5-7.35 (lH, m), 7.70 (lH, ~t, J=1.5, 7Hz), 8.25 (lH, dd, - J=l, 7Hz), 9.00 (lH, br s) Preparation 1-2) To a solution of 1-~3-ethoxycarbonyl-2-propenyl)-2,4-(lH,3H) -quinazolinedione (5.50 g) in tetrahydrofuran-methanol ~200 ml, 3:1 V/V) was added 10%
palladium on carbon (550 mg). The mixture was stirred vigorously under atmospheric pressure of hydrogen. After 6 hours, the catalyst was filtered off, and the solvent was evaporated. l-(3-Ethoxycarbonylpropyl)-2,4(lH,3H)-quinazolinedione (5.24 g) as a crystal was obtained by recrystallization from ethanol.
NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 1.95-2.05 (2H, r.n~, 2.50 (2H, t, 3=5Hz~, 4.10-4.25 t4H, m), 7.30 ~lH, t, J=7Hz), 7.50 ( lH, d, J=7Hz), 7.75 (lH, dt, J=l, 7Hz), 8.25 ~lH, dd, J=l, 7Hz), 9.00 (lH, br s) Preparation 1-3) A mixture of 1-(3-ethoxycar~onylpropyl)-2,4(lH,3H)-quinazolinedione (552 mg) and lN sodium hydroxide (6.0 ml) in methanol-tetrahydrofuran ( 26 ml, 3.3:1 V/V) was stirred for 3 hours at room temperature. After evaporation of the organic solvents, the mixture was adjusted to pH 4~5 with lN hydrochloric acid to give precipitates. Collected precipitates were washed in turn with water and ethanol to give l-(3~carboxypropyl)-2, 4(lH,3H) -quinazolinedione (393 mg) as a powder.
NMR (DMSO-d6, ~) : 1.70-1.95 (2H, m), 2.40 ~2H, t, J=6Hz), 4.05 (2H, t, J=6Hz), 7.30 (lH, t, J=6Hz), 7.55 (lH, d, J=7Hz), 7.80 (lH, dt, J=1.5, 6Hz), 8.00 (lH, dd, J=1.5, 6Hz) ~3~'~7~
_ - ~6 Preparation 1-4) To a stirred suspension of 1-(3-carbo~rpropyl~-2j4(lH,3H)-quinazolinedione (2.00 g) in tetrahydrofuran (40 ml) was added lM horane in tetrahydrofuran (24.2 ml) on an ice-bath, and the mixture was stirred for additional 2 hours at room temperatureO '~he reaction mixture was quenched with lN hydrochloric acid, and the organic solvent was evaporated. The residue was triturated with water, filtered and washed in turn with water and ethyl ether to give 1-(4-hydroxybutyl)-2,4(1H,3H)-quinazolinedione (1.74 g) as a crystal.
NMR (DMSO-d6, ~) : 1.45-1.70 (4H, m), 3.30-3.50 (3H, m), 4.05 (2H, t, J=7Hz), 4.50 (lH, t, J=5Hz), 7.30 (lH, t, J=6Hz), 7.50 (lH, d, J=6Hz), 7.80 (lH, dt, J=1.5, 5Hz), 8.05 (lH, dd, J=1.5, 5Hz) Preparation 1-5) A mixture of 1-(4-hydroxybutyl)-2,4(lH,3H)-quinazolinedione (290 mg), thionyl chloride (0.54 ml), and pyridine (98 mg) in tetrahydrofuran (10 ml) was refluxed for 2 hours. After evaporation of the solvents, the residue was dissolved in chloroform, washed in turn with water, saturated sodium bicarbo~ate and brine, dried over magnesium sulfate, and evapor ted. Crude material was crystallized from ethyl ether-isopropyl ether to give 1-(4-chlorobutyl)~2,4(lH,3H)-quinazolinedione (226 mg) as a powder.
NMR (CDC13, ~) : 1.85-2.00 (4H, m), 3.65 (2H, t, J=4Hz), 4.10-4.25 (2H, m), 7.20-7.35 (2H, m~, 7.75 (lH, dt, J=1.5, 7Hz), 8.25 (lH, dd, J=1.5, 7Hz), 8.80 (lH, br s) Preparation 2-1) To a stirred solution of 2,4-dioxo-lH-3,1-benzoxazine 7 2 ~ a 3 ~ 7 ~
(2.00 g) in dry dimethylformam-de (20 ml) was added sodium hydride (540 mg, 60% oil suspension) in several portions on an ice-bath. After 30 minutes, ethyl 4-bromocrotonate (3.79 g) was added to the mixture. After stirring for additional 2 hours at room temperature, 28% ammonium hydroxide (7.5 ml) was added on an ice-bath. The mixture was stirred for 30 minutes at the same temperature, neutralized with lN hydrochloric acid, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (120 g) eluting with ethyl acetate and hexane (1:1 V/V) to give 2-(3-ethoxycarbonyl-2-propenylamino)benzamide (2.53 g) as a solid.
NMR ~CDC13, ~) : 1.25 g (3H, t, J=6Hz), 4.00 (2H, dd, J=1.5, 4Hz), 4.20 (2H, ~, J=6Hz), 5.85 ~lH, br s), 6.00 (lH, td, J=1.5, 12Hz), 6.55-6.65 (2H, m), 7.00 ~lH, td, J=3.5, 12Hz), 7.2S-7.35 (lH, m), 7.40 (lH, dd, J=1.5, 6.5Hz) Preparation 2-2) To a solution of 2-(3-ethoxycarbonyl-2-propenylamino)benzamide ~2.35 g) in methanol (50 ml) was added 10% palladium on carbon (230 mg). The mixture was stirred vigorously under 3 atmospheric pressure of hydrogen. After 2 hours, the catalyst was filtered off, and the solvent was evaporated. The residue was chromatographed on silica gel (40 g). Elution with a mixed solvent of ethyl acetate-hexane (1:1 V/V) gave 2-(3-ethoxycarbonylpropylamino)benzamide (1.95 g)-NMR (CDC13, ~) : 1.25 (3H, t, J=6Hz), 1.90-2.10 [2H, m), 2.45 (2H, t, J=6Hz), 3.25 (2H, t, J=6Hz), 4.15 (2H, q, J=6Hz), 5.75 (lH, br s), 6.65 (lH, t, J=6Hz), 6.80 (lH, d, J=7Hz), 7.30-7.45 (2H, m) - 38 - 2~3^~7~
Preparation 2-3) A mixture of 2-(3-ethoxycarbonylpropylamino)benzam:lde (1.95 g) and N,N'-carbonyldiimidazole (2.52 g) in dioxane (20 ml) was heated to 150C. After 30 minutes, the mixture was cooled below 80C, and diluted with ethanol to give crude crystals. Collected crystals were recrystallized from ethanol to give l-(3-ethoxycarbonyl-propyl)-2,4(lH,3H)-quinazolinedione (1.53 g) as a crystal.
NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 2.00-2.15 (2H, m), 2.50 (2H, t, J=5Hz), 4.10-4.30 (4H, m), 7.30 (lH, t, J=8Hz), 7.50 (lH, d, J=8Hz), 7.25 (lH, dt, J=1.5, 8Hz), 8.25 (lH, dd, J=1.5, 8Hz), 8.70 (lH, br s) Preparation 3 A mixture of 1-(3-carboxypropyl)-2,4(lH,3H)-quinazolinedione (744 mg) and thionyl chloride (1.3 ml) in dry tetrahydrofuran (12 ml) was refluxed for 1 hour, and then evaporated. Obtained residue dissolved in ~-0 tetrahydrofuran (15 ml) w~s added to a mixture of N-(2-nitrophenyl)piperazine (683 mg) and triethylamine (607 mg~ in chloroform (15 ml) on an ice-bath. After stirring for 1 hour, precipitated materials were collected and dissolved in chloroform, washed in turn with water, saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give 1-[4-(4-(2-nitrophenyl)piperazin-l-yl)-4-oxo~utyl]-2,4(lH,3H)-quinazolinedione (1.06 g) as a solld.
NMR (CDC13, ~) : 2.00-2.20 (2H, m), 2.55 (2H, t, J=5Hz), 3.10 (4H, t, J=4Hz), 3.60-3.70 (2H, m), 3.80-3.9U (2H, m?, 4.20 (2H, t, J=6.5Hz), 7.15 (2H, d, J=6Hz), 7.30 (lH, dt, J-1.5, 6Hz), 7.50 (lH, dt, J=1.5, 6Hz), 7.70-7.85 (3H, m), 8.20 (lH, dd, J=1.5, 6Hz), 8.65 (lH, br s) - 39 - 2 ~ ~ ~ L 7 ~
Preparation 4 A mixture of 1-(3~carboxy)propyl-2,4~lH,3H~-quinazolinedione (744 mg) and thionyl chloride (1.30 ml) in dry tetrahydrofuran (10 ml) was refluxed for 1 hour, and then evaporated in vacuo. Obtained residue dissolved in dry tetrahydrofuran (5 ml) was added to a stirred mixture of 4-~4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydro-chloride (719 mg) and triethylamine (911 mg) in chloroform-tetrahydrofuran (10 ml, 1:1 V/V) on an ice-bath. After stirring for 1 hour at the same temperature, the reaction mixture was diluted with chloroform, washed with water, lN hydrochloric acid, saturated sodium bicarbonate, and brine successively, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (20 g). Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 1-[4-{4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}-4-oxobutyl]-2,4~1H,3H)-quinazolinedione (1.365 g) as an amorphous.
NMR (CDC13, ~) : 1.95-2.20 (2H, m), 2.40-2.65 (4H, m), 3.70 (lH, t, J=5Hz), 3.85 (lH, t, J=SHz), 4.10-4.30 (4H, m), 5.95-6.15 (lH, m), 7.15-7.25 (5H, m), 7.60-7.80 (2H, m), 8.20 (lH, d, J=8Hz), 9.05 (lH, br s) Preparation 5-1) To a stirred solution of methyl 2-ethoxycarbonyl-amino-4-nitrobenzoate (4.00 g) in dry dimethylformamide (40 ml) was added sodium hydride (715 mg, 60% oil suspension) in several portions on an ice-bath. After stirring for 1 hour, 1-bromo-4-chlorobutane (2.81 g) was added thereto, and the resulted mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water, and extracted with ethyl acetate.
The extract was washed in turn with water and brine, dried over magnesium sul~ate, and evaporated. The residue was chromatographed on silica gel (180 g). Elution with a mixed solvent of hexane and ethyl acetate (3:1 V/V~ ~ave methyl 2-[N-(4-chlorobutYl)-N-ethoxycar~onylamino]-4-nitrobenzoate (2.30 g) as an oil.
NMR (CDC13, ~) : 1.05-1.20 (3H, m), 1.70-1.95 (4H, m), 3.30-3.60 (3H, m), 3.90 (3H, s), 4.00-4.40 (3H, m), 8.05-8.25 (3H, m) Preparation 5-2) A mixture of methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4-nitrobenzoate (2.20 g), 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1~32 g), sodium iodide (921 mg), and potassium carbonat~ (1.69 g) in dry dimethylformamide (30 ml) was s~irred at 80C
for 16 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was chromatographed on silica gel (40 g), eluting with a mixed solvent of chloroform and methanol (50:1 V/V) to give methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoate (1.58 g) .
NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.20-1.45 (lH, m), 1.60-1.80 (4H, m), 2.50-2.65 (4H, m), 2.70-2.80 (2H, m), 3.15-3.25 (2H, m), 3.50-3.90 (2H, m), 3.90 (3H, s), 4.00-4.35 (2H, m), 6.00-6.10 (lH, m), 7.25-7.40 (5H, m), 8.00-8.20 (3H, m) _reparation 5-3) To a stirred solution of methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-N-ethoxycarbonyl-amino]-4-nitrobenzoate (1.58 g) in methanol (16 ml) was 2 3 ~ ~ !L 7 3 added 2N potassium hydroxide (5O0 ml). After stirring for 2 hours at 50C, methanol was evaporated in vacuo. The residue was diluted with water, acidified with 3N
hydrochloric acid, extr~cted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated. Crude 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl3-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.57 g~ was obtained as an amorphous.
NMR (CDC13, ~) : 0.90-1.10 (3H, m), 1.55-1.80 (2H, m), 1.90-2.05 (2H, m), 2.80-3.00 (2H, m), 3.00-3.15 (2H, m), 3.30-3.50 (2H, m), 3.65-4.10 (6H, m), 6.00 (lH, br s), 7.25-7.40 (5H, m~, 7.95-8.20 (3H, m) Preparation 5-4) A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.53 g), N,N'-disuccinimidoyl carbonate (924 mg~ and pyridine (285 mg) in dry acetonitrile (20 ml) was stirred for 3 hours at room temperature. Then, to the mixture was added 28% am~onium hydroxide (1.4 ml) on an ice-bath.
After 1 hour, the reaction mixture was diluted with water, and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated.
The residue was chromatographed on silica gel (30 g).
Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 2-[N-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}-N-ethoxycarbonylamino~-4-nitrohenzamide (600 mg) as caramel.
NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 1.50-1.75 (4H, m), 2.45-2.65 (4H, m), 2.70-2.80 (2H, m), 3.15-3.25 (2H, m), 3.60-3.75 (2H, m), 4.20 (2H, q, J=6Hz), 5.90-6.10 (2H, m), 7.20-7.40 (5H, m), 7.80 (lH, d, J-7~1z), 8.10 ~lH, d, J=1.5Hz), 8.25 (lH, dd, J=1.5, 7Hz) ~`~ - 42 - ~ i 7 ~
Preparation 6 To a stirred suspension of 1-(4-hydroxybutyl)-2,4(lH,3H)-quinazolinedione ~778 mg) in chloroform-tetrahydrofuran (40 ml, 1:1 V/V~ was added methanesulfonyl chloride (0.57 ml), and triethylamine (1.85 ml) on an ice-bath. After stirring for 18 hours at room temperature, the reaction mixture was heated at 50C for 30 hours with stirring. After evaporation of the solvents the residue was diluted with ethyl acetate. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evapoxated. l-(4-Methane-sulfonyloxybutyl)-2,4(1H,3H)-quinazolinediorle (675 mg) as a crystal was obtained by recrystallization from methanol.
NMR (CDC13, ~) : 1.85-2.00 (4H, m), 3.00 (3H, s), 4.15-4.25 (2H, m), 4.30-4.40 (2H, m), 7.20-7.35 (2H, m), 7.70 (lH, dt, J=1.5, 6~z), 8.25 (lH, dd, J=1.5, 6Hz), 8.70 (1~, br s~
Preparation 7-1) Methyl 6-chloro-2-[N-(4-chlorobutyl)-N-ethoxy-carbonylamino]benzoate was obtained in 90.7% yield in substantially the same manner as that of Preparation 5~
NMR (CDC13, ~ : 1.10-1.25 (3H, m), 1.65-1.85 ~4H, m), 3.20-3.50 ~lH, m), 3.55 (2H, t, J=6Hz), 3.65-3.85 (lH, m), 3.90 (3H, s), 4.05-4.20 (2H, m), 7.05-7.15 (lH, m), 7.35-7.45 (2H, m) Preparation 7-2~
Methyl 6-chloro-2-[N-ethoxyca~bonyl-N-{4-(4-phenyl--1,2,3,6 tetrahyxropyridin-l-yl)butyl}amino]benzoate was obtained in 78.2% yield in substantially the same manner as that of Preparation 5-2).
NMR (CDC13, ~) : 1.05-1.30 (3H, m), 1.55-1.70 (4H, m), 2.40-2.75 (6H, m), 3.10-3.20 (2H, m), 3~ 3.20-3.50 (lH, m), 3.70-3.90 (lH, m), - 43 - 2 3 ~ 3 ~ 7 ~
3.90 ~3H, s), 4.00-4.20 (2H, m~, 6.05-h.10 ~lH, m~, 7.10-7.60 (8H, m) Preparation 7-3) 6-Chloro-2-[N-ethoxycarbonyl-N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}amino]benzoic acid was obtained in 96.1% yield in substantially the same manner as that of Preparation 5-3).
IR (Nujol) : 1680, 1600, 1580 cm Preparation 7-4) 6-Chloro-2-~N-ethoxycarbonyl-N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}amino~benzamide was obtained in 21.0% yield in substantially the same manner as that of Preparation 5-4).
NMR (CDC13, ~) : 1.05-1.45 (3H, m), 1.50-1.90 (4H, m), 2.50-2.95 (4H, m), 3.20-3.40 (lH, m), 3.60-3.80 (lH, m), 4.00-4.30 (2H, m), 6.00-6.10 ~lH, m), 7.05-7.50 (8H, m) Preparat on 8-1) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonyl]amino-6-nitrobenzoate was obtained in substantially the same manner as that of Preparation 5-1).
NMR (CDC13, ~) : 1.00-1.30 (3H, m), 1.65-1.85 (4H, m), 3.50-3.60 (2H, m), 3.90 (3H, s), 4~05-4.20 (2H, m), 7.55 (lH, d, J=7Hz), 7.65 (lH, t, J=7Hz), 8.15 (lH, dd, J=l, 7Hz) Preparation 8-21 Methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-6-nitrobenzoate was o~tained in substantially the same manner as that of Preparation 5-2).
- 2 ~ 7 ~
NMR (CDC13, ~) : 1.05-1.25 (3H, m), 1.55-1.75 ~4H, m), 2.50-2.65 ~4H, m), - 2.75 ~2H, t, J=4Hz), 3.20 ~2H, d, J=3Hz), 3.90 (3H, s), 4.00-4.20 (2H, m), 6.00-6.10 ~lH, m), 7.25-7.40 ~5H, m), 7.55-7.65 ~2H, m), 8.10 ~lH, d, J=7Hz) Preparation 8-3) 2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-~l-ethoxycarbonylamino]-6-nitrobenzoic acid was obtained in substantially the same manner as that of P~eparation 5-3).
NMR (CDC13, ~) : 1.00-1.25 (3H, m), 1.55-1.80 (2H, m), 1.90-2.10 (2H, m), 2.70-3.20 (3H, m), 3.40-4.20 (9H, m), 6.G0 (lH, s), 7.25-7.50 (7H, m), 8.00 (lH, t, J=7Hz) Preparation 8-4) A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl}-N-ethoxycarbonylamino]-6-nitrobenzoic acid (680 mg) and phosphorus tribromide (0.7 ml) in methylene dichloride (30 ml) was refluxed for 3 hours. Excess of phosphorus tribromide was quenched with ethanol (2 ml) on an ice-bath. Then appeared crystalline materials were collected, and washed with ethanol to give 1-14-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione hydrobromide (414 mg).
-NMR (DMSO-d6, ~) : 1.65-1.95 (4H, m), 2.75-2.90 (2H, m?, 3.20-3.40 (3H~ m), 3.10-3.90 (2H, m), 4.00-4.20 (3H, m), 6.15-6.25 (lH, m), 7.35-7.55 (5H, m~, 7.70 (lH, d, J=6Hz), 7.80 (lH, d, J=6Hz), 8.05 (lH, t, J=6Hz) 2 ~ L
- ~5 -Preparation 8-5) To a suspension of 1-~4-(4-pher.yl-1, 2, 3,6 tetrahydro-pyridin-l-yl)butyl]-5-nitro-1,2-dihydro-4H-3,1-benzoxazine-2, 4-dione hydrobromide (410 mg) in dimethylformamide (4 ml) was added 28% ammonium hydroxide (1 ml) on an ice-bath, and the mixture was stirred for 1 hour at room temperature. The mixture was poured into ice-water, extracted with ethyl acetate, and the extracts were washed with water and brine. After dryness with magnesium sulfate and evaporation of the solvent, 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6-nitrobenzamide was obtained as an amorphous (300 mg).
NMR (CDC13, ~) : 1.60-1.80 (4H, m), 2.40-2.60 (4H, m), 2.70 (2H, t, J=5Hz), 3.10-3.25 (4H, m), 5.10-5. 20 (lH, m), 6.00-6.10 (3H, m), 6.90 (lH, dd, J=1.5, 7Hz), 7.20-7.40 (7H, m) The following compounds were obtained in substantially the same manner as that of Preparation 5-1).
Preparation 9-1) Ethyl 2-[N-(4 -chlorobutyl)-N ethoxycarbonylamino~ -5-ethoxybPnzoate NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.25 (lH, t, -J=6Hz), 1.35 (3H, t, J=6Hz), 1.45 (3H, t, J=6Hz), 1.60-1.90 (4H, m), 3.25-3.40 (lH, m), 3.55 (2H, t, J=5Hz), 3.80-4.25 (5H, m), 4.30 (2H, ~, J=6Hz), 7.05 (lH, dd, J=2, 7Hz), 7.10 (lH, d, J=7Hz), 7.50 (lH, d, J=2Hz) Preparation 9-2) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino~- 5-methoxybenzoate NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.35 (lH, dd, J=6, 12Hz), 1.70-1.90 ~4H, m), 3.30-3.45 (lH, m), 3.55 (2H, t, J=5Hz3~ 3.90 ~3H x 2, s~, 3.90-4.40 (3H, m), 7.00-7.20 (2H, m), 7.50 (lH, d, J=2Hz) Preparation 9-3) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino] 3-chlorobenzoate NMR (CDCl3, ~) : 1.10 (3H, t, J=6Hz), 1.60-1.85 (4H, m), 3.35-3.70 (4H, m), 3.90 (3H, s), 4.10 (2H, q, J=6Hz), 4.20-4.40 (lH, m), 7.35 (lH, t, J=7Hz), 7.65 (lH, dd, J=1.5, 7Hz), 7.85 (lH, dd, J=1.5, 7Hz) Preparation 9-4~
Methyl 2-IN-(4-chlorobutyl)-N-ethoxycarbonylamino3-4-methoxybenzoate NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.20-1.40 (lH, m), 3.35-3.50 (lH, m), 3.55 (2H, t, J=5~z~, 3.85 (3H, s), 3.90 ~3H, s), 3.80-4.25 (3H, m), 6.70-6.80 llH, m), 6.85 (lH, dd, J=2, 8Hæ), 8.00 (lH, d, J=8Hz) Preparation 9-5) Methyl 2-~N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4,5-dimethoxybenzoate NMR (cDcl3~ 1.10 (2H, t, J=6Hz), 1.30-1.40 (lH, m), 1.65-1.95 (4H, m), 3.30-3.60 (3H, m), 3.85 (3H, s), 3.90 (3H x 2, s), 3.95-4.35 (3H, m), 6.65 (lH, s), 7.50 (lH, s) Pre~aration 9-6) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino~-5-nitrobenzoate NMR (CDC13, ~) : 1.00-1.20 (3H, m), 1.70-l.90 (4H, ~ J
_ - 47 m3, 3.50-3.60 (2H, m), 3.70-3.80 (2H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 7.45 (lH, d, J=8~z), - 8.40 (lH, dd, J=2, 8Hz), 8.80 (lH, br s) Preparation 9-7) Methyl 2-[N-~4-chlorobutyl)-N-ethoxycarbonylamino]-6 fluorobenzoate NMR ~CDCl3, ~) : 1.05-1.30 (3H, m), 1.65-1.90 (4H, m), 3.40-3.70 (4H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 7.05 (lH, d, J=7Hz), 7.15 (lH, d, J=7Hz), 7.45 (lH, dt, J=4, 7Hz) Preparation 9-8) Methyl 2-~N-(4-chlorobutyl)-N-ethoxycarbonylamino]-6-15 methoxybenzoa~e NMR tCDCl3, ~) : 1.10-1.25 (3H, m), 1.65-1.85 (4H, m), 3.55 (2H, t, J=5Hz), 3.90 (6H, s), 4.00-4.20 (2~, m), 6.80 (lH, d, J=7Hz), 6.90 (lH, d~
J=7Hz), 7.40 (lH, t, J=7Hz) Preparation 9-9) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-6 methylbenzoate NMR (CDCl3, ~) : 1.10-1.30 (3H, m), 1.60-1.90 (4H, m), 2.40 (3H, s), 3.20-3.50 (lH, m), 3.55 (2H, t, J=5Hz), 3.70-4.00 (lH, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 7.00 (lH, d, J=7Hz), 7.20 (lH, d, J=7Hz), 7.35 (lH, t, J=7Hz) The following compounds were obtained in substantially the same manner as that of Preparation 5-2).
PreParation 10-1) Ethyl 2-[N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin-35 l-yl)butyl}-N-ethoxycarbonylamino]-S-ethoxybenz.oate 2~3 17~
NMR (CDC13, ~) 1.10 (3H, t, J=6Hz), 1.35 (3H, t, J=6Kz), 1.45 (3H, t, J=6Hæ), 1.50-1.70 (4H, m), - 2.45-2.80 (6H, m), 3.~5-3.40 (3H, m), 3.85-4.15 (5H, m), 4.30 (2H, q, J=6Hz), 6.00-6.10 (lH, m), 7.00 (lH, dd, J=2, 8Hz~, 7.10 (lH, d, J=8Hz), 7.25-7.40 (5H, m), 7.45 (lH, d, J=2Hz) Preparation 10-2) Methyl 2-[N-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-10 yl)butyl}-N-ethoxycarbonylamino~-5-methoxybenzoate NMR (CDC13, ~) : 1.10 (3H, t, J=6Hz), 1.50-1.70 (4H, m), 2.45-2.60 (4H, m), 2.65-2.75 (2H, m), 3.10-3.20 (2H, m), 3.25-3.40 (lH, m), 3.80 (3H x 2, s), 3.80-4.35 (3H, m), 6.00-6.10 (lH, m), 7.00-7.50 (8H, m) Preparation 10-3) Methyl 2-~N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin l-yl)butyl}-N-ethoxycarbonylamino]-3-chlorobenzoate NMR (CDCl3, ~) : 1.10 (2H, t, J=6Hz), 1.35 (lH, m), 1.50-1.65 !4H, m), 2.40-2.70 (6H, m), 3.10-3.20 (2H, m), 3.35-3.80 (2H, m), 3.90 (3H, s), 4.10 ~4/3H, q, J=6Hz), 4.20-4.40 (2/3H, m), 6.00-6.10 (lH, m), 7.20-7.40 (6H, m), 7.65 (lH, dd, J=1.5, 7Hz), 7.85 tlH, dd, J=1.5, 7Hz) Preparation 10-4) Methyl 2-[N-~4-t4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}-N-ethoxycarbonylamino]-4-methoxybenzoate NMR (CDCl3, ~) : 1.10 (12/5H, t, J=6Hz), 1.35 (3/5H, t, J=6Hz), 1.60-1.75 (4H, m), 2.50-2.70 (4H, m), 2.70-2.90 (2H, m), 3.20-3.30 (2H, m), 3.30-3.55 (lH, m), 3.85 (3~, s), 3.90 (3H, s), 3.80-4.30 (3H, m), 6.05 (lH, br s), 6.75 (lH, d, J=2Hz), 6.85 (lH, dd, J=2, 8Hz), 7.25-7.40 (5H, m), 8.00 (lH, d, J=8Hz) Preparation 10-5) Methyl 2-[N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-etho~ycarbonylamino]-4,5-dimethoxybenz~ate NMR (CDC13, ~) : 1.10 (2H, t, J=5Hz), 1030-1.40 (~H, m), 1.55-1.75 (4H, m), 2.45-2.70 (4H, m), 2.70-2.80 (2H, m), 3.15-3.45 ~3H, m), 3~85 (3H, s), 3.90 ~3H x 2, s), 3.95-4.35 (3H, m), 6.05 (lH, br s), 6.70 (lH, s~, 7.25-7.40 (5H, m), 7.50 (~H, s) Preparation 10-6) Methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl-N-ethoxycarbonylamino]-5-nitrobenzoate NMR (CDC13, 6) : 1.00-1.50 (3H, m), 1.60-1.80 (4H, m~, 2.50-2.70 (4H, m), 2.75-2.90 (2H, m), 3.20-3.30 (2H, m), 3.60-3.90 (2H, m), 3.90 (3H, s), 4.00-4.30 (2H, m), 6.00-6.10 (lH~ m), 7.25-7.50 (6H, m), 8.40 ~lH, ~d, J=2, 8Hz), 8.80 ~lH, br s) Pre~aration 10-7) Methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl~butyl}-N-ethoxycarbonylamino]-6~fluorobenzoate NMR (CDCl3, 6) : 1.05-1.25 (3H, m), 1.55-1.80 ~4H, m), 2.60-2.75 (4H, m), 2.80-2.95 ~2H, m), 3.25-3.40 (2H, m), 3.40-3.80 (2H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 6.00-6.10 (lH, m), 7.00-7.15 (2H, m), 7.25-7.50 (6H, m) Preparation 10-8) Methyl 2-[N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin~
yl)butyl}-N-ethoxycarbonylamino]-6-methoxybenzoate NMR (CDCl3, 6) : 1.10-1.25 ~3H, m), 1.55-1.75 ~4H, m), 2.50-2.70 (4H, m), 3.80-3.90 (2H, m), 3.75-3.85 (2H, m), 3.90 ~6H, s), 4.00-4.20 (2H, - 50 _ 2 ~ 7 ~
m), 6.00-6.10 ~lH, m), 6.80 (lH, d, J=7Hz), 6.90 (lH, d, J-7Hz), 7.25-7.45 (6H, m) _reparation 10-9) Methyl 2-[N-~4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-6-methylbenzoate NMR (CDCl3, ~) : 1.10-1.25 ~3H, m), 1.55-1.80 (4EI, m), 2.40 (3H, s), 2.55-2.75 (4H, m), 2.75-2.95 (2H, m), 3.20-3.45 (2H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 6.00-6.10 tlH, m), 7.05 (lH, d, J=7Hz), 7.15-7.40 (7H, m) The following compounds were obtained in substantially the same manner as that of Preparation 5-3).
Preparation 11-1) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5~ethoxybenzoic acid NMR (CDCl3, ~) : 1.40 (3H, t, J=6Hz), 1.50-1.75 (2H, m), 1.75-1.95 ~2H, m), 2.75-3.00 (4H, m), 3.20-3.70 ~6H, m), 3.85-4.10 (4H, m), 6.00 ~lH, br s), 6.90 (lH, dd, J=2, 7.5Hz), 6.95 (lH, d, J=7.5Hz), 7.20-7.50 (6H, m) 25 Preparation 11-2) 2-~N-{4 (4-Phenyl-1,2,3,6-tetrahy~ropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-methoxybenzoic acid N~R (CDCl3, ~) : 1.00 (3H, t, J=6Hz), 1.50-1.6S (2H, m), 1.70-2.05 ~2H, m), 2.80-3.10 (4H, m), 3.30-3.40 (2H, m~, 3.55-3.70 (2H, m), 3.80 (5H, br s), 4.00 i2H, q, J=6Hz), 6.00 (lH, br s), 6.95 (lH, dd, J=2, 8Elz), 7.00 (lH, d, J=8H~
7.20-7.40 (SH, m), 7.45 (lH, d, J=2Hz) - 51 - 2 ~, ~ 3 ~
Preparation 11-3) 2-[N-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)~
butyl}-N-ethoxycaxbonylamino]-3-chlorobenzoic acid Preparation 11-4) 2-EN-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-4-methoxybenzoic acid NMR (CDCl3, ~) : 1.05 ~3H, t, J=6Hz), 1.50-1.70 (2H, m), 1.85-2.05 (2H, m), 2.80-2.90 (2H, m), 2.95-3.10 (2H, m), 3.30-3.A0 (2H, m), 3.55-3.80 (4H, m), 3.85 (3H, s), 4.00 (2H, q, J=6Hz), 6.65 (lH, d, J=1.5Hz), 6.80 (lH, dd, J=1.5, 7.5Hz), 7.25-7.40 (5H, m), 8.00 (lH, d, J=7.5Hz) Preparation 11-5) 2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-4,5-dimethoxybenzoic acid NMR (CDCl3, ~) : 1.05 (3H, t, J=6Hz), 1.50-1.70 (2H, m), 1.90-2.10 (2H, m), 2.85-3.20 ~4H, m~, 3.30-3~50 (2H, m), 3.60-3.75 (2H, m), 3.90 (3H x 2, s), 3.80-4.10 (4H, m), 6.00 (lH, br s), 6.60 (lM, s), 7.25-7.40 (5H, m), 7.55 (lH, s) Preparation 11-6) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-nitrobenzoic acid NMR (CDC13, ~) : 1.10-1.20 (3H, m), 1.50-1.70 (2H, m), 2.00-2.20 (2H, m), 2.85-3.00 (2H, m), 3.10-3.Z0 (2H, m), 3.40-3.60 (2H, m), 3.70-4.00 (4H, m), 4.00-4.15 (2H, m), 6.00 (lH, br s), 7.25-7.40 (6H, m), 8.20-8.30 (lH, m), 8.65-8.75 (lH, m) Prepaxation 11-7) 2-[N-{4-(4-Phenyl-l,Z,3,6-tetrahydropyridn-1-yl)-- ` 23~ ~17a butyl}-N-ethoxycarbonylamino]-6-fluorobenzoic acid NMR (CDCl3, ~) : 1.05-1.30 (3H, m), 1.55-1.75 (2H, - m), 1.90-2.10 (2H, m), 2.80-3.00 (2H, m), 3.10 (2H, t, J=6Hz), 3.30-3.50 (2H, m), 3.60-3.90 (4H, m), 4.00-4.20 (2H, m), 6.00 (lH, br s), 6.90-7.10 (2H, m), 7.20-7.40 (2H, m) Preparation 11-8) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino)-6-methoxybenzoic acid NMR (CDCl3, ~) : 1.00-1.20 (3H, m), 1.5S-1.75 (2H, m), 1.85-2.10 (2H, m), 3.80-3.95 (2H, m), 3.05 (2H, t, J=6Hz), 3~35-3.50 (2H, m~, 3.60-3.80 (7H, m~, 4.00-4.15 (2H, m), 5.8D (lH, br s), 6.00 (lH, br s), 6.70 (lH, d, J=6Hz), 6.85 (lH, d, J=6Hz), 7.20-7.40 (6H, m) Preparation 11-9~
2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-6-methylbenzoic acid NMR (CDCl3, ~) : l.OQ-1.30 (3H, m), 1.30-1.80 (2H, m), 1.85-2.40 (2H, m), 2.45 (3H, s), 2.60-2.85 (lH, m), 2.90-3.40 (5H, m), 3.50-3.80 (2H, m), 4.00-4.35 (4H, m~, 6.10 (lH, br s), 7.00 (lH, d, J=7Hz), 7.15-7.40 (7H, m) The following compounds were obtained in substantially the same manner as that of Preparation 5-4).
Preparation 12-1) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-ethoxyben~amide Preparation 12-2) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-- 53 - 2~ 3 butyl}-N-ethoxycarbonylamino]-5-methoxybenzamide NMR (CDCl3, ~) : 1.25 (3H, t, J=6Hz), 1.50-1.65 (4H, - m), 2.45-2.65 (4H, m), 2.70-2.80 (2H, m), 3.20 (2H, m~, 3.60 (2H, br s), 3.80 (3H, s), 4.20 (2H, q, J=5Hz), 6.00-6.10 (lH, m~, 7.00 (lH, dd, J=2, 8Hz), 7.10 (lH, d, J=8Hz), 7.20-7.40 (6H, m) Preparation 12-3) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl3-N-ethoxyc~rbonylamino]-3-chlorobenzamide NMR (CDCl3, ~) : 1.20 (3/2H, t, J=6Hz), 1.35 (3/2H, t, J=6Hz), 1.50-1.75 (4H, m), 2.40-2.80 (6Hr m), 3.15-3.50 (3H, m), 3.70-4.00 (lH, m), 4.10-4.40 (2H, m), 5.85 ~1/2H, br s), 5.00-6.20 (2H, m), 6.80 (lH, br s), 7.20-7.40 (6H, m), 7.50-7.65 (2H, m) Preparation 12-4) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino~-4-methoxybeDzamide NMR (CDCl3, ~) : 1.25 (3H, t, J=6Hz), 1.55-1.70 (4H, m), 2.45-2.70 (4H, m~, 2.75 (2H, m), 3.15-3.25 (2H, m), 3.50-3O75 (2H, m), 3.85 (3H, s), 4.20 (2H, ~, J=6Hz), 6.00-6.10 (lH, m), 6.70 (lH, d, J=2Hzj, 6.90 (lH, dd, J=2, 7Hz), 7.20-7.40 (6H, m), 7.70 (1 or 2H, d, J=7Hz) Preparation 12-5) 2-rN-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-30 butyl}-N-ethoxycarbonyl~mino]-4,5-dimethoxybenzamide NMR (CDCl3, ~) : 1.35 (3H, t, J=6Hz), 1.55-1.65 (4H, m), 2.40-2.50 (2H, m), 3.55-3.65 (2H, m), 3.90 (3H, s), 3.95 (3H, s), 4.20 (2H, ~, J=6Hz), 5.75-5.90 (3~5H, br s), 6.00-6.10 (lH, m), 6.60 (lH, s), 7.25-7.40 (8H, m~
2~33`i.
- ~4 -Preparation 12-6) 2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-nitrobenzamide NMR (CDC13, ~) : 1.20-1.35 (3H, m), 1.55-1.90 (4H, m), 2.50-2.70 (4H, m), 2.70-2.90 (2H, m), 3.20 3.35 (2H, m), 4.10-4.30 (2H, m), 6.05 (lH, br s), 7.20-7.45 (6H, m), 8.30 (lH, d, J=2Hz), 9.00 (lH, d, J=2Hz) The following Compounds were obtained in substantially the same manner as that of Preparations 8-4) and 8-5).
Preparation 13-1) lS 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}amino]-6-fluorobenzamide NMR (CDC13, ~) : 1.65-1.85 (4H, m), 2.50-2.70 (4H, m), 2.80 (2H, t, J=4Hz), 6.05-6.10 (lH, m), 6.30 (lH, ddd, J=l, 8, lOHz), 6.50 (lH, d, J=7Hz), 7.20-7.45 (6H, m), 8.55 (lH, br s) Preparation 13-2) 2-lN~~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}amino]-6-methoxybenzamide NMR (CDCl3, ~) : 1.70-1.85 (4H, m), 2.55-2.70 (4H, m), 2.85 ~2H, t, J=5Hz), 3.15-3.35 (4H, m), 3.90 (3H, s), 5.50 (lH, br s~, 6.00-6.10 (lH, m), 6.20 (lH, d, J=7Hz), 6.35 (lH, d, J=7Hz), 7.15-7.40 (6H, m), 7.80 (lH, br s) Preparation 13-3) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}amino]-6-methylbenzamide NMR (CDC13, ~) : 1.60-1.80 (4H, m), 2.40 (3H, s), 2.50-2.70 (4H, m), 2.70-2.80 (2H, m), 3.10-3.25 2 ~ 5 3 -~7 ~
_ - 55 (4Hr m~, 4.90 (lH, br s), 5.75-5.95 (2H, m), 6.00-6.10 ~lH, m), 6.50 (2H, d, J=7Hz), 7.10 (lH, t, J=7Hz), 7.25-7.40 (6H, m) The following compounds were obtained in substantially the same manner as that of Preparation 2-1).
Preparation 14-1) 2-(3-Ethoxycar~onyl-2-propenylamino)-5-methoxy-benzamide NMR (CDC13, ~) : 1.30 (3H, t, J=5Hz), 3.80 (3H, s), 3.g5-4.05 (2H, m), 4.20 (2H, q, J=5Hz), 5.90 (1 or 2H, br s), 6.05 (lH, td, J=1.5, 12Hz), 6.50-6.60 (lH, m), 6.95-7.10 (3H, m) Preparation 14-2) 2-(3-Ethoxycarbonyl-2-propenylamino)-4-chlorobenzamide NMR (CDCl3, ~) : 1.30 (3H, t, J=6Hz), 4.00 l2H, dd, J=1.5, 5Hz), 4.20 ~2H, q, J=6Hz), 5.90 (2H, br s), 6.00 (lH, td, J=l, 12Hz), 6.55-6.65 (2H, m~, 7.0Q (lH, td, J=3, 12Hz), 7.35 (lH, d, J=7Hz) The following compounds were obtained in substantially the same manner as that of Preparation 2-2).
Preparation 15-1) 2-(3-Ethoxycarbonylpropylamino)-5-methoxybenzamide NMR (CDC13, ~) : 1.25 (3H, t, J=5Hz), 1.90-2.05 (2H, m), 2.40 (2H, t, J=6Hz), 3.20 (2H, t, J=6Hz), 3.75 (3H, s), 4.15 (2FI, q, J=6Hz), 5.90 (2H, br s), 6.6S-6.75 (lH, m), 6.95-7.05 (2H, m) 2 ~ 3 -~ ~ 3 Preparation 15-2) 2-~3-Ethoxycarbonylpropylamino)-4-chlorobenzamide - NMR (CDC13, ~) : 1.25 ~3H, t, J=6Hz), 1.90-2.10 (2H, m), 2.45 (2H, t, J=5Hz), 3.20 (2H, t, J=5Hz), 4.15 (2H, q, J=6Hz), 5.80 ~2H, br s~, 6.55 (lH, dd, J=1.5, 8Hz), 6.70 (lH, d, J=1.5Hz), 7.30 (lH, d, J=8Hz) The following compounds were obtained in 10 substantially the same manner as that of Preparation 2-3).
Preparation 16-1) 1-(3-Ethoxycarbonylpropyl)-6-methoxy-2,4(1H,3H~-quinazolinedione NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 1.95-2.10 (2H, m), 2.50 (2H, t, J=6Hz), 3.90 (3H, s), 4.10-4.25 (4H, m), 7.35 (lH, dd, J=2, 8Hz), 7.45 (lH, d, J=8Hz), 7.65 (lH, d, J=2Hz), 8.90 (lH, br s) 20 Preparation_16-2) 1-(3-Ethoxycarbonylpropyl)-7-chloro-2,4(1H,3H)-quinazolinedion~
NMR (CDCl3, ~ 30 (3H, t, J=6Hz), 1.95-2.10 (2H, m), 2.50 (2H, t, J=5Hz), 4.10-4.30 ~4H, m), 7.25 (lH, dd, J=1.5, 7Hz), 7.50 (lH, d, J=1.5Hz), 8.15 (lH, d, J-7Hz), 8.80 (lH, br s) The following compounds were obtained in substantially the same manner as that of Preparation 1-3).
Preparation 17-1) 1-(3-Carboxypropyl)-6-methoxy-2,4(1H,3H)-quinazolinedione NMR (DMSO d6, ~) : 1.70-1.90 (2H, m), 2.40 (2H, t, J=5Hz), 3.20-3.50 (2H, m), 3.80 (3H, s), 4.05 - 2 ~ ~) 3 i~ ~ 3 ~2H, t, J=5Hz), 7.40 ~lH, dd, J=1.5, 8Hz), 7.45 ~lH, d, J-1.5Hz), 7.55 ~lH, d, J=8Hz) Preparation 17-2) 1-~3-Carboxypropyl)-7-chloro-2,4(1H,3H)-~uinazolinedione NMR (DMSO-d6, ~) : i.70-1.90 (2H, m), 2.40 (2H, t, J=5Hz), 4.05 (2H, t, J=5Hz), 7.30 (lH, dd, J=l, 8Hz), 7.75 (lH, d, J=lHz), 8.00 (lH, d, J=8Hz~
The following compounds were obtained in substantially the same manner as that of Preparation 1-4).
Preparation 18-1) 1-~4-Hydroxybutyl)-6-methoxy-2,4(1H,3H)-quinazolinedione NMR (DMSO-d6, ~) 1.40-1.70 ~4H, m), 3.30-3.50 ~2H, m), 3.80 ~3H, s), 4~00 ~2H, t, J=5Xz), 7.30-7.50 (3H, m) Preparation 18-2) 1-(4-Hydroxybutyl)-7-chloro-2,4~1H,3H)-quinazolinedione NMR (DMSO-d6, ~) : 1.40-1.70 ~4H, m), 3.30-3.50 ~2H, m), 4.00-4.10 ~2H, m), 7.30 ~lH, dd, J=1.5, 7Hz), 7.60 (lH, d, J=1.5Hz), 8.00 (lH, d, J=7Hz) The following compounds were obtained in substantially the same manner as that of Preparation 1-5).
Preparation 19-1) 1-(4-Chlorobutyl)-6-methoxy-2,4(1H,3H)-~uinazolinedione NMR (CDCl3, ~) : 1.85-1.95 t4H, m), 3.60-3.70 (2H, m), 3.90 ~3H, s), 4.10-4.20 ~2H, m), 7.20 ~lH, 2 ~ a 3 ~ i7 3 _ - 58 d, J=8Hz), 7.30 (lH, dd, J=2, 8Hz), 7.65 (lH, d, J=2Hz) Preparation 19-2) 1-~4-Chlorobutyl)-7-chloro-2,4(lH,3H)-~uinazolinedione NMR (CDCl3, ~ 85-2.00 (4H, m), 3.60-3.70 (2H, m), 4.10-4.20 (7H, m), 7.20-7.30 (2H, m), 8.20 (lH, dd, J=l, 7Hz), 8.95 (lH, br s) The following compounds were obtained in substantially the same manner as that of Preparation 3.
Preparation 20-1) 1-[4-{4-(4-Tolyl)-1,2,3,6-tetrahydropyridin-1-yl}-4-oxobutyl]-2,4~lH,3H)-~Iinazolinedione NMR (CDCl3, ~) : 2.00-2.20 t2H, m~, 2.35 (3H, s), 2.45-2.65 (4H, m), 3.65-3.75 (lH, m), 3.80-3.90 (lH, m), 4.10-4.30 (4H, m), 5.95-6.10 (lH, m), 7.10-7.35 (5H, m), 7.70-7.80 (2H, m), 8.20-8.40 ~0 (2H, m) Preparation 20-2) 1-~4-{4-(2-Tolyl)piperazin-l-yl}-4-oxobutyl]-2,4(lH,3H)~quinazoline~ione N~R (CDCl3, ~) : 2.00-2.20 (2H, m), 2.35 (3H, s), 2.55 ~2H, t, J=5Hz), 2.85-3.00 (4H, m), 3.60 (2H, t, J=4Hz), 3.80 (2H, t, J=4Hz), 4.20 (2H, t, J=5Hz), 6.95-7.05 (2H, m), 7.10-7.30 (5H, m), 7.75 (2H, m), 8.20 (lH, d, J=7Hz), 8.40 (lH, br S) Preparation 20-3) 1-[4-t4-Phenylpiperazin-l-yl)-4-oxobutyl~-2,4(1H,3H)-quinazolinedione 2~3 -~7~
Preparation 20-4) 1-l4-{4-(2-Etho~yphenyl)piperazin-1-yl}-4-oxob~tyl]-2,4(lH, 3H)-quinazolinedione NMR (CDCl3, ~) : 1.50 ~3H, t, J=6Hz), 2.0~-2.20 ~2H, m), 2.55 (2H, t, J=5Hz), 3.05- 3.15 (4H, m), 3.60-3.70 (2H, m), 3.80-3.90 (2H, m), 4.10 (2H, q, J=6Hz), 4.15-4.25 (2H, m), 6.85-7.05 (4H, m), 7.20-7.30 (lH, m), 7.70-7.80 (2H, m), 8.20 (lH, d, J=7Hz), 8.80 ~lH, br s) Preparation 21 2-~N-{4-l4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-4-chlorobenzamide was obtained in substantially the same manner as that of Preparation 12-3) from 2-[N-~4-(4-phenyl-1,2,3,6-tetrahydropyridn-1-yl)butyl}-N-ethoxycarbonylamino]-4-chlorobenzoic acid, which had been prepared from methyl 2-[N-~4-chlorobutyl)-N-ethoxycarbonylamino-4-chlorobenzoate in substantially the same manner as those of Preparatio~ 9-3), 10-3~ and 11-3).
Preparation 22 6-Chloro-1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-4-oxobutyl]-2,4(lH,3H)-quinazolinedione was obtained in substantially the same manner as that of Preparation 4 from 1-(3-carboxy)propyl-6-chloro-2,4(lH,3H)-quinazolinedione, which had been prepared from 2,4(lH,3H)-quinazolinedione in substantially the same manner as those of Preparationsl-1), 1-2) and 1-3).
NMR (CDCl3, ~) : 2.40-2.65 (4H, m), 3.50-3.65 (lH, m), 3.65-3.75 (lH, m), 3.85-3.95 (lH, m), 4.10-4.30 (5H, m), 5.00-6.65 (lH, m), 7.20-7.40 (5H, m), 7.65-7.85 ~2H, m), 8.15-8.25 ('H, m), 9.25 (lH, br s) - - 2~1a~ 7~
o Example 1-1~
~ mixture of 1-~4-chlorobutyl)-2,4~1H,3H)-quinazolinedione (160 mg), N-(2-propoxyphenyl)piperazine hydrochloride (178 mg), potassium iodide (105 mg), and sodium carbonate (200 mg~ in methyl isobutyl ketone (15 ml) was refluxed for 5 nours. After dilution with ethyl acetate, the reaction mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated.
The residue was chromatographed on silica gel (15 g) 1~ eluting with chloroform-methanol (50:1 V/V) to give 1-[4-{4-(2-propoxyphenyl)piperazin-1-yl}butyl]-2,4(lH,3H)-quinazolinedione (266 mg).
mp : ~ 68~
IR (Nujol, v) : 1680, 1600 cm 1 NMR (CDC13, ~ : 1.10 (3H, t, J=6Hz), 1.60-1.90 (6H, m), 2.55 (2H, t, J=SHz), 2.60-2.80 (4H, m), 3.10-3.25 (4H, m), 3.95 (2H, t, J=6Hz), 4.15 (2H, t, J=5Hz), 6.8-7.00 (4H, m), 7.20-7.30 ( H, m), 7.40 (lH, d, J=7Hz), 7.70 (lH, dt~ J=l, 7Hz), 8.20 (lH, dd, J=l, 7Xz), 8.95 (lH, br s) Example 1-2~
A mixture of 1-(4-methanesulfonyloxybutyl)-2,4(lH,3H)-quinazolinedione (312 mg), 4-phenyl-1,2,3,6-tetrahydropyridine (200 mg) and triethylamine (303 mg) was refluxed for 105 hours. The reaction mixture was poured into ethyl acetate-water~
extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was washed with hot methanol to give 1 [4-(4-phenyl-1,2,3,6~
tetrahydropyridin-l-yl)butyl]-2,4(1H,3H)-quinazolinedione (114 mg) as a powder.
mp : 170-173.5C
IR (Nujol, v) : 1710, 1670, 1600 cm 1 - 2~ 7~
- 6~
NMR (CDC13, ~) : 1.60-1.95 (4H, m~, 2.50-2.70 (4H, m), 2.75 ~2H, t, J=4.5Hz~, 7.20-7.45 (7H, m), - 7.65 (lH, ddd, J=1.5, 6, 6Hz), 8.20 (lH, dd, J=1.5, 6Hz) Example 2-1) To a suspension of 1-[4-{4-(2-nitrophenyl)piperazin-l-yl}-4-oxo-butyl]-2,4(1H,3H)-quinazolinedione (500 mg~ in tetrahydrofuran (10 ml) was added lM borane in tetrahydrofuran (3.42 ml) on an ice-bath. After refluxing for 30 minutes, the reaction mixture was quenched with lN
hydrochloric acid (7 ml), and refluxed for additional 30 minutes. The mixture was made alkaline with saturated aqueous sodium bicarbonate, diluted with ethyl acetate.
The organic layer was washed with saturated sodiu~
bicarbonate and brine, dried over magnesium sulfate, and evaporated. The obtained residue was chromatographed on silica gel (20 g) eluting with chloroform-methanol ~20:1 ~/V) to gi~e crystals. Recrystallization from ethanol gave 1-~4-{4-(2-nitrophenyl)piperazin-1-yl}butyl~
2,4(lH,3H3-quinazolinedione (77 mg).
mp : 164-165C
IR (Nujol, v) : 1700, 1650, 1600 cm 1 NMR ~CDC13, ~) : 1.60-1.90 (4H, m), 2.45-2.80 (6H, m), 3.00-3.25 ~4H, m3, 4.15 l2H, t, J=5Hz), 7.05 (lHr dt, J=1.6Hz), 7.15 (lH, dd, J=1.6Hz), 7.20-7.40 ~3H, m), 7.50 (lH, dt, J=1.5, 6.5Hz), 7.70 (lH, dd, J=1.6Hæ), 7.80 (lH, dd, J-l, 6Hz), 8.20 (lH, dd, J=1.5, 6.5Hz), 8.65 (lH, br s) Example 2-2) To a stirred solution of 1-[4-{4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl-4-oxo]-2,4(1H,3H)-quinazolinedione (400 mg) in dry tetrahydrofuran (5 ml) was added lithium aluminum hydride (77 mg) on an ice-bath.
2 ~ L 7 ~
After stirring for 15 minutes, the reaction-mixture was quenched with sa~urated sodium bicarbonate, and diluted with chloroform. After filtration o decomposed materials, the organic filtrate was washed with saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (15 g). Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 1-[4-{4~
chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl~-2,4(lH,3H)-quinazolinedione (25 mg) after crystallization from diethyl ether.
mp : 162-166C
IR (Nujol, v) : 1680, 1600 cm 1 NMR (CDC13, ~ : 1.60-1.90 (4H, m), 2.55-2.70 (4H, m), 2.70-2.85 (2H, m), 3.20-3.30 ¦2H, m), 4.15 (2H, t, J=5Hz~, 6.05-6.15 (lH, m), 7.20-7.40 (6H, m), 7.65 (lH, dt, J=l, 6.5Hz), 8.20 ~lH, dd, J=l, 6.5Hz), 8.45 (lH, br s) Example 3 To a solution o 1-[4-{4-~2-nitrophenyl3piperazin 1-yl}butyl~-2~4(1H,3H)-quinazolinedione (90 mg) in ethanol (8 ml) was added tin(II) chloride (159 mg) at 80C. After stirring for 1 hour at the same temperature, the reaction mixture was quenched with ice and saturated aqueous sodium bicarbonate, and extracted with chloroform. The organic extract was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated to give an amorphous. l-[4-{4-(2-Aminophenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione (31 mg) was obtained by crystallization of the amorphous from diisopropyl ether.
mp : ~ 121C
IR (Nujol, v) : 1680, 160Q cm 1 NMR (CDC13, ~ : 1.60-1.90 (4H, m), 2.45-2.80 (6H, - G3 - 2 ~ 3 3 `-~7 ~
m), 2.85-3.10 (4H, m~, 3.90-4.05 (2H, m), 4.15 (2H, t, J=6Hz), 6.70-6.80 (2H, m), 6.90-7.10 - (2H, m), 7.20-7.40 (2H, m), 7.70 (lH, dt, J=1.6Hz), 8.20 (lH, dd, J=l, 6Hz), 8.60 (lH, br S s) Example 4 A mixture of 2-[N-{4--(4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl}-N-ethoxycarbon~17amino-4-nitrobenzamide (600 mg), and potassium hydroxide (144 mg) in dry ethanol (10 ml) was refluxed for 3 hours. After evaporation of the solvent, the residue was diluted with water, acidified with 3N hydrochloric acid, and extracted with chlorofoxm. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The crude residue was washed with hot ethanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydrop~ridin-1-yl)butyl]-7-nitxo-2,4(1H,3H)-quinazolinedione (450 mg) as a powder.
mp : 242-244C
IR (Nujol, ~) : 1710, 1680 cm 1 NMR (DMSO-d6, ~ : 1.65-1.95 (4H, m), 2.70-2.90 (2H, m), 3.15-4.10 (6H, m), 4.15-4.25 (2H, mj, 6.20 (lH, br s), 7.30-7~55 (5H, m), 8.05 (lH, dd, J=1.5, 6Hz), 8.15 (lH, d, J=1.5Hz~, 8.25 (lH, d, J=6Hz) Example 5 To a stirred suspension-of 1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl~-7-nitro-2,4(1H,3H)-quinazolinedione (840 mg) in dry ethanol (30 ml) was added tin(II) chloride (1.90 g) at 80C. After stirring for 3 hours, the mixture was ~uenched with 2N potassium hydroxide, diluted with chloroform. The organic layer was decanted and the residue was washed with chloroform.
Combined organic layer was dried over magnesium sulfate _ - 64 - 2 ~3 ~ !~ 7 3 and evaporated. l-~4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-amino-2,4(lH,3H)-quinazolinedione hydrochloride ~546 mg) as a crystal was obtained by recrystallization from 10% hydroger. chloride in methanol.
mp : 297-299C
IR ~Nujol, v) : 1680, 1600 cm 1 NMX (DMSO-d6, ~) : 1.60-1.95 (4H, m), 2.65-3.00 ~2H, m), 3.10-3.35 (3H, m), 3.55-4.20 (5H, m), 6.20 (lH, br s), 6.50 (lH, d, J=7Hz), 6.55 (lH, br s), 7.30-7.55 (5H, m), 7.70 (lH, d, J=7Hz) ExamPle 6 A mixture of 1-~4-(4-phenyl-1,2,3,5-tetrahydropyridin-l-yl)butyl]-7-methoxy-2,4tlH,3H)-quinazolinedione (300 mg) and 47% hydrobromic acid (3.8 ml) in acetic acid (6 ml) was refluxed for 24 hours.
After dilution with water, precipitates were collected.
A crude crystalline material was recrystallized from ethanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1 yl)butyl~-7-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide (140 mg'.
mp : 278-280C
IR (Nujol, v) : 1690, 1660, 1600 cm 1 NMR (DMSO-d6, ~) : 1.60-1.90 (4H, ~), 2.75-2.85 (2H, m), 3.20-3.40 (4H, m), 3.65-4.10 (4H, m), 6.15-6.25 (lH, m), 6.70-6.80 (2H, m), 7.35-7.55 (5H, m), 7.85 (lH, d, J=7Hz), 9.60 (lH, br s) Exzmple 7 5-Chloro-1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl]-2,4(1H,3H)-quinazolinedione was obtained in 62.2~ yield in substantially the same manner as that of Example 4.
mp : -238C
35 IR (N~jol, v) : 1690, 1590 cm 1 _ - - 65 - 2~ a NMR (CDC13, ~) : 1.70-2.20 (4H, m), 2.70-3.30 (6H, m), 3.50-3.80 (2H, m), 4.15 (2H, t, J=6Hz), 5.00 (lH, br s), 7.25-7.45 (7H, m), 7.60 (lH, t, J=7Hz) ExamPle 8 A mixture of 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6-nitrobenzamide (300 mg) and N,N'-carbonyldiimidazole (554 mg) in dioxane (3 ml) was stirred for 2 hours at 150C. The solvent was removed during the reaction. The residue was crystallized from a mixture of ethanol and ether. The crude crystalline materials were collected, washed with methylene chloride, and recrystallized from ethanol to afford 1-l4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-5-nitro-2,4~1H,3H)-quinazolinedione l265 mg).
mp : 182C (dec.) IR (Nujol) : 1710, 1680, 1610, 1530 cm 1 NMR ~DMSO-d6, ~) : 1.50-1.5S (4H, m), 2.40-2.55 (2H, m), 2.60-2.70 (2H, m)~ 3.00-3.10 (2H, m), 3.30-3.40 (2H, m), 3.90-4.00 (2H, m), 6.15-S.20 ~lH, m), 6.4Q ~lH, d, J=7Hz), 6.50 ~lH, d, J=7Hz), 7.20-7.50 (8H, m) Example 9 1-l4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)bu~yl]-5-amino-2,4(1H,3H)-quinazolinedione was obtained in substantially the same manner as that of Ex~nple 5.
mp : 204C (dec.) IR (Nujol) : 1680, 1580, 1500 cm 1 NMR (DMSO-d6, ~) : 1.50-1.55 (4H, m), 2.40-2.55 (2H, m), 2.60-2~70 (2H, m), 3.00-3.10 ~2H, m), 3.30-3.40 ~2H, m), 3.90-4.00 (2H, m), 6.15-6.20 (lH, m), 6.40 (lH, d, J=7Hz), 6.50 (lH, d, J=7Hz), 7.20-7.50 (8H, m) - 6~ -Example 10 To a solution of 5-nitro-1-[4-(4-phenyl-1,2,3,6~
tetrahydropyridin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione (500 mg) in a mixture of chloroform (9 ml) and methanol (1 ml) was added 2N solution of sulfuric acid in methanol (1.19 ml) at 0C. After evaporation of the solvent, the crystalline residue was recrystallized from 10% water in ethanol ~30 ml) to give 5-nitro-1-[4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione sulfate (497 mg) as pal.e brown crystals.
mp : 187-188C
IR (Nujol) : 3540, 1700, 1685, 1605 cm 1 NMR (DMSO-d6, ~) : 1.58-1.90 (4H, m), 2.72 (2H, br s), 3.12 (2H, t, J=5Hz), 3.45 (2H, br s), 3.80 (2H, br s), 4.10 (2H, d, J=5Hz), 6.18 (lH, s), 7.28-7.55 (6H, m), 7.73 (lH, d, J=8Hz), 7.91 (lH, t, J=8Hz), 9.50 (lH, br s) The following compounds were obtained in ~0 substantially the same manner as that of Example 1-2).
Example 11-1) 1-r4-{4-(2-Chlorophenyl)piperazin-1-yl}butyl]-2,4(lH,3H)-guinazolinedione mp : 176-178C
IR (Nujol) : 1700, 1680, 1610 cm 1 NMR (CDC13, ~) : 1.50-1.90 (4H, m), 2.50-2.85 (6H, m), 3.00-3.30 (4H, m), 4.15 (2H, t, J=6Hz), 6.90-7.10 (2H, m), 7.15-7~40 (5H, m), 7.70 (lH, dt, J=1, 7Hz), 8.20 (lH, dd, J=1, 7Hz), 8.80 (lH, br s) Example 11-2) 1-[4-{4-(2-Methoxyphenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione - 67 - 2~
mp : ~ 110C
IR (Nujol) : 1670, 1600 cm 1 - NMR (CDC13, ~) . 1.60-2.10 (4H, m), 2~50-2.60 (2H, t, J=5Hz), 2.65-2.80 (4H, m), 3.10-3.25 (4H, m~, 3.90 (3H~ s), 4.15 (2H, t, J=5Hz), 6.85-7.05 (4H, m), 7.20-7.30 (lH, m), 7.35 (lH, dt J=7Hz), 7.70 (lH, dt, J=l, 7Hz), 8.25 (lH, dd, J=l, 7Hz) The following compounds were obtained substantially 10 the same manner as that of Example 1-1).
Example 11-3) 1-[4-{4-(2-Methoxyphenyl)piperazin-l-yl}butyl]-6-methoxy-2,4(lH,3H)-~inazolinedione mp : 198-200C
IR (Nujol) : 1700, 1660, 1580 cm 1 NMR ~CDC13, ~) : 1.60-1.90 (4H, m), 2.50 (2H, t, J=5Hz), 4.15 (2H, t, J=6Hz), 6.85-7.05 (4H, m), 7.25-7.35 (2H, m), 7.65 (lH, d, J=1.5Hz), 8.75 (lH, br s) ~xample_11-4) 1-[4-{4-(2-Chlorophenyl)piperazin-l-yl}butyl]-6-methoxy-2,4~1H,3H)-quinazolinedione mp : 204-206C
IR (Nujol) : 1710, 1660 cm 1 ~MR (CDCl3, ~) : 1.60-1.90 (4H, m), 2.55 (2H, t, J=6Hz), 2.60-2.75 (4H, m), 3.05-3.20 ~4H, m), 3.90 (3H, s), 4.15 (2H, t, J=6Hz), 6.95-7.10 (2H, m), 7.20-7.30 (3H, m), 7.35 (lH, dd, J=l, 7Hz), 7.60-7.70 (lH, m), 8.85 (lH, br 5) Example 11-5) 1-[4-{4-~2-Methoxyphenyl)piperazin-l-yl}butyl]-7-chloro-2,4(1H,3H)-quinazolinedione - 68 - 2~
mp : 190-191C
IR ~Nujol) : 1700, 1680, 1600 cm 1 NMR (CDC13, ~) : 1.60-1.90 ~4H, m~, 2.55 (2H, t, J=5Hz), 2.65-2.80 (4H, m), 3.10-3~20 (4H, m), 3.90 (3H, s), 4.15 (2H, t, J=5Hz~, 6.85-7.05 (4H, m), 7.25 (lH, dd, J=1.~, 7Hz), 7.35 (lH, d, J=1.5Hz), 8~15 (lH, d, J=7Hz) Example 11-6) 1-[4-{4-(2-Chlorophenyl)piperazin-1-yl}butyl]-7-chloro-2,4(lH,3H)-quinazolinedione mp : 174-176C
IR (Nujol) : 1690, 1600 cm 1 NMR (CDC13, ~) : 1.50-1.90 (4H, m), 2.50-2.35 (6H, m), 3.05-3.30 (4H, m), 4.15 (2H, t, J=5Hz), 6.95-7.10 (2H, m), 7.20-7.30 (2H, m), 7.30-7.40 (2H, m), 8.15 (lH, d, J=8Hz), 8.55 (lH, br s) Example 11-7) 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-7-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide mp : 278-280C
Exam~le 11-8) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(lH,3H)-quinazolinedione mp : 182C (dec.) The following compounds were obtained in substantially the same manner as that of Example 2-1).
Example 12-1) 1-[4-{4-~4-Tolyl)-1,2,3,6-tetrahydropyridin 1-yl}-butyl]-2,4(lH,3H)-quinazolinedione 2~a3 l7~
mp : 152-156C
IR (Nujol) : 1710, 1670, 1600 cm 1 -NMR (CDCl3, ~) : 1.70-1.90 54H~ m), 2.3~ (3H, s), 2.55-2.70 (4H, m), 2.75-2.85 (2H, m), 3.20-3.30 (2H, m), 4.15 (2H, t, J=5Hz), 6.00-6.10 ~lH, m), 7.10-7.35 (5EI, m), 7.45 (lH, d, J=7Hz), 7.65 (lH, dt, J=l, 7Hz)~ B.20 (lH, dd, J=l, 7Hz), 8.45 (lH, br s) ExamPle 12-2) 1-~4-{4-(2-Tolyl)piperazin-l-yl}butyl~-2,4(lH,3H)-quinazolinedione mp : 74-85C
IR 5Nujol) : 1700, 1600 cm 1 MMR (CDC13, ~) : 1.60-1.90 ~4H, m), 2.30 (3H, s), 2.50 (2H, t, J=5Hz), 2.60-2.70 (4H, m), 2.95 (4H, t, J=4Hz), 4.15 (2H, t, J=5Hz), 6.95-7.05 (2H, m), 7.10-7.40 (4H, m), 7.70 5lH, dt, J=l, 7Hz), 8.20 (lH, dd, J=1.5, 7Hz), 8.75 (lH, br s) Example 12-3~
1-[4-(4-Phenylpiperazin-l-yl)butyl]-2,4(1H,3H)-quinazolinedione mp : 164-167C --IR (Nujol) : 1710, 1670, 1600 cm 1 NMR (CDCl3, ~) : 1.60-1.90 (4H, m), 2.55 52H, t, J=4Hz3, 2.60-2.75 54H, m), 3.25 (4H, t, J=4Hz), 4.15 ~2H, t, J=6Hz), 6.80-7.00 (3H, m), 7.20-7.40 54H, m), 7.70 (lH, dt, J=l, 7~1z),8.20 (lH, dd, J=l, 7Hz), 8.65 (lH, br s) Example 12-4) l-L4-{4-(2-Ethoxyphenyl)piperazin-l-yl}butyl~-2,4(1H,3H)-quinazolinedione - 2 ~ 7 ~
_ - 70 mp ~ 85C
IR (Nujol) : 1680, 1600 cm 1 NMR (CDC13, ~) : 1.45 ~3H, t, J=6~z), 1.60-1.90 (4H, m), 2.50 (2H, t, J=5Hz), 2065-2.80 (4H, m), 3.10-3.25 ~4H, m~, 4.0Q-4.20 ~4H, m), 6.80-7.00 (4H, m), 7.30 (lH, t, J=7Hz), 7.40 (lH, d, J=7Hz), 7.70 (lH, dt, J=1.5, 7Hæ), 8.20 (lH, dd, J=1.5, 7Hz), 8.75 (lH, br s) xamPle 12-5) 6-Chloro-1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-2,4(lH,3H)-quinazolinedione mp : 159C (dec.) IR (Nujol) : 1680, 1600 cm 1 NMR (CDCl3, ~) : 1.65-1.90 ~4H, m), 2.55-2.70 (4H, m), 2.70-2.85 (2H, m), 3.20-3.30 (2H, m), 4.05-4.20 (2H, m), 6.05-6.15 (lH, m), 7.20-7.45 (6H, m), 7.55 (lH, dd, J=1.5, 8Hz), 8.15 (lH, d, J=l.SHz) Example 12-6) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-7-hydroxy-2,4(lH,3H)-~uinazolinedione hydrobromide mp : 278-280C
~5 Example 12-7) 1-[4-(4-Phenyl-1,2,3r6-tetrahydropyridin-1-y:L)butyl]-5-nitro-2,4(lH,3H)-quinazolinedione mp : 182C (dec.) The following compounds were obtained in substantially the same manner as that oi Example 4.
Example 13-1) 1 [4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-2 53 ~ 3 17 ~
6-ethoxy-2,4l1H,3H)-quinazolinedione mp : 170-172C
IR tNujol) : 1690, 1650, 1580 cm 1 NM~ ~CDCl3, ~) : 1.40 (3H~ t, J-6Hz), 1.65-1.90 (4H, m), 2.55-2.70 (4H, m), 2.70-2.30 (2H, m), 3.15-3.25 t2H, m), 4.00 (2H, q, J=6Hz), 4.15 (2H, t, J=5Hz), 6.05-6.15 (lH, m), 7.15-7.40 (7H, m), 7.60 (lH, d, J=2Hz), 8.60 (lH, br s) ExamPle 13-2) -1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methoxy-2,4(lH,3H)-quinazolinedione mp : 192-194C
IR tNujol) : 1670 cm 1 NMR (CDCl3, ~) : 1.70-1.90 (4H, m), 2.55-2.70 (4H, m), 2.80 ~2H, t, J=4Hz), 3.20-3.30 (2H, m), 3.80 (3H, s), 4.15 (2H, t, J=6Hz), 6.05-6.15 (lH, m), 7.20-7.45 (7H, m), 7.60 (lH, d, J=2Hz), 8.60 (lH, br s) Example 13-3) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-8-chloro-2,4(1~,3H~-quinazolinedione mp : 194-197C
IR (Nujol) : 1680, 1600 cm 1 NMR (DMSO-d6, ~) : 1.60-1.90 (4H, m), 2.60 2.80 (2H, m), 2.90-3075 (6H, m), 4.25-4.40 (2H, m), 6.20 (lH, br s), 7.25-7.50 (6H, m), 7.85 (lH, dd, J=l, 6Hz), 8.05 (lH, dd, J=l, 6Hz) ExamPle 13-4) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-methoxy-2,4(1H,3H)-quinaz~linedione mp : 171-173C
IR (Nujol) : 1690, 1610 cm 1 2 ~
NMR ~DMSO-d6, ~) : 1.70-l.90 ~4H, m), 2.60-2.70 (4H, m), 2.85 ¦2H, t, J=5Hz), 3.25-3.35 (2H, m), 3O85 - (3H, s), 4.10 ~2H, t, J= 5;5Hz), 6.05-6.10 (lH, `~
m), 6.70 llH, d, J=2Hz), 6.80 (lH, dd, J=2, 8Hz), 7.25-7.40 (5H, m), 8.15 (lH, d, J=8Hz), 8.4~ (lH, br s) _ample 13-5) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6,7-dimethoxy-2,4(1H,3H)-quinazolinedione IR (Nujol~ : 1680, 1620 cm 1 NMR (CDC13, ~) : 1.85-2.00 (4H, m), 2.75-2.85 (2H, m), 2.85 2.95 (2H, m), 3.10 (2H, t, J=6Hz), 3.95 (~H, s), 4.05 (3H, s~, 4.20 (2H, t, J=7Hz), 6.00-6.05 (lH, m), 6.70 (lH, s), 7.25-7~40 (5H, m), 7.60 (lH, s) Exam~le 13-6) 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-7-chloro-2,4(lH,3H)-~uinazolinedione mp : 152-154C
IR (Nujol) : 1680, 1600 cm 1 NMR (CDCl3, ~) : 1060-l.90 (4H, m), 2.55-2.70 (4H, m), 2.75-2.85 (2H, t, J=5Hz), 3.20-3.30 (2H, m), 4.15 (2H, t, J-6Hz), 6.05-6.15 (lH, m), 7.20-7.4S (7H, m) "3.15 (lH, d, J=7Hz) Example 13-7) 1-~4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-nitro-2,4(lH,3H) quinazolinedi~ne mp : 194C (dec.) IR (Nujol) : 1710, 1670, 1610 cm 1 NMR (DMSO-d6, ~) : 1.65-1.75 (4H, m), 2.40-2.60 (4H, m), 2.60-2.70 (2H, m), 3.10-3.20 (2H, m), 4.05-4.20 (2H, m), 6.20 (lH, br s), 7.20-7.50 2~3~
(5~, m), 7.80 (lH, d, J=8Hz), 8.40 (lH, dd, J=2, 8Hz), 8.65 ~lH, d, J=2Hz) ExamPle 13-8) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]~
7-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide mp : 278-280C
Example 13-9) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(lH,3H)-quinazolinedione mp : 182c (dec.) The following compounds were obtained in substantially the same mann r as that of Example 6.
Ex~nple 14-1) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide mp : 274-276C
IR ~Nujol) 1570, 1480 cm 1 NMR (DMSO-d6, ~) : 1.60 1.90 (4H, m), 2.75-2.90 (2H, m), 3.20-3.40 (3~, m), 3.60-3.90 (2H, m), 3.90-4.10 (3H, m), 6.20 (lH, br s), 7.20 ~lH, dd, J=2, 8Hz), 7.30-7.55 (7H, m), 9.60 (lH, br s), 9.80 (lH, s) _xample 14-2) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl.)butyl]-6,7-dihydroxy-2,4(1H,3H3-quinazolinedione hydrobromide mp : 280-282C
IR (Nujol) : 3650-3100, 1690, 1660, 1620 cm NMR (DMSO-d6, ~) : 1.60-1.90 (4H, m), 2.75-2.85 (2H, m), 3.20-3.40 (5H, m), 3.60-3.90 (2H, m), 3.90-4.05 (3H, m), 6.20 (lH, br s), 6.80 (lH, -_ 7~ _ 2 J~ 7 5), 7-30-7-55 16H, m), 3.60 (1 or 2H, br s) Example 14-3) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl~butyl]-5-hydroxy-2,4(lH,3H~-quinazolinedione mp : 262-264C
IR ~Nujol) : 1690, 1650, 1620, 1260 cm 1 NMR (CDCl3, ~) : 1.60-1.95 (4H, m), 2.75-2.90 (2H, m), 3.20-4.00 (6H, m), 4.10 (2H, t, J=5Hz), 6.20 (lH, br s), 6.70 (lH, d, J=7Hz), 6.95 (lH, d, J=7Hz), 7.35-7.70 (6H, m) Example 15 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-amino-2,4(lH,3H)-quinazolinedione hydrochloride was obtained in substantially the same manner as that of Example 5.
mp : ~210C
IR (Nujol) : 1680, 1620 cm 1 N~R (DMSO-d6, ~) : 1.60-1.95 (4H, m), 2.70-3~00 (2H, m), 3.00-3.90 (4H, m), 3.90-4.20 (4H, m), 6.20 (lH, br s), 7.30-7.65 (7H, m), 7.85 (lH, d, J=lHz) Example 16-1) 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-(imidazol-1-yl)-2,4(1H,3H)-quinazolinedione was obtained from 2-lN-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butylamino]-6-fluoroben~amide in substantially the same manner as that of Example 8.
mp : 213-215C
IR ~Nujol) : 1700, 1670, 1600, 1490 cm 1 NMR (DMSO-d6, ~) : 1.55-1.80 (4H, m), 2.40-2.60 (2H, m), 2.60-2.70 (2H, m), 3.05-3.20 (2H, m), 3.30-3.55 (2H, m), 4.05-4.20 (2H, m), 6.20 (lH, br s~, 7.00 (lH, s), 7.10-7.20 (lH, m), - ` 75 2 ~ 3 ~
7.20-7.50 ~6H, m), 7.70 (3H, br s) Example 16-2) A mixture of 2-EN-{4-~4-phenyl-1,2,3,6-tetrahydro-pyridin-1-yl)butylamino-6-fluorobenzamide (900 mg), trichloromethyl chloroformate (1.5 ml) and active charcoal (catalytic amounts) in dioxane (20 ml) was stirred for 1 hour at 80C. The solvent was removed in vacuo. The residue was dissolved in 10% hydrogen chloride-methanol, then the solution was filtered. After evaporation of the filtrate, the residue was crystallized from ethanol-ether.
The crude crystals were collected, and washed with hot ethanol to afford 1-[4-l4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl~-5-fluoro-2,4(1H,3H~-quinazolinedione hydrochloride (80 mg).
mp : 276C (dec.) IR (Nujol) : 1680, 1610 cm 1 NMR (DMSO-d6, ~) : 1.60-1.90 (4H, m), 2.70-2.90 ~2H, m), 3.15-4.20 (8H, m), 6.20 (lH, br s), 7.10 (lH, dd, J=7Hz), 7.30-7.60 (6H, m), 7.75 (1~, dt, J=4, 7Hz) The following compounds were obtained in substantially the same manner as that of Example 16-2).
Example 16-3) 1~[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-methoxy-2,4(1H,3H)-quinazolinedione mp : 219-221C
IR ~Nujol) : 1670, 1590, 1260 cm 1 NMR ~CDCl3t ~) : 1.50-1.70 (4H, m), 2.40-2.55 (4H, m), 3.05-3.15 (2H, m), 3.80 ~3H, s), 4.00-4.10 (2H, m), 6.20 (lH, br s), 6.85 (lH, d, J=6Hz), 7.10 (lH, d, J=6Hz), 7.20-7.60 (6H, m) ~ ~ r /~ r~, ~
Example 16-4) 1-14-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-5-methyl-2,4(lH,3H)-quinazolinedione mp : 175-177C
IR (Nujol) : 1680, 1590, 1430 cm 1 NMR (CDCl3, ~) : 1.70-2.00 (4H, m), 2.55-2.70 (4H, m), 2.70-2.85 (5H, m), 3.20-3.30 (2H, m), 4.15 (2H, t, J=5Hz), 6.05-6.15 (lH, m), 7.00 (lH, d, J=7Hz), 7.20-7.50 (7H, m) Example 16-5) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4l1H,3H)-quinazolinedione mp : 182~C (dec.) Example 17 A mixture of 1-l4-(4-phenyl-1,2,3,6-tetrahydro-pyridin-1-yl)butyl]-7-amino-2,4(lH,3H)-quinazolinedione hydrochloride (70 mg~, methanesulfonyl chloride (0.02 ml) potassium carbonate t50 mg~ in dimethylformamide (1 ml) was stirred for 2 hours at room temperature. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated.
The crude residue was washed with hot ethanol, then treated with 10~ hydrogen chloride-methanol, and evaporated.1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-7-methanesulfonylamino-2,4(lH,3H)-quinazolinedione hydrochloride (18 mg) as a crystal was obtained by recrystallization from ethanol.
mp : 254C (dec.) IR tNuiol) : 1680, 1610, 1590 cm NMR (DMSO-d6, ~) : 1.65-2.05 (4H, m), 2.70-2.90 (2H, m), 3.15-3.50 (5H, m), 3.60-4.15 (6H, m), 6. 0 (lH, br s), 7.45-7.55 (5H, ~), 7.95 (lH, br s), 8.05 (lH, d, J=8Hz), 9.05-9.20 (lH, m)
.~nocher object of the present invention is to provide processes for the preparation of novel quinazoline derivatives and salts thereof.
~ further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said quinazoline derivatives and pharmaceutically acceptable salts thereof.
Still further object of the present invention is to provide a use of said quinazoline derivatives and pharmaceutically acceptable salts thereof as a dopamine receptor agonist and a metho~ of the therapeutic treatment of dopamine receptor mediated diseases, particularly hypertension, cardiovascular disorder (e.g. angina pectoris, myocardial infarction, etc.), Parkinsonism, and the like, in a human being or animal.
The object quinazoline derivatives are novel and can be represented by the following general formula:
Rl o 2 5 ~il`~ ~N ~o --R I (I) in which Rl and R2 are each hydrogen, halogen, nitro, amino, ~rotected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substit~ent(s), A is lowe~ alkylene, and the formula: NJ is N-containing heterocyclic grou~, and pharmaceutically acceptable salts thereoE.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base such as an inorganic base salt, for example, an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g.
calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt, for example, an organic amine salt ~e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); a salt with an acid such as inorganic acid addition salt (e.g.
hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid , glutamic acid, etc.~; and the like. ---According to the present invention, the objectcompound (I) or pharmaceutically acceptable salts thereof can be prepared by the processes as illustrated by the following reaction schemes.
_ _ 4 ~ 7~
Process 1 : ~
~N --7L R
R1 O (III) R1 O
~ ~ ~NH ~ ~ NH
~ or salts R? ~ ~ N ~\~thereof ~ ~ N~o A - OH A-~ ~ - R
(II) (I) ~~~~
10 or its reactive derivative or salts thereof at the hydroxy group, or salts thereof Process 2 :
Reduction of Rl O the amido R1 O
20 R ~1 ~ O glO~p ~^ ¢ J NH
A1-co_N ~ R3 A-N ~ R3 (IV) (I) or salts thereof or salts thereof Process 3 :
Reduction of R1 O the nitro R1 O
~ g~L ~Up in R~ ~ ~ N~
R ~ N ~ R~ ~ I ~ 3 A-N ~ Ra A-N ~ -- R~
~I-a) (I-b) or salts thereof or salts thereo-f ~ ~53 ~7 ~
P~ocess 4 :
RZ~ R4 3 -/~Nl\o A-N~ R A-N~- R
~V) ( I ) or salts thereof or salts thereof Process 5 :
H Rydrolysis \ ~ NH
A-N~ R3 (I-c) (I-d) ~r salts thereof or salts thereof 25 Process 6 : -Reduction of Rl O nitro group(s) Rd c I Rd ~ ~ I r A-N~ R A-N~- R
(I-e) (I-f) 35 or salts thereof or salts thereof - 2~5~
o Process 7 :
R O xl Rl O
~ ~ x2 ~ ~ N~
R2 ~ N~ (Xl) ~ N ~o A-N ~ R A-N ~ R3 10(VIII) !I!
or salts thereof or salts thereof Process 8 :
Introduction of Re ` amino-protective Rf o J ~ ~I~\N~l R A-~ ~ R3 Rf A-N ~ R3 ~I-g) (I-h) or salts thereof or salts thereof wherein Rl, R2, R3, A and the formula :
- N ~ are each a~ defined above, one of Ra and Ra is lower alkoxy while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imida~olyl, one of Rb and Rb is hydroxy while the other is hydrogen, halogen, nitro, ami.no, protected 2 ~ ~ 3 ~ 7 3 am.ino, hydroxyamino, lower alkoxy, lower alXyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of Rc and Rc is nitro while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylth.io or imidazolyl, one of R1 and Rd is hydroxyamino or amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of Re and Re is amino while the other is hydrog~n, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, s.ulfamoyl, carboxy, protected carboxy, carbamoyl, mercap~o, lower alkylthio or imidazolyl, one of R1 and R2 is protected amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazoly', Ra is aryl substituted by nitro, 3Q Rb is aryl substituted by amino, R4 is esterified carboxy, A1 is Cl-C5 alkylene, and X and X are each a leaving group.
The starting compounds used in the Processes may be - ~- 2~3~7~
new and can be prepared, for example, by the following methods or a conventional manner.
Method A :
Rl O Rl O
Reduction ~ ~ N
A -COOH A-OH
(VI) (II) or salts thereof or salts thereof Method B :
~- ~ 3 HN ~ R
Rl O ~_~ Rl O
~ ~ ~III) ~ ~ NH
2 ~ N ~ O or salts 2 ~ N~o R ~ thereof R
A -COOH A -CO-N ~ R3 (VI) (IV) or its react.ive derivativeor salts thereof at the carboxy group, or salts thereof g 2853~5 Method C :
R \ O R1 0 2 ~ N R ~nide.tion ~ N42 A-N ~ R A-N~ R3 (VII ) ~~ ~v~ ~J
or its reactive derivative or salts thereof at the carboxy group, or salts thereof Method D :
"/ N-R ~IX) ~J ` -~
2 R2 ! ~-~ R2 A-N ~ R A-N -~ R3 (VII) ~x) ~
or its reactive derivative at or salts thereof the carboxy group, or salts thereof Method E :
; or its reactive ~ ~ NH2 2 ~N~o equivalent, 2 ~ NH
R ~ or its salt R
A-N ~ R A-N--~- R3 (X) (VIII ~
35or salts thereof or salts ihereof o 2~ 7~
i hi h R1 R2 R3 R4 A, A1 and the formula : -N
are each as defined above, and X is a leaving group.
Some of the starting materials of the above Methods are new and can be prepared, for example, according to the method of Preparation as mentioned below, or by a conventional manner.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.
The term "lower" is intended to me~n 1 to 6, preferably 1 to 4 carbon atom(s~, unless otherwise indicated.
Suitable "lower alkyl" may include straight or branched one such as me~hyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, and the like, in which the most preferable example may be methyl.
Suitable "lower alkoxy" may include straight-or branched one such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, and the like, in which the most preferable example may be methoxy and ethoxy for Rl and/or R2 and methoxy, ethoxy and propoxy for the subs~ituent(s) in R3.
Suitable "aryl wh.ich may have suitable substi-tuent(s)" may include phenyl, tolyl, xylyl, cumenyl, mesithyl, naphthyl, and the like, each of which may be substituted by one or more, preferably one to three, more 2 ~ 7 ~
. 1 preferably one or two substituent(s) such as halogen (e.g.
fluorine, chlorine, bromine, iodine), lower alkyl as mentioned above (e.g. methyl, etc.), lower alkoxy as mentioned above (e.g. methoxy, ethoxy, propoxy, etc.), amino, nitro, and the like, in which more preferred example may be phenyl which is subs~ituted or unsubstituted by a group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro and amino, and the most preferred one may be phenyl, 2-(or 4-)tolyl, 2-(or 4-)-chlorophenyl, 2-methoxyphenyl, 2-ethoxyphenyl, 2-propoxyphenyl, 2-nitrophenyl and 2-aminophenyl.
Suitable "aryl substituted by nitro" and "aryl substituted by amino" means a~orementioned "aryl which may have suitable substituent(s)", in which said aryl is substituted by nitro and amino res~ectively.
Suitable "protected carboxy" may include esterified carboxy wherein "esterified carboxy" can be referred to the ones as mentioned below.
Suitable examples of the ester moiety of an esterified carboxy may be the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, etc.) which may have at least one suitable substituent(s), for example, lower alkanoyloxy(lower)alkyl ester [e.g. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-(or 2-)acetoxyethyl ester, 1-(or 2- or 3-)acetoxypropyl ester, 1-~or 2- or 3- or 4-)acetoxybutyl ester, 1-(or 2-)propionyloxyethyl ester, 1-(or 2- or 3-)propionyloxypropyl ester, 1-(or 2-)butyryl-oxyethyl ester, 1-(or 2-)isobutyryloxyethyl ester, 1-~or 2-)pyvaloyloxyethyl ester, 1-(or 2-)hexanoyloxyethyl 2~3 -~7~
- 1? -ester. isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1-~or 2-)pentanoyloxyethyl ester, etc.], lower alkanesulfonyl(lower~alkyl ester te.g. 2-mesylethyl ester, etc.), mono(or di or tri)halo(lower)alkyl ester (e.g.
2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc~);
lower alkoxycarbonyloxy(lower)alkyl ester [e.g.
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxy-carbonyloxymethyl ester, 1-(or 2-)methoxycarbonyloxyethyl ester, 1-~or 2-)ethoxycarbonyloxyethyl ester, 1-~or 2-) isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene-(lower)alkyl ester, or (5-lower alkyl-2-oxo-1,3-di-oxol-4-yl)~lower)alkyl ester [e.g. (5-methyl-2-oxo-1,3-di-oxol-4-yl)methyl ester, ~5-ethyl-2 oxo-1,3-dioxol-4-yl)-methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester, etc.]; lower al~enyl ester (e.g. vinyl ester, allyl es~er, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); ar(lower)alkyl ester ~e.g. mono- or di- or triphenyl(lower)alkyl ester, etc.] which may have at least one suitable substituent(s) (e.g. lower alkoxy, nitro, hydroxy, lower al~yl, etc.), for example, mono- or di- or triphenyl~C1-C4)alkyl ester which may have (C1-C4)alkoxy [e.g. benzyl ester, benzhydryl ester, trityl ester, phenethyl ester, 4-methoxybenzyl ester, --3,4-dimethoxybenzyl ester, bis(methoxyphenyl)methyl ester, etc.], nitrophenyl(Cl-C4)alkyl ester (e.g. 4-nitrobenzyl ester, etc.), [hydroxy]-(C1-C4)alkylphenyl(C1-C~)alkyl ester (e.g. 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.);
aryl ester which may have at least one suitable sub~tituent(s) (e.g. phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); phthalidyl ester; and the like.
3~ More preferable example of the protected carboxy thus 2~3~73 ue~ined may ~e C1-C4 alkoxycarbonyl and the most pre~erable one may be methoxycarbonyl.
Suitable "esteri~ied carboxy" may be the same one as mentioned in the explanation of "protected carbox~" in which the most preferred example may be ethoxycarbonyl.
Suitable "protected amino" may include amino protected by a conventional amino-protective group as mentioned below.
Suitable "amino-protective group" may include acyl such as carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with aromatic or heterocyclic group(s) derived from carboxylic, carbonic, sulfonic and carbamic acids.
The aliphatic acyl may include saturated or unsaturated, acyclic or cyclic ones, for example, alkanoyl such as lower alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.), alkylsulfonyl such as lower alkylsulfonyl (e.g. mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, bu~y~sulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc.), carbamoyl, N-alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, etc.), alkoxycarbonyl such as lower alkoxycarbonyl (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.), alkenyloxycarbonyl such as lower alkenyloxycarbonyl (e.g.
vinyloxycarbonyl, allyloxycarbonyl, etc.), alkenoyl such as lower alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.), cycloalkanecarbonyl such as cyclo(lower)alkanecarbonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.), and the like.
The aliphatic acyl substituted with aromatic group(s) may include aralkoxycarbonyl such as phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl, -~ - 14 - 2~5~7~
phenethyloxycarbonyl, etc.), and the like.
These acyl groups may be further substituted with one or more suitable substituent(s) such as nitro, and the like, and preferable acyl having such substituent(s) may be nitroar(lower)alkoxycarbonyl~e.g.
nitrobenzyloxycarbonyl, etc.), and the like.
More preFerable example of amino-protective group may be aliphatic acyl such as lower alkylsulfcnyl and the most preferable one may be methanesulfonyl.
More preferable example of protected amino thus defined may be aliphatic acylamino such as lower alkylsulfonylamino and the most preferable one may be methanesulfonylamino.
Suitable '7halogen" may be fluorine, chlorine, bromine, iodine, and more preferred example may be chlorine and fluorine.
Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene~ ethylethylene, propylene, and the like, in which more preferred example may be Cl-C4 alkylene and the most preferred one may be tetramethylene.
Suitable "Cl-C5 alkylene" means aforementioned "lower alkylene" except for C6 alkylene, in which more preferred example may be Cl-C4 alkylene and the most preferred one may be trimethylene.
Suitable "leaving group" may include imidazole, lower alkylimidazole (e.g. 2-methylimidazole, etc.), an acid residue such as halogen as mentioned above (e.g. chlorine, _ - - 15 - 2 ~ i 3 !~ 7 ~
etc.), sulfonyloxy (e.g. m~sy:oxy, tosyloxy, etc.), trihalo(lower)alkyloxy (e.g. trichloromethoxy, etc.) and ~he like.
Suitable 'lower alkylthio" may include straight or branched one such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, t-butylthio, pentylthio, hexylthio, and the like.
Suitable "N-containing heterocyclic group'l means saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one nitrogen atom and optionally other hetero-atom(s) such as an oxygen, sulfur, nitrogen atom and the like, and said heterocyclic group is attached to A at the ring nitrogen atom.
Preferable N-containing heterocyclic group may be :
-unsaturated 3 to 8-membered, prefercbly 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrol-1-yl, pyrrolin-1-yl, imidazol-1-yl, pyrazol-1-yl, tetrahydropyridyl (e.g.
1,~,3,6-tetrahydropyridin-1-yl, etc.), triazolyl, (e.g.
4H-1,2,4-triazol-4-yl, lH-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, etc.), tetrazolyl (e.g.
lH-tetrazol-1-yl, 2H-tetrazol-2-yl, etc.), dihydrotriazinyl (e.g. 4,5-dihydro-1,2, -t ~zin-4-yl, 2,5 dihydro-1,2,4-triazin-2-yl, etc.), etc.;
-saturated 3 to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azetidin-1-yl, pyrrolidin-1-yl, imidazolidin-1-(or 3-)yl, piperidin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, etc.;
-unsaturated 3 to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and l to 3 nitrogen atom(s), for example, oxazinyl (e.g. 4H-1,4-oxazin-4-yl, etc.), oxadiazinyl (e.g. 4H-1,2,4-oxadiazin-4-yl, etc.), ~ 16 - 2~47~
-saturated 3 to 8-membered, preferably 5- or 6-membered heteromonocyclic group containing l to 2 oxygen atom(s) and l to 3 nitrogen atom(s), for example, morpholin-4-yl, etc.;
-unsaturated 3 to 8-membered, preferably ;- or 6-membered heteromonocyclic ~ntaining l to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolinyl (e.g. 1,3-thiazolin-3-yl, 1,2-thiazolin-2-yl, etc ), ~tc.
-saturated 3 to 3-membered, preferably 5- ~r 6-membered heteromonocyclic group containing l to 2 sulfur atom(s) and l to 3 nitrogen atoms(s), for example, ,hiazolidinyl e.g. 1,3-thiazolidin-1,2-thiazolidin-2-yl, etc.l, etc.;
wherein more preferred example may be saturated or unsaturated 5- or 6-mem~ered heteromonocyclic group containing l to 4 nitrogen atom(s), and the most preferable one may be piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl.
2~
Preferable embodiments of R1, R2, R3, ~ and the formula -N~ are as follows :
Rl and R2 are each hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto or ower alkylthio, R3 is aryl which may have suitable substituent(s), r~
A is lower alkylene, and the formula : -N ~ is N-containing heterocyclic group.
Further, preferable embodiments of R1, R2, R3, A and the formula -N ~ are as follows :
- 2 ~ ~ 3 ~
R1 and R2 are each hydrogen, halogen, nitro, amino, acylamino such as lower alkylsulfonyl (e.g.
methylsulfonyl, ethylsulfonyl, etc.), hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, esterified carboxy such as lower alkoxycarbonyl, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is phenyl which is substituted or unsubstituted by one to three substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro and amino, A is lower alkylene, and the formula -N ~ is saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) such as piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl, and the like.
The processes for the prepa ation of the object compound (I) of the present invention are explained in detail in the following.
(1) Process 1 :
The compound (I) or salts thereof can be prepared by reacting the compound (II) or its reactive derivative at 2~ the hydroxy group, or salts thereof with the compound (III).
Suitable salts of the compound (II) may be the same as those for the compound (I).
Suitable salts of the compound (III) may be the same acid addition salts such as those given for the compound ~I).
Suitable reactive derivative at the hydroxy group of the compound (II) may include halide (e.g. chloride, ~ - 18 ~ 3~7~
bromide, iodide, etc.), sulfonate (e.g. methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.), and the like.
This reaction is usually carried out in the presence s of an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.~. magnesium hy~roxide, calcium hydroxide, etc.~, alkali metal hydride (e.g.
sodium hydride, potassium hydride, etc.), alkaliTIe earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.~, etc; an organic base such as trimethylamine, triethylamine, dicyclohe~ylamine, pyridine, picoline, lutidine, N-ethyl-N,N-diisopropylamine, etc.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof. -The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(2) Process 2 :
The compound (I) or salts thereof can be prepared by reducing the amido mo:iety of the compound ~IV) or salts thereof.
- 19 - 2 ~
Suitable salts of the eompound (IV) may be the same as those for the compound (I).
The reduetion method applieable for this removal reaction may inelude a eonventional one whieh is eapable of eonverting the amido group into the aminomethyl group, for example, reduetion by using a eombination of a metal (e.g. zine, zine amalgam, etc.) or a salt of chrome compound (e.g. ehromous ehloride, ehromous aeetate, ete.) and an organic or inorganie acid te.g. aeetie acid, propionie aeid, hydroehlorie aeid, sulfurie aeid, etc.); a conventional catalytic reduetion in the presenee of a eonventional metallie eatalyst sueh as palladium eatalysts (e.g. spon~y palladium, palladium blaek, palladium oxide, palladium on earbon, eolloidal palladium, palladium on barium sulfate, palladium on barium earbonate, palladium hydroxide on earbon, ete.), nickel c2talysts (e.g. redueed nickel, nickel oxide, Raney niekel, ete.), platinum eatalysts (e.g. platinum plate, spongy platinum, platinum blaek, eolloidal platinum, platinum oxide, platinum wire, ete.); lithium aluminum hydride; sodium borohydride, a combination of tri(lower)alkylborane and sodium borohydride; borane, diborane, a eombination of sodium borohydride and borone trifluoride; and the like, in whieh more preferable method is lithium aluminum hydride, borane, diborane, and a eombination of sodium borohydride and borone trifluoride.
This reaetion is usually carried out in a eonventional solvent whieh does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, aeetate buffer, ete.), and the like, or a mixture thereof.
- 20 2~3~
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
(3) Process 3 :
The compound (I-b) or salts thereof can be prepared by subjecting the compound (I-a) or salts thereof to a reduction of the nitro group in R3.
Suitable salts of the compounds ~I-a) and (I-b) may be the same as those for the compound (I).
'The present reaction is usually carried out by a conventional method as mentioned below.
Reduction method:
The reduction method applicable for this reaction may include convantional ones which are capable of converting a nitro group to a hydrox~amino or amino group, for example, reduction using tin(II) chloride or zinc powder;
reduction using a combination of a metal ~e.g. zinc, zinc amalgam, etc.) or a salt of chrome compound (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.); conventional catalytic reduction in the presence of a conventional metallic cataly~st such as palladium catalysts (e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, palladium hydroxide on carbon, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.);
reduction using aluminum am,?lgam; electrolytic reduction;
-- - 2 ~3 ~ 7 ~
and the like.
In case that the catalytic reduction is applied, the reaction is preferably carried out around neutral condition.
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, alcohol (e.g. methanol, ethanol, propanol, etc.), dioxane, tetrahydrofuran, acetic acid, buffer solution (e.g. phosphate buffer, acetate buffer, etc.), and the like, or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(4) Process 4 :
The compound (I) or salts thereof can be prepared by reacting the compound ~V) or salts thereof with a base.
Suitable salts of the compound (~II) may be the same as those for the compound (I).
Suitable base used in this reaction may be the-same ones as mentioned in Process 5.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as alcohol (e.g. methanol, ethanol, etc.), dichloromethane, pyridine, N,N~dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereo~.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
~ 22 - 2 ~ 7 ~
~) Process 5 :
The compoun~ ~I-d) or salts thereof can be prepared by hydrolyzing the compound (I-c) or salts thereof.
5Suitable salts of the compounds (I-c) and (I-d) may be the same as those for the compound (I).
The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable base may include an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g. sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide (e.g.
sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), and alkaline earth metal car~onate le.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), and the like.
Suitable acid may include an organic acid (e.g.
~ormic acid, acetic acid, propionic acid, trifluoroacetic acid, ~enzenesulfonic acid, p-toluenesulfonic acid, etc.) and an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.~. The acidic hydrolysis using trifluoroacetic acid is usually accelerated by addition of cation trapping agent (e.g.
phenol, anisole, etc.).
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g.
methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof. A liquid base or acid _ - - 23 - 2~3-~7~
can be also used as the solvent.
- The reaction temperature is not critical and the reaction is usually carried out under from cooling to heating.
(6) Process 6 :
The compound (I-f) or salts thereof can be prepared by subjecting the compound (I-e) or salts thereof to a reduction of the nitro group(s) of Rc and/or Rc.
Suitable salts of the compounds (I-e) and ~I-f) may be the same as those for the compound (I).
The method of reduction and the reaction conditions (eOg. reaction temperature, solvent, etc.) are substantially the same as those illustrated in Process 3, and thexefore are to be referred to said explanation.
(7) Proce~s 7 :
The compound (I) or salts thereof can be prepared by reacting the compound (VIII) or salts thereof with the compound (XI).
Suitable salts of the compound (VIII) may be the same as those for the compound tI).
This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, dichloromethane, alcohol (e.g.
methanol, ethanol, etc.), tetrahydrofuran, dioxane, acetone, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried Ollt under from warming to heating.
~~ ~ - 24 - 2 ~ ~ 3 ~ 7 t3 In this reaction, when at least one of R and R is halogen and the compound ~XI) is carbonyldiimidazole, at least one of R1 and R2 may be converted into imidazol-l~yl group in the ob~ect compound (I~ during the reaction.
(8) Process 8 :
The compound (I-h) or salts thereof can be prepared by introducing an amino-protective group into the compound (I-g) or salts thereof.
Suitable salts of the compounds (I-g) and (I-h) may be the same as those for the compound (I).
Suitable introducing agent of an amino-protective group is a conventional one such as an acylating agent of an amino group such as an organic carboxylic, carbonic, sulfonic and carbamic acid or its conver.tional reactive derivatives.
This reaction is usually carried out in the presence of an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide) potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g.
sodium hydride, potassium hydride, etc.), alkaline-earth metal hydride te.g. calcium hydride, etc.), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc ), an alkali metal caxbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), an alkali metal bicaxbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), etc; an organic base such as trimethylamine, triethylamine, dicyclohexylamine, pyridine, picoline, lutidine, N-ethyl-N,N-diisopropylamine, etc.
~ ` ` ~5 2 ~
Further, this reaction can be carried out in the presence of a conventional condensing agent used for a so-called "acylation", when the introducing agent of an amino-protective group is in a free acid form.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warmlng The object compounds obtained according to the above Processes can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
Methods for preparing the new starting compound or salts thereof used in the above processes are explained in detail in the following.
(A) Method A :
The compound (II~ or salts thereof can be prepared by reducing the compound (VI) or salts thereof.
Suitable salts of the compound (VI) may be the same as those for the compound (I).
The method of reduction and the reaction conditions (e.g. reaction temperature, solvent, etc.) are substantially the same as those illustrated in Process 2, 2 ~ ~ 3 ~ ~ ~
- _6 which are capable o converting the carboxy group into the hydroxymethyl group, and therefore are to be referred to said explanation.
(B) Method B :
The compound (IV) or salts thereof can be prepared by reacting the compound (VI) or its reactive derivative at the carboxy group, or salts thereof with the compound (III).
Suitable reactive derivative at the carboxy group of the compound (VI) may include acid halide (e.g. acid chloride, acid bromlde, acid iodide, etc.), an acid anhydride, an activated amide, an activated ester, and the like. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with acid such as substituted phosphoric acid Ee.g.
dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.~, dialkyiphosphorous acid, sulfurous acid; thiosulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e~g. succinimido ester, cyanomethyl ester, methoxymethyl ester, dimethyliminiomethyl r(CH3)2~=CH_]
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl _ - - 27 - 2~ 7 S
thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.~, or an ester with a N-hydroxy comp~und ~e.g. N,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, l-hydroxy-lH-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected among them according to the kind of the compound (VI) to be used.
This reaction is usually carried out in the presence of an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide, pGtassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal hydride (e.g.
sodium hydride, potassium hydride, etc.), alkaline earth metal hydride (e.g. calcium hydride, etc.), alkali metal alkoxide ~e.g. sodium methoxide, sQdium ethoxide, potassium t-butoxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbon~te, calcium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), etc; an organic base such as trimethylamine, triethylamine, dicyclohexylamine, pyridine, picoline, lutidine, N ethyl-N,N-diisopropylamine; etc.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
~ 8 - 2 Q ~ 3 ~ '7 a (C) Method C :
The compound (V) or salts thereof can be prepared by amidating the compound (VII) or its reactive derivative at the carboxy group, or salts thereof.
Suitable reactive derivative at the carboxy group of the compound ~VII) may be the same ones as mentioned in Method B.
Suitable amidating agent used in this reaction may include a conventional one which is capable of converting the carboxy group into the amido group such as ammonia or acid addition salts thereof (e.g. ammonium chloride, etc.), and the like.
This reaction can be carried out in the presence of a such base as mentioned in Method C.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, acetonitrile, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
(D) Method D :
The compound (X) or salts thereof can be prepared by reacting the compound (VII) or its reactive derivative at the carboxy group, or salts thereof with the compound (IX).
Suitable salts of the compound (X) may be the same as those for the compo~md (I).
~ 29 - ~ ~ 3 ~
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamlde, 4-methyl-2-pentanone, tetrahydrofuran, etc., or a mixture 5 thereof.
The reaction temperature is not critical and the reaction is usually carried out under from warming to heating.
(E) Method E :
The compound (VIII) or salts thereof can be prepared by reacting the compound (X) or salts thereof with ~nonia or its reactive equivalent, or its salt.
Suitable reactive equivalent of ammonia may be a conventional one and include ammonium hydroxide, and the like.
Suitable salt of ammonia may be acid addition salt such as ammonium chloride, and the like.
This reaction can be carried out in a conventional solvent which does not adversely influence the reaction such as dichloromethane, pyridine, N,N-dimethylformamide, 4-methyl-2-pentanone, tetrahydrofuran, acetonitrile, etc., or a mixture thereof.
The reaction temperature is not critical and the reaction is usually carried out under from cooling to warming.
The object ~uinazoline derivatives (I) stimulate presynaptic(neuronal) and/or postsynaptic(vascular) dopamine receptors that mediate inhibition of neurogenic release of catecholamine and~or dilatation of rena vasculature and remission of parkinsonism, respectively.
Quinazoline derivatives (I) effect on the cardiovascular _ - 30 _ 2 0 ~ ~ 1 7 ~
system as a consequence of its interaction with dopaminergic and adrener~ic receptors.
The object compound (I) and pharmaceutically acceptable salts thereof of the present invention are novel and display dopamine receptor stimulating effects;
5-HT receptor antagonism, especially 5-HT2 receptor antagonism; a1 receptor antagonism; and the like, and are useful as a dopamine receptor agonist; 5-HT receptor antagonist, especially 5-HT2 receptor antagonist;
a1 receptor antagonist; and the like, for treating or preventing hypertension such as renal hypertension and other cardiovascular disorders (e.g. angina pectoris, congestive heart failure, myocardial infarction, etc.);
Parkinsonism; hyperprolactinemia; disorders of peripheral perfusion such as Raynaud's phenomenon, Burger's diseases, and intermittent claudicatio~; thrombotic and/or smooth muscle cell p~oliferative disease such as restenosis after percutaneous transluminal coronary angioplasty;
hypercholesterolemia, hyperlipemia; urinary disturvance;
and the like.
The compound (I) and pharmaceutically acceptable salts thereof may be also useful as an adrenolytic, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, hypoglycemic anti-viral, or blood flow increasing agent.
Now in order to show the utility of the object compound (I) and pharmaceutically acceptable salts, the test data on dopamine receptor stimulating effects of the representative compound of the compound (I) of this invention are shown in the following.
~ - 31 - 2~3-~7~
Test 1 ~Dopamine receptor (DA2 receptor) binding assay]
Test Method l :
The afflnity for DA2 receptor of a Test Compound was determined following in vitro receptor binding assays.
Male rats weighing 150-300g were decapitated and the stratum were dissected from their brains. The tissue was homogenized in 30 volumes of buffer which consisted of 50 mM Tris-HCl (pH 7.4 at 25C), 120 mM sodium-chloride, 5 mM
potassium chloride, l mM calcium chloride, l mM magnesium chloride, lO ~M pargirine, and 0.1% ascorbic acid. The homogenate was centrifuged at 50,000 g for 15 minutes.
The pellet was resuspended in 30 volumes of the buffer.
The tissue suspension was centrifugPd and suspended again in the same way.
Incubation tubes received 100 ~l of [phenyl-4- H~spiperone, lO0 ~l of the Test Compound and 0.8 ml of tissue suspension during binding assays. The concentration of rphenyl-4- H]spiperone was 0.2 nM. The final tissue concentration of rat striatum was 160 ~g/ml.
The tubes were incubated at 37C for lO minutes, and then filtered under vacuum through Whatman GF/B filters and washed three times with 3 ml of ice-cold buffer. The filters were counted by liquid scintillation counter.
Specific binding of the ~3H]spiperone was determined in the presence of 1 ~M butacl~mol. The IC50 value of the Test Compound was calculated from the data of [3H]spiperone binding in the presence of lO 9M, lO 8M, lO 7M and lO 6M Test Compound.
Test Compound Compound A ~The product of Example 6]
- ~2 - 2~17~
Test Result 1 :
~ Test Compound IC50 (M) . . . _ Compound A 7.4 x 10 9 Test 2 [Inhibition of reserpine-induced DOPA
accumulation]
Test Method 2 :
Male SD rats weighing 300-400 g were used in this test. Rats were pretreated with reserpine (1 mg/kg, S.C.) 17-19 hours before sacrifice and then fasted. Test Compound was given orally to the rats 2 hours before sacrifice. ~m-Hydro~ybenzylhydrazine (100 mg/kg, i.p.) was given 30 minutes before sacrifice.] Each rat was exposed to microwaves using a head-focus microwave applicator for 1.5 seconds. The whole brain was removed and further separated into the striatum.
DOPA was determined as follows; the striatum was homogenized in 9 volumes of 0.lN perchloric acid solution t0.4% EDTA-2Na). The homogenate was centrifuged at 10,000 rpm for 1 minutes. The supernatant was applied to high performance liquid chromatography.
Test Result 2 ~Test Compound ¦ dose ~ Inhibition (~) .
Test 3 [Hypotensive effect on spontaneous hypertensive rats]
~ - 33 2 ~ 3~ ' 7 ~
Test Method 3 :
15 to 25-Week-old male spontaneous hypertensive rats with mean arterial blood pressure of about 160-200 m~Hg, weighing 300-350 g, were used. The animals were 5 cannulated in the left femoral artery and the mean blood pressure and heart rate were measured with a pressure-transducer. The animals were deprived of food for about 18 hours before oral dosing. The Test Compound was suspended in 0.5% methylcellulosP, and given orally.
Test Result 3 :
The maximum decrease of blood pressure (%) is shown in Table.
15~ p ~ (mg/kg) blood pressure (~) 20For therapeutic administration, the object compound (I~ and the pharmaceutically acceptable salts thereof of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with pharmaceutically acceptable carriers such as an organic or inorganic solid or li~uid excipient which is suitable for oral, parenteral and external administration.
The pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid Form suc~
as solution, suspension, syrup, emulsion, lemonade, and the like.
If needed, there may be included in the above preparations auxiliary substances, stabilizing agents, wetting agents and other commonly used additives such as -2 ~ 7 ~
lactose, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, and the like.
While the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases, a kind of the compound (I) to be applied, etc. In general, amount between about O.OOl mg and about 300 mg, preferably about O.l mg to about 50 mg per day may be administered to a patient. An average single dose of about O.OOl mg, O.Ol mg, 0.03 mg, O.l mg, 0.3 mg, 0.6 mg, l.0 mg, 3.0 mg, lO.0 mg, 50.0 mg, lO0.0 mg, of the object compound (I) of the present invention may be used as adrenolytic, hypotensive, cardiovascular, tranquilizer, sedative, anti-emetic, hypothermic, skeletal muscle relaxant, anti-inflammatory, and anti-viral agents.
The following Preparations and Examples are given for the purpose of illustrating this invention i~ more detail.
Preparation l l) A mixture of 2,4(lH,3H)-quinazolinedione (l.62 g), 1,1,1,3,3,3-hexamethyldisilazane (3.54 g) and ammonium sul~ate (160 mg) in toluene (5 ml) was refluxed for 3 hours. Af~er toluene and excess l,l,l,3,3,3-hexamethyl-disilazane were evaporated in vacuo, ethyl 4-bromocrotonate (3.84 g) was added thereto. The mixture was heated to 120C. After 3 hours, the reaction mixture was cooled below 100C, and ethanol was added.
Crystallized materials were collected and washed with ethanol to give l-(3-ethoxycarbonyl-2-propenyl)-2,4-(lH,3H)-quinazolinedione (l.95 g).
NMR (CDCl3, ~) : 1.25 (3H, t, J=6Hz), 4.20 (2H, q, J=6Hz), 4.90 (2H, dd, J=2, 3Hz), 5.90 (lH, td, - 35 - 2 ~
J=1.5, 13Hz), 6.95-7.10 (2H, m), 7.Z5-7.35 (lH, m), 7.70 (lH, ~t, J=1.5, 7Hz), 8.25 (lH, dd, - J=l, 7Hz), 9.00 (lH, br s) Preparation 1-2) To a solution of 1-~3-ethoxycarbonyl-2-propenyl)-2,4-(lH,3H) -quinazolinedione (5.50 g) in tetrahydrofuran-methanol ~200 ml, 3:1 V/V) was added 10%
palladium on carbon (550 mg). The mixture was stirred vigorously under atmospheric pressure of hydrogen. After 6 hours, the catalyst was filtered off, and the solvent was evaporated. l-(3-Ethoxycarbonylpropyl)-2,4(lH,3H)-quinazolinedione (5.24 g) as a crystal was obtained by recrystallization from ethanol.
NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 1.95-2.05 (2H, r.n~, 2.50 (2H, t, 3=5Hz~, 4.10-4.25 t4H, m), 7.30 ~lH, t, J=7Hz), 7.50 ( lH, d, J=7Hz), 7.75 (lH, dt, J=l, 7Hz), 8.25 ~lH, dd, J=l, 7Hz), 9.00 (lH, br s) Preparation 1-3) A mixture of 1-(3-ethoxycar~onylpropyl)-2,4(lH,3H)-quinazolinedione (552 mg) and lN sodium hydroxide (6.0 ml) in methanol-tetrahydrofuran ( 26 ml, 3.3:1 V/V) was stirred for 3 hours at room temperature. After evaporation of the organic solvents, the mixture was adjusted to pH 4~5 with lN hydrochloric acid to give precipitates. Collected precipitates were washed in turn with water and ethanol to give l-(3~carboxypropyl)-2, 4(lH,3H) -quinazolinedione (393 mg) as a powder.
NMR (DMSO-d6, ~) : 1.70-1.95 (2H, m), 2.40 ~2H, t, J=6Hz), 4.05 (2H, t, J=6Hz), 7.30 (lH, t, J=6Hz), 7.55 (lH, d, J=7Hz), 7.80 (lH, dt, J=1.5, 6Hz), 8.00 (lH, dd, J=1.5, 6Hz) ~3~'~7~
_ - ~6 Preparation 1-4) To a stirred suspension of 1-(3-carbo~rpropyl~-2j4(lH,3H)-quinazolinedione (2.00 g) in tetrahydrofuran (40 ml) was added lM horane in tetrahydrofuran (24.2 ml) on an ice-bath, and the mixture was stirred for additional 2 hours at room temperatureO '~he reaction mixture was quenched with lN hydrochloric acid, and the organic solvent was evaporated. The residue was triturated with water, filtered and washed in turn with water and ethyl ether to give 1-(4-hydroxybutyl)-2,4(1H,3H)-quinazolinedione (1.74 g) as a crystal.
NMR (DMSO-d6, ~) : 1.45-1.70 (4H, m), 3.30-3.50 (3H, m), 4.05 (2H, t, J=7Hz), 4.50 (lH, t, J=5Hz), 7.30 (lH, t, J=6Hz), 7.50 (lH, d, J=6Hz), 7.80 (lH, dt, J=1.5, 5Hz), 8.05 (lH, dd, J=1.5, 5Hz) Preparation 1-5) A mixture of 1-(4-hydroxybutyl)-2,4(lH,3H)-quinazolinedione (290 mg), thionyl chloride (0.54 ml), and pyridine (98 mg) in tetrahydrofuran (10 ml) was refluxed for 2 hours. After evaporation of the solvents, the residue was dissolved in chloroform, washed in turn with water, saturated sodium bicarbo~ate and brine, dried over magnesium sulfate, and evapor ted. Crude material was crystallized from ethyl ether-isopropyl ether to give 1-(4-chlorobutyl)~2,4(lH,3H)-quinazolinedione (226 mg) as a powder.
NMR (CDC13, ~) : 1.85-2.00 (4H, m), 3.65 (2H, t, J=4Hz), 4.10-4.25 (2H, m), 7.20-7.35 (2H, m~, 7.75 (lH, dt, J=1.5, 7Hz), 8.25 (lH, dd, J=1.5, 7Hz), 8.80 (lH, br s) Preparation 2-1) To a stirred solution of 2,4-dioxo-lH-3,1-benzoxazine 7 2 ~ a 3 ~ 7 ~
(2.00 g) in dry dimethylformam-de (20 ml) was added sodium hydride (540 mg, 60% oil suspension) in several portions on an ice-bath. After 30 minutes, ethyl 4-bromocrotonate (3.79 g) was added to the mixture. After stirring for additional 2 hours at room temperature, 28% ammonium hydroxide (7.5 ml) was added on an ice-bath. The mixture was stirred for 30 minutes at the same temperature, neutralized with lN hydrochloric acid, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (120 g) eluting with ethyl acetate and hexane (1:1 V/V) to give 2-(3-ethoxycarbonyl-2-propenylamino)benzamide (2.53 g) as a solid.
NMR ~CDC13, ~) : 1.25 g (3H, t, J=6Hz), 4.00 (2H, dd, J=1.5, 4Hz), 4.20 (2H, ~, J=6Hz), 5.85 ~lH, br s), 6.00 (lH, td, J=1.5, 12Hz), 6.55-6.65 (2H, m), 7.00 ~lH, td, J=3.5, 12Hz), 7.2S-7.35 (lH, m), 7.40 (lH, dd, J=1.5, 6.5Hz) Preparation 2-2) To a solution of 2-(3-ethoxycarbonyl-2-propenylamino)benzamide ~2.35 g) in methanol (50 ml) was added 10% palladium on carbon (230 mg). The mixture was stirred vigorously under 3 atmospheric pressure of hydrogen. After 2 hours, the catalyst was filtered off, and the solvent was evaporated. The residue was chromatographed on silica gel (40 g). Elution with a mixed solvent of ethyl acetate-hexane (1:1 V/V) gave 2-(3-ethoxycarbonylpropylamino)benzamide (1.95 g)-NMR (CDC13, ~) : 1.25 (3H, t, J=6Hz), 1.90-2.10 [2H, m), 2.45 (2H, t, J=6Hz), 3.25 (2H, t, J=6Hz), 4.15 (2H, q, J=6Hz), 5.75 (lH, br s), 6.65 (lH, t, J=6Hz), 6.80 (lH, d, J=7Hz), 7.30-7.45 (2H, m) - 38 - 2~3^~7~
Preparation 2-3) A mixture of 2-(3-ethoxycarbonylpropylamino)benzam:lde (1.95 g) and N,N'-carbonyldiimidazole (2.52 g) in dioxane (20 ml) was heated to 150C. After 30 minutes, the mixture was cooled below 80C, and diluted with ethanol to give crude crystals. Collected crystals were recrystallized from ethanol to give l-(3-ethoxycarbonyl-propyl)-2,4(lH,3H)-quinazolinedione (1.53 g) as a crystal.
NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 2.00-2.15 (2H, m), 2.50 (2H, t, J=5Hz), 4.10-4.30 (4H, m), 7.30 (lH, t, J=8Hz), 7.50 (lH, d, J=8Hz), 7.25 (lH, dt, J=1.5, 8Hz), 8.25 (lH, dd, J=1.5, 8Hz), 8.70 (lH, br s) Preparation 3 A mixture of 1-(3-carboxypropyl)-2,4(lH,3H)-quinazolinedione (744 mg) and thionyl chloride (1.3 ml) in dry tetrahydrofuran (12 ml) was refluxed for 1 hour, and then evaporated. Obtained residue dissolved in ~-0 tetrahydrofuran (15 ml) w~s added to a mixture of N-(2-nitrophenyl)piperazine (683 mg) and triethylamine (607 mg~ in chloroform (15 ml) on an ice-bath. After stirring for 1 hour, precipitated materials were collected and dissolved in chloroform, washed in turn with water, saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated to give 1-[4-(4-(2-nitrophenyl)piperazin-l-yl)-4-oxo~utyl]-2,4(lH,3H)-quinazolinedione (1.06 g) as a solld.
NMR (CDC13, ~) : 2.00-2.20 (2H, m), 2.55 (2H, t, J=5Hz), 3.10 (4H, t, J=4Hz), 3.60-3.70 (2H, m), 3.80-3.9U (2H, m?, 4.20 (2H, t, J=6.5Hz), 7.15 (2H, d, J=6Hz), 7.30 (lH, dt, J-1.5, 6Hz), 7.50 (lH, dt, J=1.5, 6Hz), 7.70-7.85 (3H, m), 8.20 (lH, dd, J=1.5, 6Hz), 8.65 (lH, br s) - 39 - 2 ~ ~ ~ L 7 ~
Preparation 4 A mixture of 1-(3~carboxy)propyl-2,4~lH,3H~-quinazolinedione (744 mg) and thionyl chloride (1.30 ml) in dry tetrahydrofuran (10 ml) was refluxed for 1 hour, and then evaporated in vacuo. Obtained residue dissolved in dry tetrahydrofuran (5 ml) was added to a stirred mixture of 4-~4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydro-chloride (719 mg) and triethylamine (911 mg) in chloroform-tetrahydrofuran (10 ml, 1:1 V/V) on an ice-bath. After stirring for 1 hour at the same temperature, the reaction mixture was diluted with chloroform, washed with water, lN hydrochloric acid, saturated sodium bicarbonate, and brine successively, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (20 g). Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 1-[4-{4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}-4-oxobutyl]-2,4~1H,3H)-quinazolinedione (1.365 g) as an amorphous.
NMR (CDC13, ~) : 1.95-2.20 (2H, m), 2.40-2.65 (4H, m), 3.70 (lH, t, J=5Hz), 3.85 (lH, t, J=SHz), 4.10-4.30 (4H, m), 5.95-6.15 (lH, m), 7.15-7.25 (5H, m), 7.60-7.80 (2H, m), 8.20 (lH, d, J=8Hz), 9.05 (lH, br s) Preparation 5-1) To a stirred solution of methyl 2-ethoxycarbonyl-amino-4-nitrobenzoate (4.00 g) in dry dimethylformamide (40 ml) was added sodium hydride (715 mg, 60% oil suspension) in several portions on an ice-bath. After stirring for 1 hour, 1-bromo-4-chlorobutane (2.81 g) was added thereto, and the resulted mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water, and extracted with ethyl acetate.
The extract was washed in turn with water and brine, dried over magnesium sul~ate, and evaporated. The residue was chromatographed on silica gel (180 g). Elution with a mixed solvent of hexane and ethyl acetate (3:1 V/V~ ~ave methyl 2-[N-(4-chlorobutYl)-N-ethoxycar~onylamino]-4-nitrobenzoate (2.30 g) as an oil.
NMR (CDC13, ~) : 1.05-1.20 (3H, m), 1.70-1.95 (4H, m), 3.30-3.60 (3H, m), 3.90 (3H, s), 4.00-4.40 (3H, m), 8.05-8.25 (3H, m) Preparation 5-2) A mixture of methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4-nitrobenzoate (2.20 g), 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1~32 g), sodium iodide (921 mg), and potassium carbonat~ (1.69 g) in dry dimethylformamide (30 ml) was s~irred at 80C
for 16 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was chromatographed on silica gel (40 g), eluting with a mixed solvent of chloroform and methanol (50:1 V/V) to give methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoate (1.58 g) .
NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.20-1.45 (lH, m), 1.60-1.80 (4H, m), 2.50-2.65 (4H, m), 2.70-2.80 (2H, m), 3.15-3.25 (2H, m), 3.50-3.90 (2H, m), 3.90 (3H, s), 4.00-4.35 (2H, m), 6.00-6.10 (lH, m), 7.25-7.40 (5H, m), 8.00-8.20 (3H, m) _reparation 5-3) To a stirred solution of methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-N-ethoxycarbonyl-amino]-4-nitrobenzoate (1.58 g) in methanol (16 ml) was 2 3 ~ ~ !L 7 3 added 2N potassium hydroxide (5O0 ml). After stirring for 2 hours at 50C, methanol was evaporated in vacuo. The residue was diluted with water, acidified with 3N
hydrochloric acid, extr~cted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated. Crude 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl3-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.57 g~ was obtained as an amorphous.
NMR (CDC13, ~) : 0.90-1.10 (3H, m), 1.55-1.80 (2H, m), 1.90-2.05 (2H, m), 2.80-3.00 (2H, m), 3.00-3.15 (2H, m), 3.30-3.50 (2H, m), 3.65-4.10 (6H, m), 6.00 (lH, br s), 7.25-7.40 (5H, m~, 7.95-8.20 (3H, m) Preparation 5-4) A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoic acid (1.53 g), N,N'-disuccinimidoyl carbonate (924 mg~ and pyridine (285 mg) in dry acetonitrile (20 ml) was stirred for 3 hours at room temperature. Then, to the mixture was added 28% am~onium hydroxide (1.4 ml) on an ice-bath.
After 1 hour, the reaction mixture was diluted with water, and extracted with chloroform. The extract was washed with brine, dried over magnesium sulfate, and evaporated.
The residue was chromatographed on silica gel (30 g).
Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 2-[N-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}-N-ethoxycarbonylamino~-4-nitrohenzamide (600 mg) as caramel.
NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 1.50-1.75 (4H, m), 2.45-2.65 (4H, m), 2.70-2.80 (2H, m), 3.15-3.25 (2H, m), 3.60-3.75 (2H, m), 4.20 (2H, q, J=6Hz), 5.90-6.10 (2H, m), 7.20-7.40 (5H, m), 7.80 (lH, d, J-7~1z), 8.10 ~lH, d, J=1.5Hz), 8.25 (lH, dd, J=1.5, 7Hz) ~`~ - 42 - ~ i 7 ~
Preparation 6 To a stirred suspension of 1-(4-hydroxybutyl)-2,4(lH,3H)-quinazolinedione ~778 mg) in chloroform-tetrahydrofuran (40 ml, 1:1 V/V~ was added methanesulfonyl chloride (0.57 ml), and triethylamine (1.85 ml) on an ice-bath. After stirring for 18 hours at room temperature, the reaction mixture was heated at 50C for 30 hours with stirring. After evaporation of the solvents the residue was diluted with ethyl acetate. The mixture was washed in turn with water and brine, dried over magnesium sulfate, and evapoxated. l-(4-Methane-sulfonyloxybutyl)-2,4(1H,3H)-quinazolinediorle (675 mg) as a crystal was obtained by recrystallization from methanol.
NMR (CDC13, ~) : 1.85-2.00 (4H, m), 3.00 (3H, s), 4.15-4.25 (2H, m), 4.30-4.40 (2H, m), 7.20-7.35 (2H, m), 7.70 (lH, dt, J=1.5, 6~z), 8.25 (lH, dd, J=1.5, 6Hz), 8.70 (1~, br s~
Preparation 7-1) Methyl 6-chloro-2-[N-(4-chlorobutyl)-N-ethoxy-carbonylamino]benzoate was obtained in 90.7% yield in substantially the same manner as that of Preparation 5~
NMR (CDC13, ~ : 1.10-1.25 (3H, m), 1.65-1.85 ~4H, m), 3.20-3.50 ~lH, m), 3.55 (2H, t, J=6Hz), 3.65-3.85 (lH, m), 3.90 (3H, s), 4.05-4.20 (2H, m), 7.05-7.15 (lH, m), 7.35-7.45 (2H, m) Preparation 7-2~
Methyl 6-chloro-2-[N-ethoxyca~bonyl-N-{4-(4-phenyl--1,2,3,6 tetrahyxropyridin-l-yl)butyl}amino]benzoate was obtained in 78.2% yield in substantially the same manner as that of Preparation 5-2).
NMR (CDC13, ~) : 1.05-1.30 (3H, m), 1.55-1.70 (4H, m), 2.40-2.75 (6H, m), 3.10-3.20 (2H, m), 3~ 3.20-3.50 (lH, m), 3.70-3.90 (lH, m), - 43 - 2 3 ~ 3 ~ 7 ~
3.90 ~3H, s), 4.00-4.20 (2H, m~, 6.05-h.10 ~lH, m~, 7.10-7.60 (8H, m) Preparation 7-3) 6-Chloro-2-[N-ethoxycarbonyl-N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}amino]benzoic acid was obtained in 96.1% yield in substantially the same manner as that of Preparation 5-3).
IR (Nujol) : 1680, 1600, 1580 cm Preparation 7-4) 6-Chloro-2-~N-ethoxycarbonyl-N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}amino~benzamide was obtained in 21.0% yield in substantially the same manner as that of Preparation 5-4).
NMR (CDC13, ~) : 1.05-1.45 (3H, m), 1.50-1.90 (4H, m), 2.50-2.95 (4H, m), 3.20-3.40 (lH, m), 3.60-3.80 (lH, m), 4.00-4.30 (2H, m), 6.00-6.10 ~lH, m), 7.05-7.50 (8H, m) Preparat on 8-1) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonyl]amino-6-nitrobenzoate was obtained in substantially the same manner as that of Preparation 5-1).
NMR (CDC13, ~) : 1.00-1.30 (3H, m), 1.65-1.85 (4H, m), 3.50-3.60 (2H, m), 3.90 (3H, s), 4~05-4.20 (2H, m), 7.55 (lH, d, J=7Hz), 7.65 (lH, t, J=7Hz), 8.15 (lH, dd, J=l, 7Hz) Preparation 8-21 Methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-6-nitrobenzoate was o~tained in substantially the same manner as that of Preparation 5-2).
- 2 ~ 7 ~
NMR (CDC13, ~) : 1.05-1.25 (3H, m), 1.55-1.75 ~4H, m), 2.50-2.65 ~4H, m), - 2.75 ~2H, t, J=4Hz), 3.20 ~2H, d, J=3Hz), 3.90 (3H, s), 4.00-4.20 (2H, m), 6.00-6.10 ~lH, m), 7.25-7.40 ~5H, m), 7.55-7.65 ~2H, m), 8.10 ~lH, d, J=7Hz) Preparation 8-3) 2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-~l-ethoxycarbonylamino]-6-nitrobenzoic acid was obtained in substantially the same manner as that of P~eparation 5-3).
NMR (CDC13, ~) : 1.00-1.25 (3H, m), 1.55-1.80 (2H, m), 1.90-2.10 (2H, m), 2.70-3.20 (3H, m), 3.40-4.20 (9H, m), 6.G0 (lH, s), 7.25-7.50 (7H, m), 8.00 (lH, t, J=7Hz) Preparation 8-4) A mixture of 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl}-N-ethoxycarbonylamino]-6-nitrobenzoic acid (680 mg) and phosphorus tribromide (0.7 ml) in methylene dichloride (30 ml) was refluxed for 3 hours. Excess of phosphorus tribromide was quenched with ethanol (2 ml) on an ice-bath. Then appeared crystalline materials were collected, and washed with ethanol to give 1-14-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione hydrobromide (414 mg).
-NMR (DMSO-d6, ~) : 1.65-1.95 (4H, m), 2.75-2.90 (2H, m?, 3.20-3.40 (3H~ m), 3.10-3.90 (2H, m), 4.00-4.20 (3H, m), 6.15-6.25 (lH, m), 7.35-7.55 (5H, m~, 7.70 (lH, d, J=6Hz), 7.80 (lH, d, J=6Hz), 8.05 (lH, t, J=6Hz) 2 ~ L
- ~5 -Preparation 8-5) To a suspension of 1-~4-(4-pher.yl-1, 2, 3,6 tetrahydro-pyridin-l-yl)butyl]-5-nitro-1,2-dihydro-4H-3,1-benzoxazine-2, 4-dione hydrobromide (410 mg) in dimethylformamide (4 ml) was added 28% ammonium hydroxide (1 ml) on an ice-bath, and the mixture was stirred for 1 hour at room temperature. The mixture was poured into ice-water, extracted with ethyl acetate, and the extracts were washed with water and brine. After dryness with magnesium sulfate and evaporation of the solvent, 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6-nitrobenzamide was obtained as an amorphous (300 mg).
NMR (CDC13, ~) : 1.60-1.80 (4H, m), 2.40-2.60 (4H, m), 2.70 (2H, t, J=5Hz), 3.10-3.25 (4H, m), 5.10-5. 20 (lH, m), 6.00-6.10 (3H, m), 6.90 (lH, dd, J=1.5, 7Hz), 7.20-7.40 (7H, m) The following compounds were obtained in substantially the same manner as that of Preparation 5-1).
Preparation 9-1) Ethyl 2-[N-(4 -chlorobutyl)-N ethoxycarbonylamino~ -5-ethoxybPnzoate NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.25 (lH, t, -J=6Hz), 1.35 (3H, t, J=6Hz), 1.45 (3H, t, J=6Hz), 1.60-1.90 (4H, m), 3.25-3.40 (lH, m), 3.55 (2H, t, J=5Hz), 3.80-4.25 (5H, m), 4.30 (2H, ~, J=6Hz), 7.05 (lH, dd, J=2, 7Hz), 7.10 (lH, d, J=7Hz), 7.50 (lH, d, J=2Hz) Preparation 9-2) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino~- 5-methoxybenzoate NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.35 (lH, dd, J=6, 12Hz), 1.70-1.90 ~4H, m), 3.30-3.45 (lH, m), 3.55 (2H, t, J=5Hz3~ 3.90 ~3H x 2, s~, 3.90-4.40 (3H, m), 7.00-7.20 (2H, m), 7.50 (lH, d, J=2Hz) Preparation 9-3) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino] 3-chlorobenzoate NMR (CDCl3, ~) : 1.10 (3H, t, J=6Hz), 1.60-1.85 (4H, m), 3.35-3.70 (4H, m), 3.90 (3H, s), 4.10 (2H, q, J=6Hz), 4.20-4.40 (lH, m), 7.35 (lH, t, J=7Hz), 7.65 (lH, dd, J=1.5, 7Hz), 7.85 (lH, dd, J=1.5, 7Hz) Preparation 9-4~
Methyl 2-IN-(4-chlorobutyl)-N-ethoxycarbonylamino3-4-methoxybenzoate NMR (CDC13, ~) : 1.10 (2H, t, J=6Hz), 1.20-1.40 (lH, m), 3.35-3.50 (lH, m), 3.55 (2H, t, J=5~z~, 3.85 (3H, s), 3.90 ~3H, s), 3.80-4.25 (3H, m), 6.70-6.80 llH, m), 6.85 (lH, dd, J=2, 8Hæ), 8.00 (lH, d, J=8Hz) Preparation 9-5) Methyl 2-~N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4,5-dimethoxybenzoate NMR (cDcl3~ 1.10 (2H, t, J=6Hz), 1.30-1.40 (lH, m), 1.65-1.95 (4H, m), 3.30-3.60 (3H, m), 3.85 (3H, s), 3.90 (3H x 2, s), 3.95-4.35 (3H, m), 6.65 (lH, s), 7.50 (lH, s) Pre~aration 9-6) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino~-5-nitrobenzoate NMR (CDC13, ~) : 1.00-1.20 (3H, m), 1.70-l.90 (4H, ~ J
_ - 47 m3, 3.50-3.60 (2H, m), 3.70-3.80 (2H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 7.45 (lH, d, J=8~z), - 8.40 (lH, dd, J=2, 8Hz), 8.80 (lH, br s) Preparation 9-7) Methyl 2-[N-~4-chlorobutyl)-N-ethoxycarbonylamino]-6 fluorobenzoate NMR ~CDCl3, ~) : 1.05-1.30 (3H, m), 1.65-1.90 (4H, m), 3.40-3.70 (4H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 7.05 (lH, d, J=7Hz), 7.15 (lH, d, J=7Hz), 7.45 (lH, dt, J=4, 7Hz) Preparation 9-8) Methyl 2-~N-(4-chlorobutyl)-N-ethoxycarbonylamino]-6-15 methoxybenzoa~e NMR tCDCl3, ~) : 1.10-1.25 (3H, m), 1.65-1.85 (4H, m), 3.55 (2H, t, J=5Hz), 3.90 (6H, s), 4.00-4.20 (2~, m), 6.80 (lH, d, J=7Hz), 6.90 (lH, d~
J=7Hz), 7.40 (lH, t, J=7Hz) Preparation 9-9) Methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-6 methylbenzoate NMR (CDCl3, ~) : 1.10-1.30 (3H, m), 1.60-1.90 (4H, m), 2.40 (3H, s), 3.20-3.50 (lH, m), 3.55 (2H, t, J=5Hz), 3.70-4.00 (lH, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 7.00 (lH, d, J=7Hz), 7.20 (lH, d, J=7Hz), 7.35 (lH, t, J=7Hz) The following compounds were obtained in substantially the same manner as that of Preparation 5-2).
PreParation 10-1) Ethyl 2-[N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin-35 l-yl)butyl}-N-ethoxycarbonylamino]-S-ethoxybenz.oate 2~3 17~
NMR (CDC13, ~) 1.10 (3H, t, J=6Hz), 1.35 (3H, t, J=6Kz), 1.45 (3H, t, J=6Hæ), 1.50-1.70 (4H, m), - 2.45-2.80 (6H, m), 3.~5-3.40 (3H, m), 3.85-4.15 (5H, m), 4.30 (2H, q, J=6Hz), 6.00-6.10 (lH, m), 7.00 (lH, dd, J=2, 8Hz~, 7.10 (lH, d, J=8Hz), 7.25-7.40 (5H, m), 7.45 (lH, d, J=2Hz) Preparation 10-2) Methyl 2-[N-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-10 yl)butyl}-N-ethoxycarbonylamino~-5-methoxybenzoate NMR (CDC13, ~) : 1.10 (3H, t, J=6Hz), 1.50-1.70 (4H, m), 2.45-2.60 (4H, m), 2.65-2.75 (2H, m), 3.10-3.20 (2H, m), 3.25-3.40 (lH, m), 3.80 (3H x 2, s), 3.80-4.35 (3H, m), 6.00-6.10 (lH, m), 7.00-7.50 (8H, m) Preparation 10-3) Methyl 2-~N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin l-yl)butyl}-N-ethoxycarbonylamino]-3-chlorobenzoate NMR (CDCl3, ~) : 1.10 (2H, t, J=6Hz), 1.35 (lH, m), 1.50-1.65 !4H, m), 2.40-2.70 (6H, m), 3.10-3.20 (2H, m), 3.35-3.80 (2H, m), 3.90 (3H, s), 4.10 ~4/3H, q, J=6Hz), 4.20-4.40 (2/3H, m), 6.00-6.10 (lH, m), 7.20-7.40 (6H, m), 7.65 (lH, dd, J=1.5, 7Hz), 7.85 tlH, dd, J=1.5, 7Hz) Preparation 10-4) Methyl 2-[N-~4-t4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl}-N-ethoxycarbonylamino]-4-methoxybenzoate NMR (CDCl3, ~) : 1.10 (12/5H, t, J=6Hz), 1.35 (3/5H, t, J=6Hz), 1.60-1.75 (4H, m), 2.50-2.70 (4H, m), 2.70-2.90 (2H, m), 3.20-3.30 (2H, m), 3.30-3.55 (lH, m), 3.85 (3~, s), 3.90 (3H, s), 3.80-4.30 (3H, m), 6.05 (lH, br s), 6.75 (lH, d, J=2Hz), 6.85 (lH, dd, J=2, 8Hz), 7.25-7.40 (5H, m), 8.00 (lH, d, J=8Hz) Preparation 10-5) Methyl 2-[N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-etho~ycarbonylamino]-4,5-dimethoxybenz~ate NMR (CDC13, ~) : 1.10 (2H, t, J=5Hz), 1030-1.40 (~H, m), 1.55-1.75 (4H, m), 2.45-2.70 (4H, m), 2.70-2.80 (2H, m), 3.15-3.45 ~3H, m), 3~85 (3H, s), 3.90 ~3H x 2, s), 3.95-4.35 (3H, m), 6.05 (lH, br s), 6.70 (lH, s~, 7.25-7.40 (5H, m), 7.50 (~H, s) Preparation 10-6) Methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl-N-ethoxycarbonylamino]-5-nitrobenzoate NMR (CDC13, 6) : 1.00-1.50 (3H, m), 1.60-1.80 (4H, m~, 2.50-2.70 (4H, m), 2.75-2.90 (2H, m), 3.20-3.30 (2H, m), 3.60-3.90 (2H, m), 3.90 (3H, s), 4.00-4.30 (2H, m), 6.00-6.10 (lH~ m), 7.25-7.50 (6H, m), 8.40 ~lH, ~d, J=2, 8Hz), 8.80 ~lH, br s) Pre~aration 10-7) Methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl~butyl}-N-ethoxycarbonylamino]-6~fluorobenzoate NMR (CDCl3, 6) : 1.05-1.25 (3H, m), 1.55-1.80 ~4H, m), 2.60-2.75 (4H, m), 2.80-2.95 ~2H, m), 3.25-3.40 (2H, m), 3.40-3.80 (2H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 6.00-6.10 (lH, m), 7.00-7.15 (2H, m), 7.25-7.50 (6H, m) Preparation 10-8) Methyl 2-[N-{4-~4-phenyl-1,2,3,6-tetrahydropyridin~
yl)butyl}-N-ethoxycarbonylamino]-6-methoxybenzoate NMR (CDCl3, 6) : 1.10-1.25 ~3H, m), 1.55-1.75 ~4H, m), 2.50-2.70 (4H, m), 3.80-3.90 (2H, m), 3.75-3.85 (2H, m), 3.90 ~6H, s), 4.00-4.20 (2H, - 50 _ 2 ~ 7 ~
m), 6.00-6.10 ~lH, m), 6.80 (lH, d, J=7Hz), 6.90 (lH, d, J-7Hz), 7.25-7.45 (6H, m) _reparation 10-9) Methyl 2-[N-~4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-6-methylbenzoate NMR (CDCl3, ~) : 1.10-1.25 ~3H, m), 1.55-1.80 (4EI, m), 2.40 (3H, s), 2.55-2.75 (4H, m), 2.75-2.95 (2H, m), 3.20-3.45 (2H, m), 3.90 (3H, s), 4.00-4.20 (2H, m), 6.00-6.10 tlH, m), 7.05 (lH, d, J=7Hz), 7.15-7.40 (7H, m) The following compounds were obtained in substantially the same manner as that of Preparation 5-3).
Preparation 11-1) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5~ethoxybenzoic acid NMR (CDCl3, ~) : 1.40 (3H, t, J=6Hz), 1.50-1.75 (2H, m), 1.75-1.95 ~2H, m), 2.75-3.00 (4H, m), 3.20-3.70 ~6H, m), 3.85-4.10 (4H, m), 6.00 ~lH, br s), 6.90 (lH, dd, J=2, 7.5Hz), 6.95 (lH, d, J=7.5Hz), 7.20-7.50 (6H, m) 25 Preparation 11-2) 2-~N-{4 (4-Phenyl-1,2,3,6-tetrahy~ropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-methoxybenzoic acid N~R (CDCl3, ~) : 1.00 (3H, t, J=6Hz), 1.50-1.6S (2H, m), 1.70-2.05 ~2H, m), 2.80-3.10 (4H, m), 3.30-3.40 (2H, m~, 3.55-3.70 (2H, m), 3.80 (5H, br s), 4.00 i2H, q, J=6Hz), 6.00 (lH, br s), 6.95 (lH, dd, J=2, 8Elz), 7.00 (lH, d, J=8H~
7.20-7.40 (SH, m), 7.45 (lH, d, J=2Hz) - 51 - 2 ~, ~ 3 ~
Preparation 11-3) 2-[N-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)~
butyl}-N-ethoxycaxbonylamino]-3-chlorobenzoic acid Preparation 11-4) 2-EN-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-4-methoxybenzoic acid NMR (CDCl3, ~) : 1.05 ~3H, t, J=6Hz), 1.50-1.70 (2H, m), 1.85-2.05 (2H, m), 2.80-2.90 (2H, m), 2.95-3.10 (2H, m), 3.30-3.A0 (2H, m), 3.55-3.80 (4H, m), 3.85 (3H, s), 4.00 (2H, q, J=6Hz), 6.65 (lH, d, J=1.5Hz), 6.80 (lH, dd, J=1.5, 7.5Hz), 7.25-7.40 (5H, m), 8.00 (lH, d, J=7.5Hz) Preparation 11-5) 2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-4,5-dimethoxybenzoic acid NMR (CDCl3, ~) : 1.05 (3H, t, J=6Hz), 1.50-1.70 (2H, m), 1.90-2.10 (2H, m), 2.85-3.20 ~4H, m~, 3.30-3~50 (2H, m), 3.60-3.75 (2H, m), 3.90 (3H x 2, s), 3.80-4.10 (4H, m), 6.00 (lH, br s), 6.60 (lM, s), 7.25-7.40 (5H, m), 7.55 (lH, s) Preparation 11-6) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-nitrobenzoic acid NMR (CDC13, ~) : 1.10-1.20 (3H, m), 1.50-1.70 (2H, m), 2.00-2.20 (2H, m), 2.85-3.00 (2H, m), 3.10-3.Z0 (2H, m), 3.40-3.60 (2H, m), 3.70-4.00 (4H, m), 4.00-4.15 (2H, m), 6.00 (lH, br s), 7.25-7.40 (6H, m), 8.20-8.30 (lH, m), 8.65-8.75 (lH, m) Prepaxation 11-7) 2-[N-{4-(4-Phenyl-l,Z,3,6-tetrahydropyridn-1-yl)-- ` 23~ ~17a butyl}-N-ethoxycarbonylamino]-6-fluorobenzoic acid NMR (CDCl3, ~) : 1.05-1.30 (3H, m), 1.55-1.75 (2H, - m), 1.90-2.10 (2H, m), 2.80-3.00 (2H, m), 3.10 (2H, t, J=6Hz), 3.30-3.50 (2H, m), 3.60-3.90 (4H, m), 4.00-4.20 (2H, m), 6.00 (lH, br s), 6.90-7.10 (2H, m), 7.20-7.40 (2H, m) Preparation 11-8) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino)-6-methoxybenzoic acid NMR (CDCl3, ~) : 1.00-1.20 (3H, m), 1.5S-1.75 (2H, m), 1.85-2.10 (2H, m), 3.80-3.95 (2H, m), 3.05 (2H, t, J=6Hz), 3~35-3.50 (2H, m~, 3.60-3.80 (7H, m~, 4.00-4.15 (2H, m), 5.8D (lH, br s), 6.00 (lH, br s), 6.70 (lH, d, J=6Hz), 6.85 (lH, d, J=6Hz), 7.20-7.40 (6H, m) Preparation 11-9~
2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-6-methylbenzoic acid NMR (CDCl3, ~) : l.OQ-1.30 (3H, m), 1.30-1.80 (2H, m), 1.85-2.40 (2H, m), 2.45 (3H, s), 2.60-2.85 (lH, m), 2.90-3.40 (5H, m), 3.50-3.80 (2H, m), 4.00-4.35 (4H, m~, 6.10 (lH, br s), 7.00 (lH, d, J=7Hz), 7.15-7.40 (7H, m) The following compounds were obtained in substantially the same manner as that of Preparation 5-4).
Preparation 12-1) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-ethoxyben~amide Preparation 12-2) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-- 53 - 2~ 3 butyl}-N-ethoxycarbonylamino]-5-methoxybenzamide NMR (CDCl3, ~) : 1.25 (3H, t, J=6Hz), 1.50-1.65 (4H, - m), 2.45-2.65 (4H, m), 2.70-2.80 (2H, m), 3.20 (2H, m~, 3.60 (2H, br s), 3.80 (3H, s), 4.20 (2H, q, J=5Hz), 6.00-6.10 (lH, m~, 7.00 (lH, dd, J=2, 8Hz), 7.10 (lH, d, J=8Hz), 7.20-7.40 (6H, m) Preparation 12-3) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl3-N-ethoxyc~rbonylamino]-3-chlorobenzamide NMR (CDCl3, ~) : 1.20 (3/2H, t, J=6Hz), 1.35 (3/2H, t, J=6Hz), 1.50-1.75 (4H, m), 2.40-2.80 (6Hr m), 3.15-3.50 (3H, m), 3.70-4.00 (lH, m), 4.10-4.40 (2H, m), 5.85 ~1/2H, br s), 5.00-6.20 (2H, m), 6.80 (lH, br s), 7.20-7.40 (6H, m), 7.50-7.65 (2H, m) Preparation 12-4) 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino~-4-methoxybeDzamide NMR (CDCl3, ~) : 1.25 (3H, t, J=6Hz), 1.55-1.70 (4H, m), 2.45-2.70 (4H, m~, 2.75 (2H, m), 3.15-3.25 (2H, m), 3.50-3O75 (2H, m), 3.85 (3H, s), 4.20 (2H, ~, J=6Hz), 6.00-6.10 (lH, m), 6.70 (lH, d, J=2Hzj, 6.90 (lH, dd, J=2, 7Hz), 7.20-7.40 (6H, m), 7.70 (1 or 2H, d, J=7Hz) Preparation 12-5) 2-rN-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-30 butyl}-N-ethoxycarbonyl~mino]-4,5-dimethoxybenzamide NMR (CDCl3, ~) : 1.35 (3H, t, J=6Hz), 1.55-1.65 (4H, m), 2.40-2.50 (2H, m), 3.55-3.65 (2H, m), 3.90 (3H, s), 3.95 (3H, s), 4.20 (2H, ~, J=6Hz), 5.75-5.90 (3~5H, br s), 6.00-6.10 (lH, m), 6.60 (lH, s), 7.25-7.40 (8H, m~
2~33`i.
- ~4 -Preparation 12-6) 2-[N-{4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-5-nitrobenzamide NMR (CDC13, ~) : 1.20-1.35 (3H, m), 1.55-1.90 (4H, m), 2.50-2.70 (4H, m), 2.70-2.90 (2H, m), 3.20 3.35 (2H, m), 4.10-4.30 (2H, m), 6.05 (lH, br s), 7.20-7.45 (6H, m), 8.30 (lH, d, J=2Hz), 9.00 (lH, d, J=2Hz) The following Compounds were obtained in substantially the same manner as that of Preparations 8-4) and 8-5).
Preparation 13-1) lS 2-~N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}amino]-6-fluorobenzamide NMR (CDC13, ~) : 1.65-1.85 (4H, m), 2.50-2.70 (4H, m), 2.80 (2H, t, J=4Hz), 6.05-6.10 (lH, m), 6.30 (lH, ddd, J=l, 8, lOHz), 6.50 (lH, d, J=7Hz), 7.20-7.45 (6H, m), 8.55 (lH, br s) Preparation 13-2) 2-lN~~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}amino]-6-methoxybenzamide NMR (CDCl3, ~) : 1.70-1.85 (4H, m), 2.55-2.70 (4H, m), 2.85 ~2H, t, J=5Hz), 3.15-3.35 (4H, m), 3.90 (3H, s), 5.50 (lH, br s~, 6.00-6.10 (lH, m), 6.20 (lH, d, J=7Hz), 6.35 (lH, d, J=7Hz), 7.15-7.40 (6H, m), 7.80 (lH, br s) Preparation 13-3) 2-[N-{4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}amino]-6-methylbenzamide NMR (CDC13, ~) : 1.60-1.80 (4H, m), 2.40 (3H, s), 2.50-2.70 (4H, m), 2.70-2.80 (2H, m), 3.10-3.25 2 ~ 5 3 -~7 ~
_ - 55 (4Hr m~, 4.90 (lH, br s), 5.75-5.95 (2H, m), 6.00-6.10 ~lH, m), 6.50 (2H, d, J=7Hz), 7.10 (lH, t, J=7Hz), 7.25-7.40 (6H, m) The following compounds were obtained in substantially the same manner as that of Preparation 2-1).
Preparation 14-1) 2-(3-Ethoxycar~onyl-2-propenylamino)-5-methoxy-benzamide NMR (CDC13, ~) : 1.30 (3H, t, J=5Hz), 3.80 (3H, s), 3.g5-4.05 (2H, m), 4.20 (2H, q, J=5Hz), 5.90 (1 or 2H, br s), 6.05 (lH, td, J=1.5, 12Hz), 6.50-6.60 (lH, m), 6.95-7.10 (3H, m) Preparation 14-2) 2-(3-Ethoxycarbonyl-2-propenylamino)-4-chlorobenzamide NMR (CDCl3, ~) : 1.30 (3H, t, J=6Hz), 4.00 l2H, dd, J=1.5, 5Hz), 4.20 ~2H, q, J=6Hz), 5.90 (2H, br s), 6.00 (lH, td, J=l, 12Hz), 6.55-6.65 (2H, m~, 7.0Q (lH, td, J=3, 12Hz), 7.35 (lH, d, J=7Hz) The following compounds were obtained in substantially the same manner as that of Preparation 2-2).
Preparation 15-1) 2-(3-Ethoxycarbonylpropylamino)-5-methoxybenzamide NMR (CDC13, ~) : 1.25 (3H, t, J=5Hz), 1.90-2.05 (2H, m), 2.40 (2H, t, J=6Hz), 3.20 (2H, t, J=6Hz), 3.75 (3H, s), 4.15 (2FI, q, J=6Hz), 5.90 (2H, br s), 6.6S-6.75 (lH, m), 6.95-7.05 (2H, m) 2 ~ 3 -~ ~ 3 Preparation 15-2) 2-~3-Ethoxycarbonylpropylamino)-4-chlorobenzamide - NMR (CDC13, ~) : 1.25 ~3H, t, J=6Hz), 1.90-2.10 (2H, m), 2.45 (2H, t, J=5Hz), 3.20 (2H, t, J=5Hz), 4.15 (2H, q, J=6Hz), 5.80 ~2H, br s~, 6.55 (lH, dd, J=1.5, 8Hz), 6.70 (lH, d, J=1.5Hz), 7.30 (lH, d, J=8Hz) The following compounds were obtained in 10 substantially the same manner as that of Preparation 2-3).
Preparation 16-1) 1-(3-Ethoxycarbonylpropyl)-6-methoxy-2,4(1H,3H~-quinazolinedione NMR (CDC13, ~) : 1.30 (3H, t, J=6Hz), 1.95-2.10 (2H, m), 2.50 (2H, t, J=6Hz), 3.90 (3H, s), 4.10-4.25 (4H, m), 7.35 (lH, dd, J=2, 8Hz), 7.45 (lH, d, J=8Hz), 7.65 (lH, d, J=2Hz), 8.90 (lH, br s) 20 Preparation_16-2) 1-(3-Ethoxycarbonylpropyl)-7-chloro-2,4(1H,3H)-quinazolinedion~
NMR (CDCl3, ~ 30 (3H, t, J=6Hz), 1.95-2.10 (2H, m), 2.50 (2H, t, J=5Hz), 4.10-4.30 ~4H, m), 7.25 (lH, dd, J=1.5, 7Hz), 7.50 (lH, d, J=1.5Hz), 8.15 (lH, d, J-7Hz), 8.80 (lH, br s) The following compounds were obtained in substantially the same manner as that of Preparation 1-3).
Preparation 17-1) 1-(3-Carboxypropyl)-6-methoxy-2,4(1H,3H)-quinazolinedione NMR (DMSO d6, ~) : 1.70-1.90 (2H, m), 2.40 (2H, t, J=5Hz), 3.20-3.50 (2H, m), 3.80 (3H, s), 4.05 - 2 ~ ~) 3 i~ ~ 3 ~2H, t, J=5Hz), 7.40 ~lH, dd, J=1.5, 8Hz), 7.45 ~lH, d, J-1.5Hz), 7.55 ~lH, d, J=8Hz) Preparation 17-2) 1-~3-Carboxypropyl)-7-chloro-2,4(1H,3H)-~uinazolinedione NMR (DMSO-d6, ~) : i.70-1.90 (2H, m), 2.40 (2H, t, J=5Hz), 4.05 (2H, t, J=5Hz), 7.30 (lH, dd, J=l, 8Hz), 7.75 (lH, d, J=lHz), 8.00 (lH, d, J=8Hz~
The following compounds were obtained in substantially the same manner as that of Preparation 1-4).
Preparation 18-1) 1-~4-Hydroxybutyl)-6-methoxy-2,4(1H,3H)-quinazolinedione NMR (DMSO-d6, ~) 1.40-1.70 ~4H, m), 3.30-3.50 ~2H, m), 3.80 ~3H, s), 4~00 ~2H, t, J=5Xz), 7.30-7.50 (3H, m) Preparation 18-2) 1-(4-Hydroxybutyl)-7-chloro-2,4~1H,3H)-quinazolinedione NMR (DMSO-d6, ~) : 1.40-1.70 ~4H, m), 3.30-3.50 ~2H, m), 4.00-4.10 ~2H, m), 7.30 ~lH, dd, J=1.5, 7Hz), 7.60 (lH, d, J=1.5Hz), 8.00 (lH, d, J=7Hz) The following compounds were obtained in substantially the same manner as that of Preparation 1-5).
Preparation 19-1) 1-(4-Chlorobutyl)-6-methoxy-2,4(1H,3H)-~uinazolinedione NMR (CDCl3, ~) : 1.85-1.95 t4H, m), 3.60-3.70 (2H, m), 3.90 ~3H, s), 4.10-4.20 ~2H, m), 7.20 ~lH, 2 ~ a 3 ~ i7 3 _ - 58 d, J=8Hz), 7.30 (lH, dd, J=2, 8Hz), 7.65 (lH, d, J=2Hz) Preparation 19-2) 1-~4-Chlorobutyl)-7-chloro-2,4(lH,3H)-~uinazolinedione NMR (CDCl3, ~ 85-2.00 (4H, m), 3.60-3.70 (2H, m), 4.10-4.20 (7H, m), 7.20-7.30 (2H, m), 8.20 (lH, dd, J=l, 7Hz), 8.95 (lH, br s) The following compounds were obtained in substantially the same manner as that of Preparation 3.
Preparation 20-1) 1-[4-{4-(4-Tolyl)-1,2,3,6-tetrahydropyridin-1-yl}-4-oxobutyl]-2,4~lH,3H)-~Iinazolinedione NMR (CDCl3, ~) : 2.00-2.20 t2H, m~, 2.35 (3H, s), 2.45-2.65 (4H, m), 3.65-3.75 (lH, m), 3.80-3.90 (lH, m), 4.10-4.30 (4H, m), 5.95-6.10 (lH, m), 7.10-7.35 (5H, m), 7.70-7.80 (2H, m), 8.20-8.40 ~0 (2H, m) Preparation 20-2) 1-~4-{4-(2-Tolyl)piperazin-l-yl}-4-oxobutyl]-2,4(lH,3H)~quinazoline~ione N~R (CDCl3, ~) : 2.00-2.20 (2H, m), 2.35 (3H, s), 2.55 ~2H, t, J=5Hz), 2.85-3.00 (4H, m), 3.60 (2H, t, J=4Hz), 3.80 (2H, t, J=4Hz), 4.20 (2H, t, J=5Hz), 6.95-7.05 (2H, m), 7.10-7.30 (5H, m), 7.75 (2H, m), 8.20 (lH, d, J=7Hz), 8.40 (lH, br S) Preparation 20-3) 1-[4-t4-Phenylpiperazin-l-yl)-4-oxobutyl~-2,4(1H,3H)-quinazolinedione 2~3 -~7~
Preparation 20-4) 1-l4-{4-(2-Etho~yphenyl)piperazin-1-yl}-4-oxob~tyl]-2,4(lH, 3H)-quinazolinedione NMR (CDCl3, ~) : 1.50 ~3H, t, J=6Hz), 2.0~-2.20 ~2H, m), 2.55 (2H, t, J=5Hz), 3.05- 3.15 (4H, m), 3.60-3.70 (2H, m), 3.80-3.90 (2H, m), 4.10 (2H, q, J=6Hz), 4.15-4.25 (2H, m), 6.85-7.05 (4H, m), 7.20-7.30 (lH, m), 7.70-7.80 (2H, m), 8.20 (lH, d, J=7Hz), 8.80 ~lH, br s) Preparation 21 2-~N-{4-l4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl}-N-ethoxycarbonylamino]-4-chlorobenzamide was obtained in substantially the same manner as that of Preparation 12-3) from 2-[N-~4-(4-phenyl-1,2,3,6-tetrahydropyridn-1-yl)butyl}-N-ethoxycarbonylamino]-4-chlorobenzoic acid, which had been prepared from methyl 2-[N-~4-chlorobutyl)-N-ethoxycarbonylamino-4-chlorobenzoate in substantially the same manner as those of Preparatio~ 9-3), 10-3~ and 11-3).
Preparation 22 6-Chloro-1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-4-oxobutyl]-2,4(lH,3H)-quinazolinedione was obtained in substantially the same manner as that of Preparation 4 from 1-(3-carboxy)propyl-6-chloro-2,4(lH,3H)-quinazolinedione, which had been prepared from 2,4(lH,3H)-quinazolinedione in substantially the same manner as those of Preparationsl-1), 1-2) and 1-3).
NMR (CDCl3, ~) : 2.40-2.65 (4H, m), 3.50-3.65 (lH, m), 3.65-3.75 (lH, m), 3.85-3.95 (lH, m), 4.10-4.30 (5H, m), 5.00-6.65 (lH, m), 7.20-7.40 (5H, m), 7.65-7.85 ~2H, m), 8.15-8.25 ('H, m), 9.25 (lH, br s) - - 2~1a~ 7~
o Example 1-1~
~ mixture of 1-~4-chlorobutyl)-2,4~1H,3H)-quinazolinedione (160 mg), N-(2-propoxyphenyl)piperazine hydrochloride (178 mg), potassium iodide (105 mg), and sodium carbonate (200 mg~ in methyl isobutyl ketone (15 ml) was refluxed for 5 nours. After dilution with ethyl acetate, the reaction mixture was washed in turn with water and brine, dried over magnesium sulfate, and evaporated.
The residue was chromatographed on silica gel (15 g) 1~ eluting with chloroform-methanol (50:1 V/V) to give 1-[4-{4-(2-propoxyphenyl)piperazin-1-yl}butyl]-2,4(lH,3H)-quinazolinedione (266 mg).
mp : ~ 68~
IR (Nujol, v) : 1680, 1600 cm 1 NMR (CDC13, ~ : 1.10 (3H, t, J=6Hz), 1.60-1.90 (6H, m), 2.55 (2H, t, J=SHz), 2.60-2.80 (4H, m), 3.10-3.25 (4H, m), 3.95 (2H, t, J=6Hz), 4.15 (2H, t, J=5Hz), 6.8-7.00 (4H, m), 7.20-7.30 ( H, m), 7.40 (lH, d, J=7Hz), 7.70 (lH, dt~ J=l, 7Hz), 8.20 (lH, dd, J=l, 7Xz), 8.95 (lH, br s) Example 1-2~
A mixture of 1-(4-methanesulfonyloxybutyl)-2,4(lH,3H)-quinazolinedione (312 mg), 4-phenyl-1,2,3,6-tetrahydropyridine (200 mg) and triethylamine (303 mg) was refluxed for 105 hours. The reaction mixture was poured into ethyl acetate-water~
extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was washed with hot methanol to give 1 [4-(4-phenyl-1,2,3,6~
tetrahydropyridin-l-yl)butyl]-2,4(1H,3H)-quinazolinedione (114 mg) as a powder.
mp : 170-173.5C
IR (Nujol, v) : 1710, 1670, 1600 cm 1 - 2~ 7~
- 6~
NMR (CDC13, ~) : 1.60-1.95 (4H, m~, 2.50-2.70 (4H, m), 2.75 ~2H, t, J=4.5Hz~, 7.20-7.45 (7H, m), - 7.65 (lH, ddd, J=1.5, 6, 6Hz), 8.20 (lH, dd, J=1.5, 6Hz) Example 2-1) To a suspension of 1-[4-{4-(2-nitrophenyl)piperazin-l-yl}-4-oxo-butyl]-2,4(1H,3H)-quinazolinedione (500 mg~ in tetrahydrofuran (10 ml) was added lM borane in tetrahydrofuran (3.42 ml) on an ice-bath. After refluxing for 30 minutes, the reaction mixture was quenched with lN
hydrochloric acid (7 ml), and refluxed for additional 30 minutes. The mixture was made alkaline with saturated aqueous sodium bicarbonate, diluted with ethyl acetate.
The organic layer was washed with saturated sodiu~
bicarbonate and brine, dried over magnesium sulfate, and evaporated. The obtained residue was chromatographed on silica gel (20 g) eluting with chloroform-methanol ~20:1 ~/V) to gi~e crystals. Recrystallization from ethanol gave 1-~4-{4-(2-nitrophenyl)piperazin-1-yl}butyl~
2,4(lH,3H3-quinazolinedione (77 mg).
mp : 164-165C
IR (Nujol, v) : 1700, 1650, 1600 cm 1 NMR ~CDC13, ~) : 1.60-1.90 (4H, m), 2.45-2.80 (6H, m), 3.00-3.25 ~4H, m3, 4.15 l2H, t, J=5Hz), 7.05 (lHr dt, J=1.6Hz), 7.15 (lH, dd, J=1.6Hz), 7.20-7.40 ~3H, m), 7.50 (lH, dt, J=1.5, 6.5Hz), 7.70 (lH, dd, J=1.6Hæ), 7.80 (lH, dd, J-l, 6Hz), 8.20 (lH, dd, J=1.5, 6.5Hz), 8.65 (lH, br s) Example 2-2) To a stirred solution of 1-[4-{4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl-4-oxo]-2,4(1H,3H)-quinazolinedione (400 mg) in dry tetrahydrofuran (5 ml) was added lithium aluminum hydride (77 mg) on an ice-bath.
2 ~ L 7 ~
After stirring for 15 minutes, the reaction-mixture was quenched with sa~urated sodium bicarbonate, and diluted with chloroform. After filtration o decomposed materials, the organic filtrate was washed with saturated aqueous sodium bicarbonate and brine dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel (15 g). Elution with a mixed solvent of chloroform and methanol (50:1 V/V) gave 1-[4-{4~
chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl}butyl~-2,4(lH,3H)-quinazolinedione (25 mg) after crystallization from diethyl ether.
mp : 162-166C
IR (Nujol, v) : 1680, 1600 cm 1 NMR (CDC13, ~ : 1.60-1.90 (4H, m), 2.55-2.70 (4H, m), 2.70-2.85 (2H, m), 3.20-3.30 ¦2H, m), 4.15 (2H, t, J=5Hz~, 6.05-6.15 (lH, m), 7.20-7.40 (6H, m), 7.65 (lH, dt, J=l, 6.5Hz), 8.20 ~lH, dd, J=l, 6.5Hz), 8.45 (lH, br s) Example 3 To a solution o 1-[4-{4-~2-nitrophenyl3piperazin 1-yl}butyl~-2~4(1H,3H)-quinazolinedione (90 mg) in ethanol (8 ml) was added tin(II) chloride (159 mg) at 80C. After stirring for 1 hour at the same temperature, the reaction mixture was quenched with ice and saturated aqueous sodium bicarbonate, and extracted with chloroform. The organic extract was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and evaporated to give an amorphous. l-[4-{4-(2-Aminophenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione (31 mg) was obtained by crystallization of the amorphous from diisopropyl ether.
mp : ~ 121C
IR (Nujol, v) : 1680, 160Q cm 1 NMR (CDC13, ~ : 1.60-1.90 (4H, m), 2.45-2.80 (6H, - G3 - 2 ~ 3 3 `-~7 ~
m), 2.85-3.10 (4H, m~, 3.90-4.05 (2H, m), 4.15 (2H, t, J=6Hz), 6.70-6.80 (2H, m), 6.90-7.10 - (2H, m), 7.20-7.40 (2H, m), 7.70 (lH, dt, J=1.6Hz), 8.20 (lH, dd, J=l, 6Hz), 8.60 (lH, br S s) Example 4 A mixture of 2-[N-{4--(4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl}-N-ethoxycarbon~17amino-4-nitrobenzamide (600 mg), and potassium hydroxide (144 mg) in dry ethanol (10 ml) was refluxed for 3 hours. After evaporation of the solvent, the residue was diluted with water, acidified with 3N hydrochloric acid, and extracted with chlorofoxm. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The crude residue was washed with hot ethanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydrop~ridin-1-yl)butyl]-7-nitxo-2,4(1H,3H)-quinazolinedione (450 mg) as a powder.
mp : 242-244C
IR (Nujol, ~) : 1710, 1680 cm 1 NMR (DMSO-d6, ~ : 1.65-1.95 (4H, m), 2.70-2.90 (2H, m), 3.15-4.10 (6H, m), 4.15-4.25 (2H, mj, 6.20 (lH, br s), 7.30-7~55 (5H, m), 8.05 (lH, dd, J=1.5, 6Hz), 8.15 (lH, d, J=1.5Hz~, 8.25 (lH, d, J=6Hz) Example 5 To a stirred suspension-of 1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl~-7-nitro-2,4(1H,3H)-quinazolinedione (840 mg) in dry ethanol (30 ml) was added tin(II) chloride (1.90 g) at 80C. After stirring for 3 hours, the mixture was ~uenched with 2N potassium hydroxide, diluted with chloroform. The organic layer was decanted and the residue was washed with chloroform.
Combined organic layer was dried over magnesium sulfate _ - 64 - 2 ~3 ~ !~ 7 3 and evaporated. l-~4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-amino-2,4(lH,3H)-quinazolinedione hydrochloride ~546 mg) as a crystal was obtained by recrystallization from 10% hydroger. chloride in methanol.
mp : 297-299C
IR ~Nujol, v) : 1680, 1600 cm 1 NMX (DMSO-d6, ~) : 1.60-1.95 (4H, m), 2.65-3.00 ~2H, m), 3.10-3.35 (3H, m), 3.55-4.20 (5H, m), 6.20 (lH, br s), 6.50 (lH, d, J=7Hz), 6.55 (lH, br s), 7.30-7.55 (5H, m), 7.70 (lH, d, J=7Hz) ExamPle 6 A mixture of 1-~4-(4-phenyl-1,2,3,5-tetrahydropyridin-l-yl)butyl]-7-methoxy-2,4tlH,3H)-quinazolinedione (300 mg) and 47% hydrobromic acid (3.8 ml) in acetic acid (6 ml) was refluxed for 24 hours.
After dilution with water, precipitates were collected.
A crude crystalline material was recrystallized from ethanol to give 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1 yl)butyl~-7-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide (140 mg'.
mp : 278-280C
IR (Nujol, v) : 1690, 1660, 1600 cm 1 NMR (DMSO-d6, ~) : 1.60-1.90 (4H, ~), 2.75-2.85 (2H, m), 3.20-3.40 (4H, m), 3.65-4.10 (4H, m), 6.15-6.25 (lH, m), 6.70-6.80 (2H, m), 7.35-7.55 (5H, m), 7.85 (lH, d, J=7Hz), 9.60 (lH, br s) Exzmple 7 5-Chloro-1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-l-yl)butyl]-2,4(1H,3H)-quinazolinedione was obtained in 62.2~ yield in substantially the same manner as that of Example 4.
mp : -238C
35 IR (N~jol, v) : 1690, 1590 cm 1 _ - - 65 - 2~ a NMR (CDC13, ~) : 1.70-2.20 (4H, m), 2.70-3.30 (6H, m), 3.50-3.80 (2H, m), 4.15 (2H, t, J=6Hz), 5.00 (lH, br s), 7.25-7.45 (7H, m), 7.60 (lH, t, J=7Hz) ExamPle 8 A mixture of 2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butylamino]-6-nitrobenzamide (300 mg) and N,N'-carbonyldiimidazole (554 mg) in dioxane (3 ml) was stirred for 2 hours at 150C. The solvent was removed during the reaction. The residue was crystallized from a mixture of ethanol and ether. The crude crystalline materials were collected, washed with methylene chloride, and recrystallized from ethanol to afford 1-l4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-5-nitro-2,4~1H,3H)-quinazolinedione l265 mg).
mp : 182C (dec.) IR (Nujol) : 1710, 1680, 1610, 1530 cm 1 NMR ~DMSO-d6, ~) : 1.50-1.5S (4H, m), 2.40-2.55 (2H, m), 2.60-2.70 (2H, m)~ 3.00-3.10 (2H, m), 3.30-3.40 (2H, m), 3.90-4.00 (2H, m), 6.15-S.20 ~lH, m), 6.4Q ~lH, d, J=7Hz), 6.50 ~lH, d, J=7Hz), 7.20-7.50 (8H, m) Example 9 1-l4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)bu~yl]-5-amino-2,4(1H,3H)-quinazolinedione was obtained in substantially the same manner as that of Ex~nple 5.
mp : 204C (dec.) IR (Nujol) : 1680, 1580, 1500 cm 1 NMR (DMSO-d6, ~) : 1.50-1.55 (4H, m), 2.40-2.55 (2H, m), 2.60-2~70 (2H, m), 3.00-3.10 ~2H, m), 3.30-3.40 ~2H, m), 3.90-4.00 (2H, m), 6.15-6.20 (lH, m), 6.40 (lH, d, J=7Hz), 6.50 (lH, d, J=7Hz), 7.20-7.50 (8H, m) - 6~ -Example 10 To a solution of 5-nitro-1-[4-(4-phenyl-1,2,3,6~
tetrahydropyridin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione (500 mg) in a mixture of chloroform (9 ml) and methanol (1 ml) was added 2N solution of sulfuric acid in methanol (1.19 ml) at 0C. After evaporation of the solvent, the crystalline residue was recrystallized from 10% water in ethanol ~30 ml) to give 5-nitro-1-[4-~4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-2,4(1H,3H)-quinazolinedione sulfate (497 mg) as pal.e brown crystals.
mp : 187-188C
IR (Nujol) : 3540, 1700, 1685, 1605 cm 1 NMR (DMSO-d6, ~) : 1.58-1.90 (4H, m), 2.72 (2H, br s), 3.12 (2H, t, J=5Hz), 3.45 (2H, br s), 3.80 (2H, br s), 4.10 (2H, d, J=5Hz), 6.18 (lH, s), 7.28-7.55 (6H, m), 7.73 (lH, d, J=8Hz), 7.91 (lH, t, J=8Hz), 9.50 (lH, br s) The following compounds were obtained in ~0 substantially the same manner as that of Example 1-2).
Example 11-1) 1-r4-{4-(2-Chlorophenyl)piperazin-1-yl}butyl]-2,4(lH,3H)-guinazolinedione mp : 176-178C
IR (Nujol) : 1700, 1680, 1610 cm 1 NMR (CDC13, ~) : 1.50-1.90 (4H, m), 2.50-2.85 (6H, m), 3.00-3.30 (4H, m), 4.15 (2H, t, J=6Hz), 6.90-7.10 (2H, m), 7.15-7~40 (5H, m), 7.70 (lH, dt, J=1, 7Hz), 8.20 (lH, dd, J=1, 7Hz), 8.80 (lH, br s) Example 11-2) 1-[4-{4-(2-Methoxyphenyl)piperazin-1-yl}butyl]-2,4(1H,3H)-quinazolinedione - 67 - 2~
mp : ~ 110C
IR (Nujol) : 1670, 1600 cm 1 - NMR (CDC13, ~) . 1.60-2.10 (4H, m), 2~50-2.60 (2H, t, J=5Hz), 2.65-2.80 (4H, m), 3.10-3.25 (4H, m~, 3.90 (3H~ s), 4.15 (2H, t, J=5Hz), 6.85-7.05 (4H, m), 7.20-7.30 (lH, m), 7.35 (lH, dt J=7Hz), 7.70 (lH, dt, J=l, 7Hz), 8.25 (lH, dd, J=l, 7Hz) The following compounds were obtained substantially 10 the same manner as that of Example 1-1).
Example 11-3) 1-[4-{4-(2-Methoxyphenyl)piperazin-l-yl}butyl]-6-methoxy-2,4(lH,3H)-~inazolinedione mp : 198-200C
IR (Nujol) : 1700, 1660, 1580 cm 1 NMR ~CDC13, ~) : 1.60-1.90 (4H, m), 2.50 (2H, t, J=5Hz), 4.15 (2H, t, J=6Hz), 6.85-7.05 (4H, m), 7.25-7.35 (2H, m), 7.65 (lH, d, J=1.5Hz), 8.75 (lH, br s) ~xample_11-4) 1-[4-{4-(2-Chlorophenyl)piperazin-l-yl}butyl]-6-methoxy-2,4~1H,3H)-quinazolinedione mp : 204-206C
IR (Nujol) : 1710, 1660 cm 1 ~MR (CDCl3, ~) : 1.60-1.90 (4H, m), 2.55 (2H, t, J=6Hz), 2.60-2.75 (4H, m), 3.05-3.20 ~4H, m), 3.90 (3H, s), 4.15 (2H, t, J=6Hz), 6.95-7.10 (2H, m), 7.20-7.30 (3H, m), 7.35 (lH, dd, J=l, 7Hz), 7.60-7.70 (lH, m), 8.85 (lH, br 5) Example 11-5) 1-[4-{4-~2-Methoxyphenyl)piperazin-l-yl}butyl]-7-chloro-2,4(1H,3H)-quinazolinedione - 68 - 2~
mp : 190-191C
IR ~Nujol) : 1700, 1680, 1600 cm 1 NMR (CDC13, ~) : 1.60-1.90 ~4H, m~, 2.55 (2H, t, J=5Hz), 2.65-2.80 (4H, m), 3.10-3~20 (4H, m), 3.90 (3H, s), 4.15 (2H, t, J=5Hz~, 6.85-7.05 (4H, m), 7.25 (lH, dd, J=1.~, 7Hz), 7.35 (lH, d, J=1.5Hz), 8~15 (lH, d, J=7Hz) Example 11-6) 1-[4-{4-(2-Chlorophenyl)piperazin-1-yl}butyl]-7-chloro-2,4(lH,3H)-quinazolinedione mp : 174-176C
IR (Nujol) : 1690, 1600 cm 1 NMR (CDC13, ~) : 1.50-1.90 (4H, m), 2.50-2.35 (6H, m), 3.05-3.30 (4H, m), 4.15 (2H, t, J=5Hz), 6.95-7.10 (2H, m), 7.20-7.30 (2H, m), 7.30-7.40 (2H, m), 8.15 (lH, d, J=8Hz), 8.55 (lH, br s) Example 11-7) 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-7-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide mp : 278-280C
Exam~le 11-8) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(lH,3H)-quinazolinedione mp : 182C (dec.) The following compounds were obtained in substantially the same manner as that of Example 2-1).
Example 12-1) 1-[4-{4-~4-Tolyl)-1,2,3,6-tetrahydropyridin 1-yl}-butyl]-2,4(lH,3H)-quinazolinedione 2~a3 l7~
mp : 152-156C
IR (Nujol) : 1710, 1670, 1600 cm 1 -NMR (CDCl3, ~) : 1.70-1.90 54H~ m), 2.3~ (3H, s), 2.55-2.70 (4H, m), 2.75-2.85 (2H, m), 3.20-3.30 (2H, m), 4.15 (2H, t, J=5Hz), 6.00-6.10 ~lH, m), 7.10-7.35 (5EI, m), 7.45 (lH, d, J=7Hz), 7.65 (lH, dt, J=l, 7Hz)~ B.20 (lH, dd, J=l, 7Hz), 8.45 (lH, br s) ExamPle 12-2) 1-~4-{4-(2-Tolyl)piperazin-l-yl}butyl~-2,4(lH,3H)-quinazolinedione mp : 74-85C
IR 5Nujol) : 1700, 1600 cm 1 MMR (CDC13, ~) : 1.60-1.90 ~4H, m), 2.30 (3H, s), 2.50 (2H, t, J=5Hz), 2.60-2.70 (4H, m), 2.95 (4H, t, J=4Hz), 4.15 (2H, t, J=5Hz), 6.95-7.05 (2H, m), 7.10-7.40 (4H, m), 7.70 5lH, dt, J=l, 7Hz), 8.20 (lH, dd, J=1.5, 7Hz), 8.75 (lH, br s) Example 12-3~
1-[4-(4-Phenylpiperazin-l-yl)butyl]-2,4(1H,3H)-quinazolinedione mp : 164-167C --IR (Nujol) : 1710, 1670, 1600 cm 1 NMR (CDCl3, ~) : 1.60-1.90 (4H, m), 2.55 52H, t, J=4Hz3, 2.60-2.75 54H, m), 3.25 (4H, t, J=4Hz), 4.15 ~2H, t, J=6Hz), 6.80-7.00 (3H, m), 7.20-7.40 54H, m), 7.70 (lH, dt, J=l, 7~1z),8.20 (lH, dd, J=l, 7Hz), 8.65 (lH, br s) Example 12-4) l-L4-{4-(2-Ethoxyphenyl)piperazin-l-yl}butyl~-2,4(1H,3H)-quinazolinedione - 2 ~ 7 ~
_ - 70 mp ~ 85C
IR (Nujol) : 1680, 1600 cm 1 NMR (CDC13, ~) : 1.45 ~3H, t, J=6~z), 1.60-1.90 (4H, m), 2.50 (2H, t, J=5Hz), 2065-2.80 (4H, m), 3.10-3.25 ~4H, m~, 4.0Q-4.20 ~4H, m), 6.80-7.00 (4H, m), 7.30 (lH, t, J=7Hz), 7.40 (lH, d, J=7Hz), 7.70 (lH, dt, J=1.5, 7Hæ), 8.20 (lH, dd, J=1.5, 7Hz), 8.75 (lH, br s) xamPle 12-5) 6-Chloro-1-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-2,4(lH,3H)-quinazolinedione mp : 159C (dec.) IR (Nujol) : 1680, 1600 cm 1 NMR (CDCl3, ~) : 1.65-1.90 ~4H, m), 2.55-2.70 (4H, m), 2.70-2.85 (2H, m), 3.20-3.30 (2H, m), 4.05-4.20 (2H, m), 6.05-6.15 (lH, m), 7.20-7.45 (6H, m), 7.55 (lH, dd, J=1.5, 8Hz), 8.15 (lH, d, J=l.SHz) Example 12-6) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-7-hydroxy-2,4(lH,3H)-~uinazolinedione hydrobromide mp : 278-280C
~5 Example 12-7) 1-[4-(4-Phenyl-1,2,3r6-tetrahydropyridin-1-y:L)butyl]-5-nitro-2,4(lH,3H)-quinazolinedione mp : 182C (dec.) The following compounds were obtained in substantially the same manner as that oi Example 4.
Example 13-1) 1 [4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-2 53 ~ 3 17 ~
6-ethoxy-2,4l1H,3H)-quinazolinedione mp : 170-172C
IR tNujol) : 1690, 1650, 1580 cm 1 NM~ ~CDCl3, ~) : 1.40 (3H~ t, J-6Hz), 1.65-1.90 (4H, m), 2.55-2.70 (4H, m), 2.70-2.30 (2H, m), 3.15-3.25 t2H, m), 4.00 (2H, q, J=6Hz), 4.15 (2H, t, J=5Hz), 6.05-6.15 (lH, m), 7.15-7.40 (7H, m), 7.60 (lH, d, J=2Hz), 8.60 (lH, br s) ExamPle 13-2) -1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methoxy-2,4(lH,3H)-quinazolinedione mp : 192-194C
IR tNujol) : 1670 cm 1 NMR (CDCl3, ~) : 1.70-1.90 (4H, m), 2.55-2.70 (4H, m), 2.80 ~2H, t, J=4Hz), 3.20-3.30 (2H, m), 3.80 (3H, s), 4.15 (2H, t, J=6Hz), 6.05-6.15 (lH, m), 7.20-7.45 (7H, m), 7.60 (lH, d, J=2Hz), 8.60 (lH, br s) Example 13-3) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-8-chloro-2,4(1~,3H~-quinazolinedione mp : 194-197C
IR (Nujol) : 1680, 1600 cm 1 NMR (DMSO-d6, ~) : 1.60-1.90 (4H, m), 2.60 2.80 (2H, m), 2.90-3075 (6H, m), 4.25-4.40 (2H, m), 6.20 (lH, br s), 7.25-7.50 (6H, m), 7.85 (lH, dd, J=l, 6Hz), 8.05 (lH, dd, J=l, 6Hz) ExamPle 13-4) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-methoxy-2,4(1H,3H)-quinaz~linedione mp : 171-173C
IR (Nujol) : 1690, 1610 cm 1 2 ~
NMR ~DMSO-d6, ~) : 1.70-l.90 ~4H, m), 2.60-2.70 (4H, m), 2.85 ¦2H, t, J=5Hz), 3.25-3.35 (2H, m), 3O85 - (3H, s), 4.10 ~2H, t, J= 5;5Hz), 6.05-6.10 (lH, `~
m), 6.70 llH, d, J=2Hz), 6.80 (lH, dd, J=2, 8Hz), 7.25-7.40 (5H, m), 8.15 (lH, d, J=8Hz), 8.4~ (lH, br s) _ample 13-5) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6,7-dimethoxy-2,4(1H,3H)-quinazolinedione IR (Nujol~ : 1680, 1620 cm 1 NMR (CDC13, ~) : 1.85-2.00 (4H, m), 2.75-2.85 (2H, m), 2.85 2.95 (2H, m), 3.10 (2H, t, J=6Hz), 3.95 (~H, s), 4.05 (3H, s~, 4.20 (2H, t, J=7Hz), 6.00-6.05 (lH, m), 6.70 (lH, s), 7.25-7~40 (5H, m), 7.60 (lH, s) Exam~le 13-6) 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-7-chloro-2,4(lH,3H)-~uinazolinedione mp : 152-154C
IR (Nujol) : 1680, 1600 cm 1 NMR (CDCl3, ~) : 1060-l.90 (4H, m), 2.55-2.70 (4H, m), 2.75-2.85 (2H, t, J=5Hz), 3.20-3.30 (2H, m), 4.15 (2H, t, J-6Hz), 6.05-6.15 (lH, m), 7.20-7.4S (7H, m) "3.15 (lH, d, J=7Hz) Example 13-7) 1-~4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-nitro-2,4(lH,3H) quinazolinedi~ne mp : 194C (dec.) IR (Nujol) : 1710, 1670, 1610 cm 1 NMR (DMSO-d6, ~) : 1.65-1.75 (4H, m), 2.40-2.60 (4H, m), 2.60-2.70 (2H, m), 3.10-3.20 (2H, m), 4.05-4.20 (2H, m), 6.20 (lH, br s), 7.20-7.50 2~3~
(5~, m), 7.80 (lH, d, J=8Hz), 8.40 (lH, dd, J=2, 8Hz), 8.65 ~lH, d, J=2Hz) ExamPle 13-8) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]~
7-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide mp : 278-280C
Example 13-9) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(lH,3H)-quinazolinedione mp : 182c (dec.) The following compounds were obtained in substantially the same mann r as that of Example 6.
Ex~nple 14-1) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-hydroxy-2,4(lH,3H)-quinazolinedione hydrobromide mp : 274-276C
IR ~Nujol) 1570, 1480 cm 1 NMR (DMSO-d6, ~) : 1.60 1.90 (4H, m), 2.75-2.90 (2H, m), 3.20-3.40 (3~, m), 3.60-3.90 (2H, m), 3.90-4.10 (3H, m), 6.20 (lH, br s), 7.20 ~lH, dd, J=2, 8Hz), 7.30-7.55 (7H, m), 9.60 (lH, br s), 9.80 (lH, s) _xample 14-2) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl.)butyl]-6,7-dihydroxy-2,4(1H,3H3-quinazolinedione hydrobromide mp : 280-282C
IR (Nujol) : 3650-3100, 1690, 1660, 1620 cm NMR (DMSO-d6, ~) : 1.60-1.90 (4H, m), 2.75-2.85 (2H, m), 3.20-3.40 (5H, m), 3.60-3.90 (2H, m), 3.90-4.05 (3H, m), 6.20 (lH, br s), 6.80 (lH, -_ 7~ _ 2 J~ 7 5), 7-30-7-55 16H, m), 3.60 (1 or 2H, br s) Example 14-3) 1-[4-~4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl~butyl]-5-hydroxy-2,4(lH,3H~-quinazolinedione mp : 262-264C
IR ~Nujol) : 1690, 1650, 1620, 1260 cm 1 NMR (CDCl3, ~) : 1.60-1.95 (4H, m), 2.75-2.90 (2H, m), 3.20-4.00 (6H, m), 4.10 (2H, t, J=5Hz), 6.20 (lH, br s), 6.70 (lH, d, J=7Hz), 6.95 (lH, d, J=7Hz), 7.35-7.70 (6H, m) Example 15 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-amino-2,4(lH,3H)-quinazolinedione hydrochloride was obtained in substantially the same manner as that of Example 5.
mp : ~210C
IR (Nujol) : 1680, 1620 cm 1 N~R (DMSO-d6, ~) : 1.60-1.95 (4H, m), 2.70-3~00 (2H, m), 3.00-3.90 (4H, m), 3.90-4.20 (4H, m), 6.20 (lH, br s), 7.30-7.65 (7H, m), 7.85 (lH, d, J=lHz) Example 16-1) 1-~4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-(imidazol-1-yl)-2,4(1H,3H)-quinazolinedione was obtained from 2-lN-~4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butylamino]-6-fluoroben~amide in substantially the same manner as that of Example 8.
mp : 213-215C
IR ~Nujol) : 1700, 1670, 1600, 1490 cm 1 NMR (DMSO-d6, ~) : 1.55-1.80 (4H, m), 2.40-2.60 (2H, m), 2.60-2.70 (2H, m), 3.05-3.20 (2H, m), 3.30-3.55 (2H, m), 4.05-4.20 (2H, m), 6.20 (lH, br s~, 7.00 (lH, s), 7.10-7.20 (lH, m), - ` 75 2 ~ 3 ~
7.20-7.50 ~6H, m), 7.70 (3H, br s) Example 16-2) A mixture of 2-EN-{4-~4-phenyl-1,2,3,6-tetrahydro-pyridin-1-yl)butylamino-6-fluorobenzamide (900 mg), trichloromethyl chloroformate (1.5 ml) and active charcoal (catalytic amounts) in dioxane (20 ml) was stirred for 1 hour at 80C. The solvent was removed in vacuo. The residue was dissolved in 10% hydrogen chloride-methanol, then the solution was filtered. After evaporation of the filtrate, the residue was crystallized from ethanol-ether.
The crude crystals were collected, and washed with hot ethanol to afford 1-[4-l4-phenyl-1,2,3,6-tetrahydro-pyridin-l-yl)butyl~-5-fluoro-2,4(1H,3H~-quinazolinedione hydrochloride (80 mg).
mp : 276C (dec.) IR (Nujol) : 1680, 1610 cm 1 NMR (DMSO-d6, ~) : 1.60-1.90 (4H, m), 2.70-2.90 ~2H, m), 3.15-4.20 (8H, m), 6.20 (lH, br s), 7.10 (lH, dd, J=7Hz), 7.30-7.60 (6H, m), 7.75 (1~, dt, J=4, 7Hz) The following compounds were obtained in substantially the same manner as that of Example 16-2).
Example 16-3) 1~[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-methoxy-2,4(1H,3H)-quinazolinedione mp : 219-221C
IR ~Nujol) : 1670, 1590, 1260 cm 1 NMR ~CDCl3t ~) : 1.50-1.70 (4H, m), 2.40-2.55 (4H, m), 3.05-3.15 (2H, m), 3.80 ~3H, s), 4.00-4.10 (2H, m), 6.20 (lH, br s), 6.85 (lH, d, J=6Hz), 7.10 (lH, d, J=6Hz), 7.20-7.60 (6H, m) ~ ~ r /~ r~, ~
Example 16-4) 1-14-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl~-5-methyl-2,4(lH,3H)-quinazolinedione mp : 175-177C
IR (Nujol) : 1680, 1590, 1430 cm 1 NMR (CDCl3, ~) : 1.70-2.00 (4H, m), 2.55-2.70 (4H, m), 2.70-2.85 (5H, m), 3.20-3.30 (2H, m), 4.15 (2H, t, J=5Hz), 6.05-6.15 (lH, m), 7.00 (lH, d, J=7Hz), 7.20-7.50 (7H, m) Example 16-5) 1-[4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4l1H,3H)-quinazolinedione mp : 182~C (dec.) Example 17 A mixture of 1-l4-(4-phenyl-1,2,3,6-tetrahydro-pyridin-1-yl)butyl]-7-amino-2,4(lH,3H)-quinazolinedione hydrochloride (70 mg~, methanesulfonyl chloride (0.02 ml) potassium carbonate t50 mg~ in dimethylformamide (1 ml) was stirred for 2 hours at room temperature. The reaction mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated.
The crude residue was washed with hot ethanol, then treated with 10~ hydrogen chloride-methanol, and evaporated.1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-7-methanesulfonylamino-2,4(lH,3H)-quinazolinedione hydrochloride (18 mg) as a crystal was obtained by recrystallization from ethanol.
mp : 254C (dec.) IR tNuiol) : 1680, 1610, 1590 cm NMR (DMSO-d6, ~) : 1.65-2.05 (4H, m), 2.70-2.90 (2H, m), 3.15-3.50 (5H, m), 3.60-4.15 (6H, m), 6. 0 (lH, br s), 7.45-7.55 (5H, ~), 7.95 (lH, br s), 8.05 (lH, d, J=8Hz), 9.05-9.20 (lH, m)
Claims (16)
1. A compound of the formula :
in which R1 and R2 are each hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substituent(s), A is lower alkylene, and the formula: is N-containing heterocylcic group, or pharmaceutically acceptable salts thereof.
in which R1 and R2 are each hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substituent(s), A is lower alkylene, and the formula: is N-containing heterocylcic group, or pharmaceutically acceptable salts thereof.
2. The compound of Claim 1, wherein R1 and R2 are each hydrogen, halogen, nitro, amino, acylamino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, esterified carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is phenyl which is substituted or unsubstituted by one to three substituent(s) selected from the group consisting of halogen, lower alkyl, lower alkoxy, nitro and amino, and the formula: is unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), saturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to
3 nitrogen atom(s), saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), or saturated 5- or 6-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s).
3. The compound of Claim 2, wherein the formula: is saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s).
3. The compound of Claim 2, wherein the formula: is saturated or unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s).
4. The compound of Claim 3, wherein the formula: is pyrrol-1-yl, pyrrolin-1-yl, imidazol-l-yl, pyrazol-l-yl, tetrahydropyridyl, triazolyl, tetrazolyl, dihydrotriazinyl, azetidin-l-yl, pyrrolidin-l-yl, imidazolidin-l-(or 3-)yl, piperidin-1-yl, pyrazolidin-1-yl, piperazin-1-yl, oxazinyl, oxadiazinyl, morpholin-4-yl, thiazolinyl, or thiazolidin-1-yl.
5. The compound of Claim 4, wherein R1 and R2 are each hydrogen, halogen, nitro, amino, lower alkanesulfonylamino, lower alkoxy, lower alkyl, hydroxy or imidazolyl, and the formula: is piperazin-1-yl and 1,2,3,6-tetrahydropyridin-1-yl.
6. The compound of Claim 5, wherein R1 and R2 are each hydrogen, halogen, nitro, amino, Cl-C4 alkanesulfonylamino, C1-C4 alkoxy, C1-C4 alkyl, hydroxy or imidazol-1-yl, R3 is phenyl which is substituted or unsubstituted by the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro and amino, and A is C1-C4 alkylene.
7. The compound of Claim 6, wherein R1 and R2 are each hydrogen, chlorine, fluorine, nitro, amino, methanesulfonylamino, methoxy, ethoxy, methyl, hydroxy or imidazolyl, R3 is phenyl which is substituted or unsubstituted by the group consisting of chloro, methyl, methoxy, ethoxy, propoxy, nitro and amino, and A is tetramethylene.
8. The compound of Claim 7, wherein the formula :
is piperazin-l-yl.
is piperazin-l-yl.
9. The compound of Claim 7, wherein the formula :
is 1,2,3,6-tetrahydropyridin-1-yl.
is 1,2,3,6-tetrahydropyridin-1-yl.
10. The compound of Claim 9, which is 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-nitro-2,4(1H,3H)-quinazolinedione, 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-7-hydroxy-2,4(1H,3H)-quinazolinedione hydrobromide, 1-[4-14-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-nitro-2,4(1H,3H) quinazolinedione or sulfate thereof, 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-nitro-2,4(1H,3H)-quinazolinedione, 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-hydroxy-2,4(1H,3H)-quinazolinedione or hydrobromide thereof, 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6,7-dihydroxy-2,4(1H,3H)-quinazolinedione or hydrobromide thereof, or 1-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-5-hydroxy-2,4(1H,3H)-quinazolinedione.
11. A process for the preparation of a compound of the formula :
(I) in which R1 and R2 are each hydrogen, halogen, nitro amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substituent(s), A is lower alkylene, and the formula: is N-containing heterocylcic group, or salts thereof, which comprises (a) reacting a compound of the formula :
(II) or its reactive derivative at the hydroxy group, or salts thereof, with a compound of the formula :
(III) or salts thereof, to give the compound of the formula (I) or salts thereof; or (b) reducing the amido moiety of a compound of the formula :
(IV) or salts thereof, to give the compound of the formula (I) or salts thereof; or (c) subjecting a compound of the formula :
(I-a) or salts thereof to a reduction of the nitro group in R?, to give a compound of the formula :
(I-b) or salts thereof; or (d) reacting a compound of the formula :
(V) or salts thereof with a base, to give the compound of the formula (I) or salts thereof; or (e) hydrolyzing a compound of the formula :
(I-c) or salts thereof, to give a compound of the formula :
(I-d) or salts thereof; or (f) subjecting a compound of the formula :
(I-e) or salts thereof, to a reduction of the nitro group(s) of R? and/or R? to give a compound of the formula :
(I-f) or salts thereof; or (g) reacting a compound of the formula :
(VIII) or salts thereof with a compound of the formula :
X1-CO-X2 (XI) to give the compound of the formula (I) or salts thereof; or (h) reacting a compound of the formula :
(I-g) or salts thereof, with an amino-protective group introducing agent to give a compound of the formula :
(I-h) or salts thereof;
wherein R1, R2, R3, A and the formula :
are each as defined above, one of R? and R? is lower alkoxy while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is hydroxy while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is nitro while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is hydroxyamino or amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is protected amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R? is aryl substituted by nitro, R? is aryl substituted by amino, R4 is esterified carboxy, and A1 is C1-C5 alkylene.
(I) in which R1 and R2 are each hydrogen, halogen, nitro amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R3 is aryl which may have suitable substituent(s), A is lower alkylene, and the formula: is N-containing heterocylcic group, or salts thereof, which comprises (a) reacting a compound of the formula :
(II) or its reactive derivative at the hydroxy group, or salts thereof, with a compound of the formula :
(III) or salts thereof, to give the compound of the formula (I) or salts thereof; or (b) reducing the amido moiety of a compound of the formula :
(IV) or salts thereof, to give the compound of the formula (I) or salts thereof; or (c) subjecting a compound of the formula :
(I-a) or salts thereof to a reduction of the nitro group in R?, to give a compound of the formula :
(I-b) or salts thereof; or (d) reacting a compound of the formula :
(V) or salts thereof with a base, to give the compound of the formula (I) or salts thereof; or (e) hydrolyzing a compound of the formula :
(I-c) or salts thereof, to give a compound of the formula :
(I-d) or salts thereof; or (f) subjecting a compound of the formula :
(I-e) or salts thereof, to a reduction of the nitro group(s) of R? and/or R? to give a compound of the formula :
(I-f) or salts thereof; or (g) reacting a compound of the formula :
(VIII) or salts thereof with a compound of the formula :
X1-CO-X2 (XI) to give the compound of the formula (I) or salts thereof; or (h) reacting a compound of the formula :
(I-g) or salts thereof, with an amino-protective group introducing agent to give a compound of the formula :
(I-h) or salts thereof;
wherein R1, R2, R3, A and the formula :
are each as defined above, one of R? and R? is lower alkoxy while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is hydroxy while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is nitro while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is hydroxyamino or amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, one of R? and R? is protected amino while the other is hydrogen, halogen, nitro, amino, protected amino, hydroxyamino, lower alkoxy, lower alkyl, hydroxy, sulfamoyl, carboxy, protected carboxy, carbamoyl, mercapto, lower alkylthio or imidazolyl, R? is aryl substituted by nitro, R? is aryl substituted by amino, R4 is esterified carboxy, and A1 is C1-C5 alkylene.
12. A pharmaceutical composition comprising, as an active ingredient, a compound of Claim 1 in admixture with a pharmaceutically acceptable carrier or excipient.
13. A compound of Claim 1 for use as a medicament.
14. A compound of Claim 1 for use as a dopamine receptor agonist.
15. A method for the treatment of dopamine receptor mediated diseases which comprises administering a compound of Claim 1 to a human being or animal.
16. A process for preparing a pharmaceutical composition which comprises admixing a compound of Claim 1 with a pharmaceutically acceptable carrier or excipient.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9022306.6 | 1990-10-15 | ||
| GB909022306A GB9022306D0 (en) | 1990-10-15 | 1990-10-15 | Quinazoline derivatives and their preparation |
| GB9118337.6 | 1991-08-27 | ||
| GB919118337A GB9118337D0 (en) | 1991-08-27 | 1991-08-27 | Quinazoline derivatives and their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2053475A1 true CA2053475A1 (en) | 1992-04-16 |
Family
ID=26297803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002053475A Abandoned CA2053475A1 (en) | 1990-10-15 | 1991-10-15 | Quinazoline derivatives and their preparation |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5304560A (en) |
| EP (1) | EP0481342A1 (en) |
| JP (1) | JP3164119B2 (en) |
| KR (1) | KR920008031A (en) |
| CN (1) | CN1060841A (en) |
| AU (1) | AU648110B2 (en) |
| CA (1) | CA2053475A1 (en) |
| FI (1) | FI914826A7 (en) |
| HU (1) | HUT59390A (en) |
| IE (1) | IE913473A1 (en) |
| NO (1) | NO914036L (en) |
| PT (1) | PT99227B (en) |
| TW (1) | TW201308B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025371A (en) * | 1996-10-28 | 2000-02-15 | Versicor, Inc. | Solid phase and combinatorial library syntheses of fused 2,4-pyrimidinediones |
| US6413724B1 (en) | 1996-10-28 | 2002-07-02 | Versicor, Inc. | Solid phase and combinatorial library syntheses of fused 2,4-pyrimidinediones |
| EP3332645A1 (en) | 2016-12-12 | 2018-06-13 | Bayer Cropscience AG | Use of substituted pyrimidine diones or their salts as agents to combat abiotic plant stress |
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|---|---|---|---|---|
| ATE126796T1 (en) * | 1990-01-02 | 1995-09-15 | Fujisawa Pharmaceutical Co | QUINAZOLINE DERIVATIVES AND THEIR PRODUCTION. |
| US5994542A (en) * | 1995-11-14 | 1999-11-30 | Sumitomo Chemical Company, Limited | Process for producing 1-substituted tetrahydroquinazolines |
| US6133275A (en) * | 1998-05-06 | 2000-10-17 | Abbott Laboratories | 3-phenylpyrrolidine alpha-1 adrenergic compounds |
| CA2341370A1 (en) * | 1998-08-20 | 2000-03-02 | Smithkline Beecham Corporation | Novel substituted triazole compounds |
| ES2259476T3 (en) | 1998-08-21 | 2006-10-01 | Daiichi Asubio Pharma Co., Ltd. | DERIVATIVES OF QUINAZOLINA AND ITS PHARMACEUTICAL APPLICATIONS. |
| US6521630B1 (en) | 1999-08-31 | 2003-02-18 | Pfizer Inc. | Tetrahydroquinazoline-2,4-diones and therapeutic uses thereof |
| EP1233950B1 (en) | 1999-11-23 | 2005-10-05 | Smithkline Beecham Corporation | 3,4-DIHYDRO-(1H)QUINAZOLIN-2-ONE COMPOUNDS AS CSBP/P39 kINASE INHIBITORS |
| JP2003514900A (en) | 1999-11-23 | 2003-04-22 | スミスクライン・ビーチャム・コーポレイション | 3,4-Dihydro- (1H) -quinazolin-2-one compounds as CSBP / p38 kinase inhibitors |
| ATE281439T1 (en) | 1999-11-23 | 2004-11-15 | Smithkline Beecham Corp | 3,4-DIHYDRO-(1H)CHINAZOLINE-2-ONE COMPOUNDS AS CSBP/P38 KINASE INHIBITORS |
| US6759410B1 (en) * | 1999-11-23 | 2004-07-06 | Smithline Beecham Corporation | 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors |
| AU1626001A (en) * | 1999-11-23 | 2001-06-04 | Smithkline Beecham Corporation | 3,4-dihydro-(1h)-quinazolin-2-ones and their use as csbp/p38 kinase inhibitors |
| CN1245979C (en) * | 2000-02-22 | 2006-03-22 | 第一阿斯比奥制药株式会社 | Drug for preventing and treating dermatitis containing chymase inhibitor as active ingredient |
| US7235551B2 (en) * | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
| CN100525768C (en) * | 2000-10-23 | 2009-08-12 | 史密丝克莱恩比彻姆公司 | Novel compounds |
| KR20040103972A (en) * | 2002-04-19 | 2004-12-09 | 스미스클라인 비참 코포레이션 | Novel Compounds |
| WO2005026153A1 (en) * | 2003-09-12 | 2005-03-24 | Warner-Lambert Company Llc | Quinazoline-2, 4-diones as antibacterial agents |
| CA2546002C (en) * | 2003-11-20 | 2012-09-18 | Janssen Pharmaceutica N.V. | 7-phenylalkyl substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitors |
| BRPI0416206A (en) | 2003-11-20 | 2006-12-26 | Janssen Pharmaceutica Nv | 6-Alkenyl and 6-phenylalkyl-substituted 2-quinolinones and 2-quinoxalinones as poly (adp-ribose) polymerase inhibitors |
| SG151249A1 (en) * | 2003-12-05 | 2009-04-30 | Janssen Pharmaceutica Nv | 6-substituted 2-quinolinones and 2-quinoxalinones as poly(adp-ribose) polymerase inhibitors |
| ATE540936T1 (en) * | 2004-06-30 | 2012-01-15 | Janssen Pharmaceutica Nv | SUBSTITUTED 2-ALKYL-QUINAZOLINONE DERIVATIVES AS PARP INHIBITORS |
| EA011552B1 (en) | 2004-06-30 | 2009-04-28 | Янссен Фармацевтика Н.В. | Quinazolinedione derivatives as parp inhibitors |
| SG154433A1 (en) * | 2004-06-30 | 2009-08-28 | Janssen Pharmaceutica Nv | Phthalazine derivatives as parp inhibitors |
| PE20061193A1 (en) * | 2005-03-25 | 2006-12-02 | Glaxo Group Ltd | DERIVATIVES OF 3,4-DIHYDROPYRIMIDO [4,5-d] PYRIMIDIN-2- [1H] -0NA AS KINASE INHIBITORS p38 |
| US20080096905A1 (en) * | 2005-03-25 | 2008-04-24 | Glaxo Group Limited | Process For Preparing Pyrido[2,3-D]Pyrimidin-7-One And 3,4-Dihydropyrimido{4,5-D}Pyrimidin-2(1H)-One Derivatives |
| MY145343A (en) * | 2005-03-25 | 2012-01-31 | Glaxo Group Ltd | Novel compounds |
| US7423042B2 (en) * | 2005-03-25 | 2008-09-09 | Glaxo Group Limited | Compounds |
| GB0507298D0 (en) * | 2005-04-11 | 2005-05-18 | Novartis Ag | Organic compounds |
| US8299256B2 (en) * | 2007-03-08 | 2012-10-30 | Janssen Pharmaceutica Nv | Quinolinone derivatives as PARP and TANK inhibitors |
| US8404713B2 (en) * | 2007-10-26 | 2013-03-26 | Janssen Pharmaceutica Nv | Quinolinone derivatives as PARP inhibitors |
| ES2367760T3 (en) * | 2008-03-27 | 2011-11-08 | Janssen Pharmaceutica, N.V. | DERIVATIVES OF QUINAZOLINONA AS INHIBITORS OF THE POLYMERIZATION OF THE TUBULIN. |
| CN101981013B (en) | 2008-03-27 | 2013-05-29 | 詹森药业有限公司 | Tetrahydrophenanthridinones and tetrahydrocyclopentaquinolinones as PARP and tubulin polymerization inhibitors |
| CN102786483B (en) * | 2011-05-19 | 2016-03-30 | 复旦大学 | 4-(4-Phenylpiperazinyl) pharmaceutical usage of quinazoline derivative |
| EP4141009A1 (en) * | 2021-08-30 | 2023-03-01 | Saltigo GmbH | Method for the preparation of a mixture containing hydroxy-ethyl isobutyl piperidine carboxylate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3274194A (en) * | 1963-03-29 | 1966-09-20 | Miles Lab | Quinazolinedione derivatives |
| US4335127A (en) * | 1979-01-08 | 1982-06-15 | Janssen Pharmaceutica, N.V. | Piperidinylalkyl quinazoline compounds, composition and method of use |
| US4522945A (en) * | 1979-10-12 | 1985-06-11 | Janssen Pharmaceutica N.V. | (Piperidinylalkyl) quinazoline derivatives |
| JPS5948777B2 (en) * | 1980-07-07 | 1984-11-28 | 株式会社クボタ | Manufacturing method of thick tiles |
| JPS608274A (en) * | 1983-06-27 | 1985-01-17 | Fujisawa Pharmaceut Co Ltd | Novel quinazolinone derivative, its preparation and antiallergic agent |
| US4716161A (en) * | 1984-04-17 | 1987-12-29 | Mitsubishi Chemical Industries Limited | Phenylpiperazine derivatives and their acid addition salts |
| US4711883A (en) * | 1985-09-30 | 1987-12-08 | Ortho Pharmaceutical Corporation | Substituted 3-(4-phenyl-1-piperazinyl)alkylquinazolin-2,4-(1H,3H) diones, methods of preparation, compositions and method of use |
-
1991
- 1991-10-02 IE IE347391A patent/IE913473A1/en not_active Application Discontinuation
- 1991-10-09 EP EP91117203A patent/EP0481342A1/en not_active Ceased
- 1991-10-11 AU AU85800/91A patent/AU648110B2/en not_active Ceased
- 1991-10-12 TW TW080108057A patent/TW201308B/zh active
- 1991-10-14 NO NO91914036A patent/NO914036L/en unknown
- 1991-10-14 FI FI914826A patent/FI914826A7/en not_active Application Discontinuation
- 1991-10-14 KR KR1019910018015A patent/KR920008031A/en not_active Withdrawn
- 1991-10-14 HU HU913243A patent/HUT59390A/en unknown
- 1991-10-14 CN CN91109920A patent/CN1060841A/en active Pending
- 1991-10-14 PT PT99227A patent/PT99227B/en not_active IP Right Cessation
- 1991-10-15 JP JP33299691A patent/JP3164119B2/en not_active Expired - Fee Related
- 1991-10-15 CA CA002053475A patent/CA2053475A1/en not_active Abandoned
-
1993
- 1993-08-09 US US08/103,315 patent/US5304560A/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6025371A (en) * | 1996-10-28 | 2000-02-15 | Versicor, Inc. | Solid phase and combinatorial library syntheses of fused 2,4-pyrimidinediones |
| US6413724B1 (en) | 1996-10-28 | 2002-07-02 | Versicor, Inc. | Solid phase and combinatorial library syntheses of fused 2,4-pyrimidinediones |
| EP3332645A1 (en) | 2016-12-12 | 2018-06-13 | Bayer Cropscience AG | Use of substituted pyrimidine diones or their salts as agents to combat abiotic plant stress |
Also Published As
| Publication number | Publication date |
|---|---|
| FI914826L (en) | 1992-04-16 |
| EP0481342A1 (en) | 1992-04-22 |
| NO914036D0 (en) | 1991-10-14 |
| HU913243D0 (en) | 1992-01-28 |
| KR920008031A (en) | 1992-05-27 |
| JP3164119B2 (en) | 2001-05-08 |
| AU8580091A (en) | 1992-04-16 |
| FI914826A0 (en) | 1991-10-14 |
| HUT59390A (en) | 1992-05-28 |
| CN1060841A (en) | 1992-05-06 |
| TW201308B (en) | 1993-03-01 |
| US5304560A (en) | 1994-04-19 |
| AU648110B2 (en) | 1994-04-14 |
| FI914826A7 (en) | 1992-04-16 |
| PT99227B (en) | 1999-04-30 |
| PT99227A (en) | 1992-09-30 |
| JPH04261170A (en) | 1992-09-17 |
| IE913473A1 (en) | 1992-04-22 |
| NO914036L (en) | 1992-04-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |