GB2041358A - Benzoxadiazoles and benzothiadiazoles - Google Patents
Benzoxadiazoles and benzothiadiazoles Download PDFInfo
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- GB2041358A GB2041358A GB7943112A GB7943112A GB2041358A GB 2041358 A GB2041358 A GB 2041358A GB 7943112 A GB7943112 A GB 7943112A GB 7943112 A GB7943112 A GB 7943112A GB 2041358 A GB2041358 A GB 2041358A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
Compounds of formula I, <IMAGE> wherein X is oxygen or sulphur, and R1-R6 are various substituents. The compounds are useful for treating coronary insufficiency, intermittent claudication, cerebrovascular insults, spasms in muscles and hypertension.
Description
SPECIFICATION Benzoxadiazoles and benzothiadiazoles, their preparation and pharmaceutical compositions containing them
The present invention relates to benzoxadiazoles and benzothiadiazoles having a 4-dihyropyridine moiety.
The present invention providesin particular compounds of formula I,
wherein
R1 is hydrogen, alkyl(C1-8), hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), alkenyl(C3-8), alkinyl(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C14-8), phenylalkyl(C7-8) or phenylalkenyl(C9-12), the phenyl ring
being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy (C1-4),
R2 and R5, independently, are hydrogen, alkyl(C1-8), phenylalkyl(C7-10) cycloalkyl(C3-7) or
cycloalkylalkyl(C4-8),
R3 and R4, independently are CN, COR7, COOR,, S(O)@R7 or
wherein n is0,ior2, R, is alkyl(C,~6), alkenyl(C3-8), alkinyl(C3~6), cycloalkyl(C3-7), cycloalkylalkyl(C48), hydroxyalkyl(C20), alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8) alkyl(C1-4) aminoalkyl(C2-8),
di[alkyl(C1-4)]aminoalkyl, phenyl, phenylalkyl(C7-10), a 5- or 6-membered heterocyclic ring
containing one heteroatom selected from nitrogen, oxygen or sulphur and may contain additionally
1, 2 or 3 ring nitrogen atoms, or alkyl(C1-4) substituted by a 5- or 6-membered heterocyclic ring
containing one heteroatom selected from nitrogen, oxygen or sulphur and may contain additionally 1 , 2 or 3 ring nitrogen atoms,
A is alkylene (C1-8),
R8 and R9, independently, are alkyl(C1-8), alkenyl or alkinyl (C3-6), cycloalkyl(C3-7, cycloalkylalkyl(C4-8),
hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8),
alkyl(C1-4) aminoalkyl(C2-8), di[alkyl(C1-4)]aminoalkyl, phenyl, phenylalkyl(C7-10), or
R8 and R8 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may
contain a further heteromember selected from oxygen, sulphur and a group =NR10, wherein Rio is alkyl(C,~4), and
R8 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro, hydroxy, azido, amino, alkyl(C1-4)amino, di[alkyl(C1-4)]amino
cabalkoxy(C2-5), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(C,~4)sulfamyl or
di[alkyl(C1-4)]sulfamyl, and
X is oxygen or sulphur, with the proviso that when R, is hydrogen, alkyl(C,~6J, alkenyl(C3-6), alkinyl
(C3-6), cyclalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phenyl ring
being unsubstituted or mono-, di- or tri-substituted independently by halogen, hydroxy, alkyl(C,~4) or
alkoxy(C1-4), R2 and R5, independently, are hydrogen or alkyl(c1-8),
R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthi(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro or hydroxy, and
X is oxygen or sulphur, then at 'east one of the substituents R3 and R4 is other than COR,', wherein R7' is alkyl(C1-@), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and is other than COOR7", wherein R711 is alkyl(C16), alkenyl(C3-6), alkinyl(C3~6), cyclalkyl(C3-7), cycloalkylalkyl(C48), hydroxyalkyl (C2~6), alkoxyalkyl (C3~6) or hydroxyalkoxyalkyl (C4~8).
In any of the above radicals alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms. Any alkyl, alkoxy, alkylthio or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 to 2 carbon atoms. The hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino group of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl moiety in
COOR7 is preferably not attached to the a-carbon atom and is preferably attached to the distal terminal carbon atom. Any hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl or alkylaminoalkyl radical preferably has an ethylene or propylene moiety substituted by hydroxy, alkoxy, hydroxyalkoxy, amino or alkylamino respectively. The alkyl moiety of cycloalkylalkyl is conveniently methyl. Halogen means fluorine, chlorine or bromine and is especially chlorine.Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl is conveniently cyclopropyl or cyclopentyl or cyclohexyl. The multiple bond of alkenyl, alkinyl or phenylalkenyl in R1 or COOR, is preferably not in the α,ss position. Alkenyl or alkinyl preferably has 3 to 5 carbon atoms. Alkenyl is conveniently allyl or 2-methylallyl. Alkinyl is conveniently propinyl.
Phenylalkenyl preferably has the trans-configuration and is for example cinnamyl. When R, is optionally substituted phenylalkyl, the phenyl group is preferably unsubstituted. When the phenyl group is di- or tri-substituted, preferably the substituents are the same.
When R, is alkyl, this is preferably branched. When R, contains a heterocyclic ring this may be for example furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, morpholinyl or triazinyl.
When R8 and R9 together with the nitrogen atom to which they are bound, form a heterocyclic ring, this is preferably saturated and may be for example pyrrolidine, piperidine, piperazine, Nalkylpiperazine, morpholine, azepane, diazepane or N-alkyl-diazepane.
R1 is conveniently hydrogen, R2 is conveniently identical to R5. R2 is conveniently alkyl. R3 and/or R4 is conveniently COOR, or
R, is conveniently alkyl, preferably branched or alkoxyalkyl, where the alkoxy moiety is preferably branched. A is conveniently ethylene. R8 and R9 are conveniently alkyl or phenylalkyl.
The present invention also provides a process for the production of a compound of formula I as defined above, comprising replacing the moiety -HC=Y in a compound of formula II,
wherein
R8 and X are as defined above, and -HC=Y is i) formyl, ii) a radical of formula
or iii) a radical of formula
wherein Z and Z' are independently oxygen or NR1, and
R, to R5 are as defined above, by a moiety of formula III,
wherein R, to R5 are as defined above.
The process may be effected in conventional manner for analogous dihydropyridine synthesis, e.g.
according to Hantzsch. When the moiety -HC=Y is formyl and when it is desired to produce a compound of formula I, wherein R2 is identical to R5 and R3 is identical to R4, it is convenient to react a compound of formula II with a compound of formula IV, R5C0-CH2-R4 IV wherein R4 and R5 are as defined above, in the presence of a compound of formula V, H2NR, V wherein R1 is as defined above.
Preferably at least 2 moles of a compound of formula IV per mole of a compound of formula II are present. Alternatively a compound of formula II may be reacted with a compound of formula VI,
R5-C(NH-R1)=CH-R4 VI wherein Rr, R4 and R5 are as defined above.
Preferably at least 2 moles of a compound of formula VI per mole of a compound of formula Il are
present. Preferably also R, is hydrogen.
When the moiety-NH=Y is formyl and preferably when it is desired to produce a compound of
Formula I wherein R2 is different to R5 and/or R3 is different to R4, it is also possible to react such a
compound of formula II with a compound of formula IV and a compound of formula VII, R2-C(NH-R1)=CH-R3 VII wherein R2, R, and R3 are as defined above.
It will be appreciated that a compound of formula VI may be formed as an intermediate during the reaction of a compound of formula IV and a compound of formula V. A compound of formula II, wherein -HC=Y is a radical ii) or iii), may be formed as an intermediate in the above reactions. They may however be produced by different processes.
Alternatively or particularly for the production of a compound of formula I, wherein R@ is different
to R5 and/or R3 is different to R4, it is convenient to react a compound of formula II, wherein the moiety -HC=Y is a radical ii) with a compound of formula IV or VI, and where appropriate, with a compound of
formula V. A compound of formula II, wherein the moiety -HC=Y is a radical iii) may be an
intermediate.
In the above reactions it is possible in certain instances when R2, R3, R4 and R% are not identical that more than one isomer of formula I may be formed. If so these may be separated in conventional manner, e.g. by column or thin layer chromatography.
When the starting material is a compound of formula II, whereinHC=Y is a radical iii), the reaction is a ring cyclisation. When Z and Z' are both oxygen, then an amine of formula V should be present.
However, all the above reactions may be effected under the same conditions.
The reaction may be effected conveniently in solution. A suitable solvent is water, ethanol, dioxane, dimethyl formamide, dimethyl sulphoxide, pyridine or glacial acetic acid. Suitable reaction temperatures may be from 20 to 1600 C, preferably from 60 to 1 200C.
Insofar as the production of starting materials is not particularly described these compounds are known or may be produced in analogous manner to known compounds.
The basic compounds of formula I may be converted into acid addition salt forms in conventional manner and vice versa. Suitable acids are e.g. maleic acid, oxalic acid, methanesulphonic acid, hydrochloric acid and hydrobromic acid.
In the following Examples the temperatures given are in degrees Centigrade and are uncorrected.
EXAMPLE 1 1,3-Benzoxadiazol-4-yl)-2,6-dimethyl-1,4dihydro-3-methoxycabonyl-pyridine-5-carboxylic acid benzyl ester
3,0 g of 2,1 ,3-benzoxadiazoí-4-aldehyde, 3,9 g of acetoacetic acid benzyl ester, 2,3 g of 3-amino crotonic acid methyl ester and 10 ml of ethanol are refluxed for 6 hours. The mixture is subsequently evaporated and the residual oil is chromatographed on silica gel with chloroform/acetic acid ethyl ester (8:1) to yield the title compound. The product is recrystallised from cyclohexane/diisopropylether, m.p.
131-136 .
By using the process described in Example 1, and corresponding starting compounds, e.g. a compound of formula II, whereinHC=Y is a radical i) and compounds of formula IV and V, and for
Examples 2-9 and 12-16 a compound of formula II, whereinHC=Y is a radical ii), wherein Z is oxygen and a compound of formula VI, the following compounds of formula I may be obtained, wherein y indicates the position of the dihydropyridine moiety:
Ex. R1 R2 R3 R4 R5 R6 X Y m.p. 2 H CH3 CN COO-1-Bu CH3 H O 4 129-124.5 3 H CH3 COOC2H5 SO2CH3 CH3 H O 4 204-205 4 H CH3 CN COOC2H5 CH3 H O 4 187-177 5 H CH3 CN COOC2H5 CH3 H s 4 187-190 6 H CH3 CN COOCH2CH(CH3)2 CH3 H s 4 166-171 7 H CH3 COOCH3 COC6H5 CH3 H O 4 182-201 8 H CH3 # COOC2H5 CH3 H O 4 180-184** 9 H CH3 # COOC2H6 CH3 H s 4 173-175** 10 H CH3 COO(CH2)2N(CH3)2 COO(CH2)2N(CH3)2 CH3 H O 4 188-191* fumarate 11 H CH3 COO(CH2)2N(CH3)2 COO(CH2)2(CH3)2 CH3 H s 4 158-159 fumarate 12 H CH3 COO(CH2)2N(CH3)2 COOC2H5 CH3 H O 4 13 H CH3 COO(CH2)2N(CH3)2 COOC2H5 CH3 H s 4 166-176 hydrogen fumarate
Ex. R1 R2 R3 R4 R5 R6 X Y m.p. 14 H CH3 # COOC2H5 CH3 H s 5 oil 15 H CH3 # COOC2H5 CH3 H O 5 oil 16 H CH3 # COOCH3 CH3 H O 4 182-195** 17 H # COOC2H5 COOC2H5 CH3 H O 4 87-99 18 H # COOCH3 COOCH3 CH3 H O 4 160-163 19 H # COOCH3 COOCH3 # H O 4 118-120 20 H # COOC2H5 COOC2H5 # H O 4 110-112 21 H CH3 COO(CH2)20-C3H5 COOCH3 CH3 H O 4 158 * decomposition ** hydrochloride
The compounds of formula I exhibit pharmacological activity. In particular, they lead to a dilation of the coronary vessels as demonstrated by the results of tests measuring the blood flow to the myocardium of an anaesthetised cat by means of the microsphere method (Rudolph A.M. and Heymann
M.S.: Circulation Research 21,183,1967) upon administration of from 30 to 50 yg/kg i.v. or of from 50 to 1 50 yg/kg i.d. of the active substance.
The compounds of formula I also possess a favourable effect against angina pectoris, as shown by the increase of the coronary flow of an anaesthetised cat upon administration of the active substance.
The compounds of formula I are therefore indicated for use in the treatment of coronary insufficiency.
The compounds of formula I increase the blood flow to limbs, e.g. leg musculature, as can be shown by means of the microsphere method on the anaesthetised cat upon administration of from 30 to 50 yg/kg i.v. or from 50 to 1 50 yg/kg i.d. of the compounds.
The compounds of formula I are therefore indicated for use in the treatment of intermittent claudication and other peripheral disturbances of blood flow to limb muscles.
The compounds of formula I increase cerebral blood flow, as can be shown by means of the microsphere method on the anaesthetised cat upon administration of from 30 to 50 Mg/kg i.v. or from 50 to 150 g/kg i.d. of the compounds.
The compounds of formula I are therefore indicated for use in the treatment of cerebrovascular insults.
The compounds of formula I possess calcium-antagonistic activity as indicated in standard tests, for example by an inhibition of a calcium induced contraction of isolated dog coronary arteries suspended in a depolarizing solution at concentration of 10-10 to 10-8 M of the compounds according to the principles of Godfraind and Kaba, Brit. J. Pharm. 36, 549-560, 1969.
The compounds of formula I are therefore indicated for use as spasmolytic agents for the treatment of spasms of muscles. For the above indications an indicated daily dose is from about 5 to 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1.25 mg to about 50 mg, or in sustained release form.
Additionally, the compounds of formula I exhibit antihypertensive activity, as indicated in standard tests, e.g. in the Grollman rat test [see A. Grollman, Proc. Soc. Expt. Biol. and Med. 57, 104 (1944)] on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the compounds:
The compounds of formula I are therefore further indicated for use as antihypertensive agents. For this use an indicated daily dose is from about 5 to about 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing about 1.25 mg to about 500 mg, or in sustained release form.
A compound of formula I may be administered in free base form. Alternatively any sufficiently basic compound of formula I, e.g. Those compounds wherein R3 or R4 contain an amino moiety, may be administered in pharmaceutically acceptable acid addition salt form. Such acid addition salt forms exhibit the same order of activity as the free base forms. The present invention also provides a pharmaceutical composition comprising a compound of formula I in association with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional techniques to be in conventional forms, for example capsules or tablets.
The compounds of Examples 1, 8 and 16 are the preferred compounds. The coronary insufficiency, the intermittent claudication, the cerebrovascular insufficiency and the spasmolytic activities are the preferred utilities for compounds of formula I.
In one group of compounds
R, is hydrogen, alkyl(C,~6), hydrnxyalkyl(C26), alkoxyalkyl(C36), alkenyl(C3-8), alkinyl(C3~6), cycloalkyl(C3-7), cycloalkylalkyl(C46), phenylalkyl(C,~9) or phenylalkenyl(C9-12), the phenyl ring being
unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1~4) or
alkoxy(C1-4), R2 and R5, independently, are hydrogen, alkyl(C,~6) or phenylalkyl(C7-10), R3 and R4, independently are CN, COR7, COOR7 or S(O)nR7, wherein n is 0, 1 or 2, R7 is alkyl(C1-8, alkenyl(C3~6), alkinyl(C3-8), cycloalkyl(C3~7), cycloalkylalkyl(C48), hydrnxyalkyl(C26), alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-6), alkyl(C1-4)aminoalkyl(C2-8), phenyl, phenylalkyl(C710), a 5- or 6-membered heterocyclic ring containing one heteroatom selected from
nitrogen, oxygen or sulphur, or alkyl (C,~4) substituted by a 5- or 6-membered heterocyclic ring
containing one heteroatom selected from nitrogen, oxygen or sulphur,
R6 is hydrogen, halogen, alkyl(C1-4) alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nito, hydroxy, azido, amino, alkyl(C1-4)amino, alkanoyl(C1-5)amino,carbalkoxy(C2-4),
aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(C1-4)sulfamyl or di[alkyl(C1-4)]sulfamyl, and
X Is oxygen or sulphur, with the proviso that when R, is hydrogen, alkyl(C1-8), alkenyl(C3-8), alkinyl(C3~6), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phenylring being
unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(1~4), R2 and R5, independently, are hydrogen or alkyl(C1-4),
R5 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4, alkylsulfonyl(C1-4), tifluoromethyl,
nitro or hydroxy, and
X is oxygen or sulphur, then at least one of the substituents R3 and R, is other than COR,', wherein R,' is
alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and is other than
COOR7", wherein R7" is alkyl(C1-8, alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8),
hydroxyalkyl(C2-8), alkoxyalkyl(C3-8) or hydroxyalkoxyalkyl(C4-8).
In another group of compounds
R1 is hydrogen, alkyl(C1-8), hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), alkenyl(C3-8), alkinyl(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phenyl ring being
unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy(C1-4),
R2 and R5, independently, are hydrogen, alkyl(C1-6), or phenylalkyl(C7-10),
R3 is
and
R4 is CN, COR7, COOR7, S(O)nR7 or
wherein n is2,
R7 is alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), hydroxyalkyl(C2-8),
alkoxyalkyl(C3-8), alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8), alkyl(1-4)aminoalkyl(C2-8), phenyl or
Phenylalkyl(C7-10),
A is alkylene(C1-6),
R8 and R9, independently, are alkyl(C1-6),alkenyl or alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl(C4-8),
hydroxyalkyl(C2-6),alkoxyalkyl(C3-6), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8),
alkyl(C1-4)aminoalkyl(C2-8), phenyl, phenylalkyl(C7-10), or
R8 and R9 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may
contain a further heterometer selected from oxygen, sulphur and a group =N-R10, wherein R10 is
alkyl(C1-4), and
R5 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro hydroxy, azido, amino, alkyl(C1-4)amino, alkanyl(C1-5) amino, carbalkoxy(C2-5) aminocarbonyl,
trifluoromethoxy, cyano or sulfamyl, and
X is oxygen or sulphur.
In another group of compounds
R1 is hydrogen, alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8),
phenylalkyl(C7-8) or phenylalkenyl(C9-12), the phenyl ring being unsubstituted or mono- di- or
trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(C1-4),
R2 and R5 independently, are hydrogen, alkyl(C1-6), phenylalkyl(C7-10), cycloalkyl(C3-7) or cycloalkylalkyl(C46), R3 and R5, independenty, are COR7' or COOR7", wherein R7' is alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-6),
cyclalkyl(C3-7), cycloalkylalkyl(C4-3), and R7" is alkyl(C1-@), alkenyl(C3-8), alkinyl(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), hydroxyalkyl(C2-8), alkoxyalkyl(C2-8) or
hydroxyalkoxyalkyl(C4-8), R@ is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro or hydroxy, and
X is oxygen or sulphur, with the proviso, that at least one of the substituents R2 and R5 is phenylalkyl
(C7-10), cycloalkyl(C3-7) or cycloalkylalkyl(C4-8).
A group of compounds of formula I,
wherein R@ is alkyl(C1-8), alkoxyalkyl(C3-8), alkenyl(C3-5), alkinyl(C3-8), cycloalkyl(C3-7),
R2 and R5, independently, are hydrogen or alkyl(C1-8),
R3 and R4, independently, are COOR7, wherein R, is other than phenylalkyl.
These compounds show surprisingly beneficial pharmacological activity than is expected for
compounds of this type, e.g. long lasting coronary sufficiency activity in the tests mentioned above and
good tolerability.
In another group
R1 is alkyl(C1-8), hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C48), phenylalkyl (C7~9) or phenylalkenyl(C9-12), the phenyl ring being unsubstituted
or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(C1-4),
R2 and R5 independently, are hydrogen, alkyl(C1-8), phenylalkyl(C7-10), cycloalkyl(C3-7) or cycloalkylalkyl(C49), R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or
wherein n, R,, A, R3 and R3 and subject to the proviso as defined above, provided that R3 and R4 are not both COOR7, wherein R7 is alkyl(C1-8).
In another group of compounds
R1 is alkyl(C1-8), alkenyl(C3-8), alinyl(C3-8), cycloalkyl(C3-7),
R2 and R5, in dependently, are hydrogen or alkyl(C1-8)
R3 and R4, independently, are CN, COR,. COOR7, S(O)nR7 or
wherein n, Fl7, A, R8 and R9 and subject to the proviso as defined above and provided that R9 and R4 are not both COOR7, wherein R, is alkyl(C1-8),
In a sub-group R5 is alkylsulfonyl(C1-4), hydroxy, azido, amino, alkyl(C1-4) amino, di[alkyl(C1-4)]amino, alkanoyl(C1-5)amino, aminocarbonyl, tri-fluoromethoxy, sulfamoyl, alkyl(C14)sulfamyl, or di[alkyl(C1-4)]sulfamyl.
In another group of compounds
R1 is hydrogen, alkyl(C1-8), hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), alkenyl(C3-8), alkiny(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C8-9) or phenylalkenyl(C8-12), the phenyl ring
being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy(C1-4),
R2 and R5 independently, are hydrogen, alkyl(C1-8), phenylalkyl(C7-10), cycloalkyl(C3-7) or
cycloalkyl(C4-8),
R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or
wherein n, Fl7, A, Ra and R3 and subject to the proviso as defined above, provided that R3 and R4 are not independently COR7, wherein R7 is alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-8) or COOR7, wherein R7 is other than phenyl or phenylalkyl as defined above.
Claims (37)
1. A process for the production of a compound of formula I,
wherein
R1 is hydrogen, alkyl(C1-5), hydroxyalkyl(C2-5), alkoxyalkyl(C3-8), alkenyl(C3-8), alkinyl(C3-8),
cycloalkyl(C3-8), cycloalkylalkyl(C4-8), phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phenyl ring
being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy(C1-4),
R2 and R5, independently, are hydrogen, alkyl(C1-6), phenylalkyl(C7-10), cycloalkyl(C3-7) or
cycloalkylalkyl(C4-8),
R3 and R4, Independently are CN, COR7, COOR7, S(O)nR7 or
wherein n is0, 1 or2, R7 is alkyl(C7-8), alkenyl(C3-6), alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), hydroxyalkyl(C2-8),
alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8), alkyl(C1-4) amiinoalkyl(C2-8),
di[alkyl(C1-4)]aminoalkyl, phenyl, phenylalkyl(C7-10), a 5- or 6-membered heterocyclic ring
containing one heteroatom selected from nitrogen, oxygen or sulphur and may contain additionally
1, 2 or 3 ring nitrogen atoms, or alkyl(C1~4) substituted by a 5- or 6-membered heterocyclic ring
containing one heteroatom selected from nitrogen, oxygen or sulphur and may contain additionally
1, 2 or 3 ring nitrogen atoms,
A is alkylene(C1-8),
R8 and R9, independently, are alkyl(C1-8), alkenyl or alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8),
hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8),
alkyl(C1-4)aminoalkyl(C2-8), di[1-4)]aminoalkyl, phenyl, phenylalkyl(C7-10), or Ra and R9 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may
contain a further heteromember selected from oxygen, sulphur and a group =N-R10, wherein R10 is
alkyl(C1-4), and
R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro, hydroxy, azido, amino, alkyl(C1-4) amino, di[alkyl(C1-4)]amino, alkanoyl(C1-5)amino, carbalkoxy(C25), aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(C,~4)sulfamyl or
di[alkyl(C1-4)]sulfamyl, and
X is oxygen or sulphur, with the proviso that when R, is hydrogen, alkyl(C1-6), alkenyl(C3-8), alkinyl
(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-8) or phenylalkenyl(C9-12), the phenyl ring
being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy(C1-4),
R2 and R5, in dependently, are hydrogen or alkyl(C1~6), R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro or hydroxy, and
X is oxygen or sulphur, then at least one of the substituents R3 and R4 is other than COR,', wherein R,' is
alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and is other than
COOR7", wherein R7" is alkyl(C1-6), alkenyl(C3-8), alinyl(C3-8), cycloalkyl(C-7), cycloalkylalkyl(C4-8), hydroxyalkyl (C2~6), alkoxya lkyl(C36) or hydroxyalkoxyalkyl(C4-8), which comprises replacing the moiety-HC=Y in a compound of formula II,
wherein
R6 and X are as defined above, and -HC=Y is i) formyl, ii) a radical of formula
or iii) a radical of formula
wherein Z and Z' are independently oxygen or NR1, and
R, to R5 are as defined above, by a moiety of formula Ill,
wherein R, to R5 are as defined above.
2. A process for the production of a compound of formula I, as stated in claim 1, substantially as hereinbefore described with reference to any of the Examples.
3. A compound of formula I, whenever produced by a process according to claim 1 or 2.
4. A compound of formula I, as defined in claim 1.
5. A compound of claim 4, wherein
R1 is hydrogen, alkyl(C1-6), hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), alkenyl(C3-8), alkinyl(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phenyl ring being
unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy(C1-4),
R2 and R5, independently, are hydrogen, alkyl(C,~6) or phenylalkyl(C7-10),
R3 and R4, independently are CN, COR7, COOR7 or S(O)nR7, wherein n is 0, 1 or 2,
R7, is alkyl(C1-8), alkenyl(C3-5), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), hydroxyalkyl(C2-8),
alkoxyalkyl(C3-5), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8), alkyl(C1-4)aminoalkyl(C2-8), phenyl,
phenylalkyl(C7-10), a 5- or 6-membered heterocyclic ring containing one heteroatom selected from
nitrogen, oxygen or sulphur, or alkyl (C1-4) substituted by a 5- or 6-membered heterocyclic ring
containing one heteroatom selected from nitrogen, oxygen or sulphur,
R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro, hydroxy, azido, amino, alkyl(C1-4) amino, alkanoyl(C1-5)amino, carbaloxy(C2-4),
aminocarbonyl, trifluoromethoxy, cyano, sulfamyl, alkyl(C,~4)sulfamyl or di[alkyl(C1-4)]sulfamyl, and
X is oxygen or sulphur, with the proviso that when R1 is hydrogen, alkyl(C1-6), alkenyl(C3~6), alkinyl(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-8) or phenylalkenyl(C9-12), the phenylring being
unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C,~4) or alkoxy(1~4) R2 and R5, independently, are hydrogen or alkyl(C1-4),
R5 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro or hydroxy, and
X is oxygen or sulphur, then at least one of the substituents R3 and R4 is other than COR', wherein R,' is
alkyl(C1-5), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and is other than
COOR7", wherein R7" is alkyl(C1-8, alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-5),
hydroxyalkyl(C2-8), alkoxyalkyl(C3-8) or hydroxyalkoxyalkyl(C4-8).
6. A compound as claim 4, wherein
R1 is hydrogen, alkyl(C1-5), hydroxyalkyl(C2-5), alkoxyalkyl(C3-8), alkenyl(C3-8),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C7-8) or phenylalkenyl(C9-12), the phenyl ring being
unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy(C1-4),
R2 and R5, independently, are hydrogen, alkyl(C16) or phenylalkyl(C7-10),
R3 is
and
R4 is CN, COR7, COOR7, S(O)nR7 or
wherein n is2,
R7 is alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8), hydroxyalkyl(C2-8),
alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8), alkyl(C1-4)aminoalkyl(C2-8), phenyl or
phenylalkyl(C7-10).
A is alkylene(C1-8),
R8 and R9 independently, are alkyl(C1-8), alkenyl or alkinyl(C3-8), cycloalkyl(C3-7), cycloalkylalkyl(C4-8),
hydroxyalkyl(C2-5), alkoxyalkyl(C3-8), hydroxyalkoxyalkyl(C4-8), aminoalkyl(C2-8),
alkyl(C1-4)aminoalkyl(C2-8), phenyl, phenylalkyl(C7-10), or
R8 and R9 together with the nitrogen atom form a 5-, 6- or 7-membered heterocyclic ring, which may
contain a further heteromember selected from oxygen, sulphur and a group =N-R10, wherein R10 is
alkyl(C1-4), and
R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio)C1-4), alkylsulfonyl(C1-4), trifluoromethyl,
nitro hydroxy, azido, amino, alkyl(C1-4)amino, alkanoyl(C~5)amino, carbalkoxy(C2-8), aminocarbonyl,
trifluoromethoxy, cyano or sulfamyl, and
X is oxygen or sulphur.
7. A compound of claim 4, wherein
R1 is hydrogen, alkyl(C1-5), alkenyl(C3-8), alkinyl(C3-6), cycloalkyl(C3-7), cycloalkylalkyl(C4-8),
phonylalkyl(C7-9) or phenylalkenyl(C912), the phenyl ring being unsubstituted or mono-, di- or
trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(C1-4),
R2 and R5, independently, are hydrogen, alkyl(C1-3), phenylalkyl(C7-10), cyclalkyl(C3-7) or
cycloalkylalkyl(C4-8),
R3 and R4, independently, are COR7' or COOR7", wherein R7' is alkyl(C1-5), alkenyl(C3-6), alkinyl(C3-6),
cycloalkyl(C3-7), cycloalkylalkyl(C4-8), and R7" is alkyl(C1-6), alkenyl(C3-6), alkinyl(C3-8),
cyclalkyl(C3-7), cycloalkylalkyl(C4-8), hydroxyalkyl(C2-8), alkoxyalkyl(C3-6) or
hydroxyalkoxyalkyl(C4-8).
R6 is hydrogen, halogen, alkyl(C1-4), alkoxy(C1-4), alkylthio(C1-4), alkylsulfonyl(C1-4)trifluoromethyl,
nitro or hydroxy, and
X is oxygen or sulphur, with the proviso, that at least one of the substituents R2 and R5 is phenylalkyl(C710), cycloalkyl(C3-7) or cycloalkylalkyl(C46).
8. A compound of claim 4, which is 4-(2,1,3-benzoxadiazolyl-4)-2,6-dimethyl-1,4-dihydro-3- methoxy-carbonyl-pyridine-5-carboxylic acid benzyl ester.
9. A compound of claim 4, which is 4-(2,1 ,3-benzoxadiazolyl-4)-2,6-dimethyl-1 ,4-dihydro-3ethoxycarbonyl-pyridine-5-carboxylic acid N-benzyl-N-methyl-2-a mi no-ethyl ester.
10. A compound of claim 4, which is 4-(2,1,3-benzoxadiazol-4-yl)-2,6-dimethyl-1,4-dihydro-3- methoxy-carbonyl-pyridi ne-5-carboxylic acid N-benzyl-N-methyl-2-a mino-ethyl ester.
11. A compound of claim 4, wherein R1 is hydrogen, R2 and R5 are each methyl, R8 is hydrogen and the dihydropyridine moiety is in the 4-position.
12. A compound of claim 11, wherein R3, R4 and X are respectively CN, COO-i-BU and 0.
13. A compound of claim 11, wherein R3, R4 and X are respectively COOC2H5, SO2CH3 and 0.
14. A compound of claim 11, wherein R3, R4 and X are respectively CN, COOC2H5 and 0.
15. A compound of claim 11, wherein R3, R4 and X are respectively CN, COOC2H5 and S.
16. A compound of claim 11, wherein R3, R4 and X are respectively CN, COOCH2CH(CH3)2 and S.
17. A compound of claim 11, wherein R3, R4 and X are respectively COOCH3, COC6H5 and 0.
18. A compound of claim 11. wherein R3, R4 and X are respectively
COOC2H5 and 0.
19. A compound of claim 11, wherein R3, Ra and X are respectively
COOH2H5 and S.
20. A compound of claim 1 1, wherein R3, R4 and X are respectively COO(CH2)2N(CH3)2, COO(CH2)2N(CH3)2 and 0.
21. A compound of claim 11, wherein R3, R4 and X are respectively COO(CH2)2N(CH3)2,
COO(CH2)2N(CH3)2 and S.
22. A compound of claim 11, wherein R3, R4 and X are respectively COO(CH2)2N(CH3)2, COOC2H5 and 0.
23. A compound of claim 11, wherein R3, R4 and X are respectively COO(CH2)2N(CH3)2, COOC2H5 and S.
24. A compound of claim 11, wherein R3, R4 and X are respectively COO(CH2)2-C6H5, COOCH3 and 0.
25. A compound of claim 4, wherein R, is hydrogen, R2 and R5 are each methyl, R6 is hydrogen and the dihydropyridine moiety is in the 5-position.
26. A compound of claim 25, wherein R3, R4 and X are respectively
COOC2Hs and S.
27. A compound of claim 25, wherein R3, R4 and X are respectively
COOC2H5 and 0.
28. A compound of claim 4, wherein R1 is hydrogen, R2 is #, R6 is hydrogen and the dihydropyridine moiety is in the 4-position.
29. A compound of claim 28, wherein R3, R4, R5 and X are respectively COOC2Hs, COOC2Hs, CH3 and 0.
30. A compound of claim 28, wherein R3, R4, R5 and X are respectively COOCH3, COOCH3, CH3 and O.
31. A compound of claim 28, wherein R3, R4, R5 and X are respectively COOCH3, COOCH3, A
and 0.
32. A compound of claim 28, wherein R3, R4, R5 and X are respectively COOC2H5, COOC2H5, A and 0.
33. A compound of claim 4, wherein
R1 is alkyl(C1-8), alkoxyalkyl(C3-8), alkenyl(C3-8), alkinyl(C3-6), cycloalkyl(C3-7),
R2 and R5, independently, are hydrogen or alkyl(C1-8),
R3 and R4, independently, are COOR7, wherein R7 is other than phenylalkyl.
34. A compound of claim 4, wherein
R1 is alkyl(C1-8), hydroxyalkyl(C2-8), alkoxyalkyl(C3-8), alkenyl(C3-6), alkinyl(C3-8), cyclalkyl(C3-7),
cycloalkylalkyl(C4-8), phenylalkyl(C7-9) or phenylalkenyl(C9-12), the phenyl ring being unsubstituted
or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or alkoxy(C1-4),
R2 and R3, independently, are hydrogen, alkyl(C1-8), phenylalkyl(C7-10), cycloalkyl(C3-7), or cycloalkylalkyl(C48), R3 and R4, independently are CN, COR7, COOR7, S(O)nR, or
wherein n, R7, A, R8 and R9 and subject to the proviso as defined above, provided that R3 and R4 are not both COOR7, wherein R7 is alkyl(C1-8).
35. A compound of claim 4, wherein
R1 is alkyl(C1-8), alkenyl(C3-8), alkinyl(C3-6), cycloalkyl(C3-7),
R2 and R5, independently, are hydrogen or alkyl(C1-8),
R3 and R4, independently, are CN, COR,, COOR,, S(O)nR7 or
wherein n, Fl7, A, R8 and R9 and subject to the proviso as defined above and provided that R3 and R4 are not both COOR7, wherein R7 is alkyl(C1-8).
36. A compound of claim 4, wherein
R1 is hydrogen, alkyl(C1-6), hydroxyalkyl(C2-6), alkoxyalkyl(C3-6), alkenyl(C3-6), alkinyl(C3-6),
cyclalkyl(C3-7), cycloalkylalkyl(C4-8), phenylalkyl(C8-9) or phenyloalkenyl(C9-12), the phenyl ring
being unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, alkyl(C1-4) or
alkoxy)C1-4),
R2 and R5, Independently, are hydrogen, alkyl(C1-8), phenylalkyl(C7-10), cycloalkyl(C3-7) or
cycloalkylalkyl(C4-8),
R3 and R4, independently are CN, COR7, COOR7, S(O)nR7 or
wherein n, Fl7, A, R8 and R9 are subject to the proviso as-defined above, provided that R3 and R4 are not independently COR, wherein R7 is alkyl(C1-8), alkenyl(C3-5), alkinyl(C3-5) or COOR7, wherein R7 is other than phenyl or phenylalkyl as defined above.
37. A pharmaceutical composition comprising a compound of any one of claims 4 to 36 in association with a pharmaceutical carrier or diluent.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1288878A CH640852A5 (en) | 1978-12-18 | 1978-12-18 | 1,4-Dihydropyridine derivatives, their preparation and use |
| CH1289078A CH643841A5 (en) | 1978-12-18 | 1978-12-18 | Novel 1,4-dihydropyridine derivatives, their preparation and use |
| CH347279 | 1979-04-11 | ||
| CH347779 | 1979-04-11 | ||
| CH562779 | 1979-06-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2041358A true GB2041358A (en) | 1980-09-10 |
| GB2041358B GB2041358B (en) | 1982-11-17 |
Family
ID=27509137
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7943112A Expired GB2041358B (en) | 1978-12-18 | 1979-12-14 | Benzoxadiazoles and benzothiadiazoles |
Country Status (7)
| Country | Link |
|---|---|
| CA (1) | CA1131228A (en) |
| DE (1) | DE2949464A1 (en) |
| GB (1) | GB2041358B (en) |
| IL (1) | IL58974A (en) |
| NZ (1) | NZ192421A (en) |
| PT (1) | PT70601A (en) |
| SE (1) | SE7910151L (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0080220A1 (en) * | 1981-11-17 | 1983-06-01 | FISONS plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| GB2117761A (en) * | 1982-03-10 | 1983-10-19 | Sandoz Ltd | 1 4-dihydropyridine derivatives their preparation and pharmaceutical composition |
| EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| GB2122192A (en) * | 1982-06-15 | 1984-01-11 | Sandoz Ltd | Dihydropyridines |
| EP0128010A2 (en) * | 1983-06-02 | 1984-12-12 | Teijin Limited | 1,4-Dihydropyridine derivative, process for production thereof and pharmaceutical use thereof |
| WO1986002640A1 (en) * | 1984-10-31 | 1986-05-09 | Bristol-Myers Company | Dihydropyridin-3,5-dicarboxylates incorporating aryloxypropanolamine moieties |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3022030A1 (en) * | 1980-06-12 | 1981-12-17 | Bayer Ag, 5090 Leverkusen | 4-THIAZOLE or 4-IMIDAZOLE-SUBSTITUTED, 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| CH655658B (en) * | 1980-09-18 | 1986-05-15 | ||
| WO1985000169A1 (en) * | 1983-06-21 | 1985-01-17 | Sandoz Ag | 1,4-dihydropyridine derivatives, production thereof and pharmaceutical preparations containing them |
| FR2554109A1 (en) * | 1983-11-01 | 1985-05-03 | Sandoz Sa | NOVEL 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PREPARATION AND USE IN THERAPEUTICS AS MEDICAMENTS |
| IT1201454B (en) * | 1985-08-19 | 1989-02-02 | Boehringer Biochemia Srl | 1,4-dihydropyridine-2-SUBSTITUTED |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670824C3 (en) * | 1967-03-20 | 1978-08-03 | Bayer Ag, 5090 Leverkusen | 1,4-Dihydropyridine-33-dicarboxylic acid alkyl ester |
| DE2117571C3 (en) * | 1971-04-10 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Asymmetrical 1,4-dihydropyridine-33-dicarboxylic acid esters, process for their preparation and their use as pharmaceuticals |
| DE2218644C3 (en) * | 1972-04-18 | 1982-08-19 | Bayer Ag, 5090 Leverkusen | Basic esters of 1,4-dihydropyridines, processes for their preparation and their use as pharmaceuticals |
| GB1455502A (en) * | 1973-02-20 | 1976-11-10 | Yamanouchi Pharma Co Ltd | 1,4-dihydropyridine derivatives |
| FR2320750A1 (en) * | 1975-08-12 | 1977-03-11 | Hexachimie | 1,4-DIHYDRO PYRIDINES AND THEIR THERAPEUTIC APPLICATION |
| DE2616991A1 (en) * | 1976-04-17 | 1977-10-27 | Bayer Ag | Thio-substd. dihydro-pyridine derivs. - coronary vasodilators and antihypertensives prepd. e.g. by reacting dicarbonyl cpds. with amines and thio-substd. ketones |
| DE2740080A1 (en) * | 1977-09-06 | 1979-03-15 | Bayer Ag | 2-Aminoalkyl-1,4-di:hydro-pyridine derivs. - with broad spectrum of effects on the heart and circulation, e.g. lowering blood pressure and spasmolytic effect |
-
1979
- 1979-12-08 DE DE19792949464 patent/DE2949464A1/en not_active Ceased
- 1979-12-10 SE SE7910151A patent/SE7910151L/en not_active Application Discontinuation
- 1979-12-14 GB GB7943112A patent/GB2041358B/en not_active Expired
- 1979-12-17 NZ NZ192421A patent/NZ192421A/en unknown
- 1979-12-17 IL IL58974A patent/IL58974A/en unknown
- 1979-12-17 PT PT70601A patent/PT70601A/en unknown
- 1979-12-17 CA CA342,085A patent/CA1131228A/en not_active Expired
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0080220A1 (en) * | 1981-11-17 | 1983-06-01 | FISONS plc | Dihydropyridines, methods for their production and their formulation and use as pharmaceuticals |
| GB2117761A (en) * | 1982-03-10 | 1983-10-19 | Sandoz Ltd | 1 4-dihydropyridine derivatives their preparation and pharmaceutical composition |
| EP0094159A1 (en) * | 1982-05-10 | 1983-11-16 | Takeda Chemical Industries, Ltd. | Dihydropyridine derivatives, their production and use |
| GB2122192A (en) * | 1982-06-15 | 1984-01-11 | Sandoz Ltd | Dihydropyridines |
| EP0128010A2 (en) * | 1983-06-02 | 1984-12-12 | Teijin Limited | 1,4-Dihydropyridine derivative, process for production thereof and pharmaceutical use thereof |
| EP0128010A3 (en) * | 1983-06-02 | 1987-07-01 | Teijin Limited | 1,4-dihydropyridine derivative, process for production thereof and pharmaceutical use thereof |
| WO1986002640A1 (en) * | 1984-10-31 | 1986-05-09 | Bristol-Myers Company | Dihydropyridin-3,5-dicarboxylates incorporating aryloxypropanolamine moieties |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ192421A (en) | 1982-09-07 |
| IL58974A (en) | 1983-03-31 |
| SE7910151L (en) | 1980-06-19 |
| IL58974A0 (en) | 1980-03-31 |
| GB2041358B (en) | 1982-11-17 |
| CA1131228A (en) | 1982-09-07 |
| PT70601A (en) | 1980-01-01 |
| DE2949464A1 (en) | 1980-06-26 |
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