CA1228549A - Use of 1,4-dihydropyridines in antiarteriosclerotic agents and their preparation - Google Patents
Use of 1,4-dihydropyridines in antiarteriosclerotic agents and their preparationInfo
- Publication number
- CA1228549A CA1228549A CA000430227A CA430227A CA1228549A CA 1228549 A CA1228549 A CA 1228549A CA 000430227 A CA000430227 A CA 000430227A CA 430227 A CA430227 A CA 430227A CA 1228549 A CA1228549 A CA 1228549A
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- Prior art keywords
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- dihydropyridine
- dosage unit
- nitro
- tablets
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Use of 1,4-dihydropyridines in antiarteriosclerotic agents and their preparation ABSTRACT OF THE DISCLOSURE
A method of countering arteriosclerosis in a patient comprising administering to such patient an anti-arteriosclerotic effective amount of a 1,4-dihydropyridine of the formula in which R1 and R2 each independently is alkyl or alkoxyalkyl having up to 12 C atoms, the alkyl radical optionally being substituted by fluorine or chlorine, and R3 is one or two substituents independently selected from the group comprising nitro, trifluoromethyl, halogen and cyano.
The material is effective even upon oral administration.
A method of countering arteriosclerosis in a patient comprising administering to such patient an anti-arteriosclerotic effective amount of a 1,4-dihydropyridine of the formula in which R1 and R2 each independently is alkyl or alkoxyalkyl having up to 12 C atoms, the alkyl radical optionally being substituted by fluorine or chlorine, and R3 is one or two substituents independently selected from the group comprising nitro, trifluoromethyl, halogen and cyano.
The material is effective even upon oral administration.
Description
so - 1 - 231~9-5554 The present invention relates to the use of dodder-pardons to counter atherosclerotic vascular changes in the form of fibromusculoelastic plaques, anti arteriosclerotic agents con-tenon them and their preparation. Some of the compounds to be used according to the invention and their vasodilator, hypotensive and coronary activity are known from DEMOS (German Published specification) 2,117,571; DEMOS (German Published Specification) 1,670,827; DEMOS (German Published Specification) 2,117,573;
DYES (German Published Specification) 2,549,568 and DEMOS (German Published Specification) 2,841,667.
It has likewise been disclosed that the compound knifed-pine (compare DEMOS (German Published Specification) 1,67~,827) and other calcium antagonists inhibit entry ox Cay into smooth muscle cells. In addition, it has since been disclosed for nifedipine -that it can suppress infiltration of cholesterol into the vessel wall of rabbits fed with cholesterol (compare Do Henry and Bentley, KIWI.: J. Olin. Invest. 68, 1366-9, 1981).
The use of the ~ihydropyridines according to the invent lion as anti arteriosclerotic agents which inhibit the formation, caused by damage -to vessel walls, of fibromusculoelastic plaques produced by a proliferating intima has not hitherto been disclosed.
Cardiovascular diseases, which are diagnosed as the cause of more than 50~ of the cases of death in the mortality statistics in industrialized countries, very frequently have their cause in arteriosclerotic changes in the arterial part ox the vascular system. Intimal proliferation its rewarded as a important early stage in the etiology of atheroc3enesls. Arteriosclerotic changes of this type, which can lead to partial or complete occlu-soon of the vessel, cause damage to tissue and can load to local tissue necrosis, infarction, for example in the heart or brain.
The present invention relates to 1,4-dihydropyridines of the general formula (I) \~'~
R OX COO (I) in which Al and R2 are identical or different and each represent alkyd or alkoxyalkyl having up to 12 C atoms, the alkyd radical optionally being substituted by fluorine or chlorine, and R3 represents one or -two identical or different substituents from the group comprising vitro, trifluoromethyl, halogen or ennui, err use to counter arteriosclerosis.
'rho invention therefore provides pharmaceutical compositions yin dosage unit form suitable for oral a~lininixtrcl-tion to a mammal ire countering the formation of fibromusculo elclstic plaques produced by intimal proliferation in mammals, whelk compositions comprise a compound of general formula (I) dew Ed avow, in admixture with a suitable pharmaceutically acceptable I error or cliluent.
In anther aspect the inventiorl provides a process for 35~
preparing a therapeutic agent for countering the formation of fibromusculo elastic plaques produced by intimal proliferation in a mammal, in ready-to-use drug form, characterized in that the therapeutic agent includes as active ingredient a compound of formula (I) as defined above.
Those compounds of the general formula (I) are portico laxly suitable, in which Al and R2 are identical or different and each represent alkyd having 1 -to 4 C atoms or alkoxyal~yl having up to 6 carbon atoms, and R3 represents one or two subs-tituents in the ortho or mote position from the group comprising vitro, chlorine or trifluoromethyl.
Compounds of the general formula (I) which may be very particularly emphasized are those in which Al and R2 represent alkyd having 1 to 4 carbon atoms and R represents vitro.
prom a knowledge of the state of the art, it could not be expected that the compounds usable according to the invention have such an advantageous anti arteriosclerotic effect.
Arteriosclerosis is a complex disease, the original - pa -US
lion of which can frequently be affected or caused by the following processes:
a) Damage to a vessel wall with subsequent proliferation of smooth muscle cells and production of a fibromusco-elastic lesion Infiltration of lipids into this lesion and c) Formation of a mural thrombus and its incorporation into the vessel wall.
The following examples illustrate, the advantageous specific inhibitory effect on proliferation of the compounds to be used according to the invention.
Test method Proliferation of the intima is induced on rats by vascular lesion. By subjecting the carotid artery to hypotherm;a(-10C, Z minutes), partial or complete removal of the endothelium in a localized region is produced.
Proliferation of the intima occurs after a short period of about 10 days and this largely corresponds to the early stages of arteriosclerotic plaques in humans. The zones of proliferation are excised and weighed. The jet weight is about 200 to 300 in the chilled segment of 1 cm. The animals also receive a heft diet (3 I
of cholesterol).
The incorporated lipids are stained Vito the fat-soluble distaff Sudan IV and can be determined as an additional parameter compare F. Setter et Allah Export-mentally induced thromboatherosclerosis. Folio annul-Gina 28, as ~1980)).
Surprisingly, the compounds shown as examples in the following table also have anti arteriosclerotic astute after oral administration, the proliferation of the intima being significantly inhibited lo A Z1 534
DYES (German Published Specification) 2,549,568 and DEMOS (German Published Specification) 2,841,667.
It has likewise been disclosed that the compound knifed-pine (compare DEMOS (German Published Specification) 1,67~,827) and other calcium antagonists inhibit entry ox Cay into smooth muscle cells. In addition, it has since been disclosed for nifedipine -that it can suppress infiltration of cholesterol into the vessel wall of rabbits fed with cholesterol (compare Do Henry and Bentley, KIWI.: J. Olin. Invest. 68, 1366-9, 1981).
The use of the ~ihydropyridines according to the invent lion as anti arteriosclerotic agents which inhibit the formation, caused by damage -to vessel walls, of fibromusculoelastic plaques produced by a proliferating intima has not hitherto been disclosed.
Cardiovascular diseases, which are diagnosed as the cause of more than 50~ of the cases of death in the mortality statistics in industrialized countries, very frequently have their cause in arteriosclerotic changes in the arterial part ox the vascular system. Intimal proliferation its rewarded as a important early stage in the etiology of atheroc3enesls. Arteriosclerotic changes of this type, which can lead to partial or complete occlu-soon of the vessel, cause damage to tissue and can load to local tissue necrosis, infarction, for example in the heart or brain.
The present invention relates to 1,4-dihydropyridines of the general formula (I) \~'~
R OX COO (I) in which Al and R2 are identical or different and each represent alkyd or alkoxyalkyl having up to 12 C atoms, the alkyd radical optionally being substituted by fluorine or chlorine, and R3 represents one or -two identical or different substituents from the group comprising vitro, trifluoromethyl, halogen or ennui, err use to counter arteriosclerosis.
'rho invention therefore provides pharmaceutical compositions yin dosage unit form suitable for oral a~lininixtrcl-tion to a mammal ire countering the formation of fibromusculo elclstic plaques produced by intimal proliferation in mammals, whelk compositions comprise a compound of general formula (I) dew Ed avow, in admixture with a suitable pharmaceutically acceptable I error or cliluent.
In anther aspect the inventiorl provides a process for 35~
preparing a therapeutic agent for countering the formation of fibromusculo elastic plaques produced by intimal proliferation in a mammal, in ready-to-use drug form, characterized in that the therapeutic agent includes as active ingredient a compound of formula (I) as defined above.
Those compounds of the general formula (I) are portico laxly suitable, in which Al and R2 are identical or different and each represent alkyd having 1 -to 4 C atoms or alkoxyal~yl having up to 6 carbon atoms, and R3 represents one or two subs-tituents in the ortho or mote position from the group comprising vitro, chlorine or trifluoromethyl.
Compounds of the general formula (I) which may be very particularly emphasized are those in which Al and R2 represent alkyd having 1 to 4 carbon atoms and R represents vitro.
prom a knowledge of the state of the art, it could not be expected that the compounds usable according to the invention have such an advantageous anti arteriosclerotic effect.
Arteriosclerosis is a complex disease, the original - pa -US
lion of which can frequently be affected or caused by the following processes:
a) Damage to a vessel wall with subsequent proliferation of smooth muscle cells and production of a fibromusco-elastic lesion Infiltration of lipids into this lesion and c) Formation of a mural thrombus and its incorporation into the vessel wall.
The following examples illustrate, the advantageous specific inhibitory effect on proliferation of the compounds to be used according to the invention.
Test method Proliferation of the intima is induced on rats by vascular lesion. By subjecting the carotid artery to hypotherm;a(-10C, Z minutes), partial or complete removal of the endothelium in a localized region is produced.
Proliferation of the intima occurs after a short period of about 10 days and this largely corresponds to the early stages of arteriosclerotic plaques in humans. The zones of proliferation are excised and weighed. The jet weight is about 200 to 300 in the chilled segment of 1 cm. The animals also receive a heft diet (3 I
of cholesterol).
The incorporated lipids are stained Vito the fat-soluble distaff Sudan IV and can be determined as an additional parameter compare F. Setter et Allah Export-mentally induced thromboatherosclerosis. Folio annul-Gina 28, as ~1980)).
Surprisingly, the compounds shown as examples in the following table also have anti arteriosclerotic astute after oral administration, the proliferation of the intima being significantly inhibited lo A Z1 534
2~1S~
Table Substance Dose Proliferation Redllction ~mg/kg, day)* go I%) -Control - 309 substance pro. 159 49 example 310 pro. 270 13 substance pro. 73 44 example 130 pro. lo 16 Control - 130 * divided into two doses Apart from cytostatic agents having alkylating effects and glucocorticoids, which inhibit cell proliferation non-specifically, only heparin has hitherto been effective in this model after parenteral administration.
Lipid-lowering substances, such as cholestyramine, neomycin and nicotinic acid were ineffective. The dose-dependent effect of heparin, which serves as a reference standard in the present case, is already knoll (compare R. Slit et at., Suppression by heparin of intima proliferation in the injured carotid artery (rat)., Arch. Pharmacol., Supply 311, Abstr. 1~8~ 198Q).
Ileparin has the significant disadvantage of parcnteral administration.
Virtually no effect occurs after oral administration. The oral effectiveness Ox tile compo-mds according to the invention is surprising and could not be ~xpoctod from knowledge of the state of the art.
on suitable dose is usually in the range of from I to 150 my, profor.lbly lo to lo my. A preferred form of composition is a tablet.
ration I)IIP derivatives as anti atherosclerotic agents 2'-îYitrophenyl~-2,6-dimethyl-3,5-dicarbomethoxy-11,4-di,hydropyridiale SLY
I` No SHEA 2 C~¢~CO2 C~3 45 g of Z-nitrobenzaldehyde, 80 ml of methyl acetoacetate, 75 ml of methanol and 32 Al of ammonia are heated under reflex for several hours filtered, cooled S and, after filtering off with suction, 75 9 of yellow crystals of melting point 172 to 174C are obtained.
4-~3'-Nitrophenyl)-2,6-dimethyL-3,5-di-(carboxylicc acid 2 propcxyethyl ester)-1,4-dihydropyridjne NO
I/
SHEA KIWI, SHEA OCHl SHEA 2 C KIWI Cal Cal OOZE, C~2 SUE
lo IL
C~3 CX3 7u5 9 of 3-nitrobenza~dehydef 19 9 of 7--propoxy-ethyl acetoacetate and 5.5 ml of ammonia on 40 ml of alcohol are heated under reflex for 6 to 8 hours and, after cooling down, 21 9 of yellow crystals are obtained, which are recrystallized from ligroin with addition of a little Bunsen. Melting point 83 to 86C.
Table Substance Dose Proliferation Redllction ~mg/kg, day)* go I%) -Control - 309 substance pro. 159 49 example 310 pro. 270 13 substance pro. 73 44 example 130 pro. lo 16 Control - 130 * divided into two doses Apart from cytostatic agents having alkylating effects and glucocorticoids, which inhibit cell proliferation non-specifically, only heparin has hitherto been effective in this model after parenteral administration.
Lipid-lowering substances, such as cholestyramine, neomycin and nicotinic acid were ineffective. The dose-dependent effect of heparin, which serves as a reference standard in the present case, is already knoll (compare R. Slit et at., Suppression by heparin of intima proliferation in the injured carotid artery (rat)., Arch. Pharmacol., Supply 311, Abstr. 1~8~ 198Q).
Ileparin has the significant disadvantage of parcnteral administration.
Virtually no effect occurs after oral administration. The oral effectiveness Ox tile compo-mds according to the invention is surprising and could not be ~xpoctod from knowledge of the state of the art.
on suitable dose is usually in the range of from I to 150 my, profor.lbly lo to lo my. A preferred form of composition is a tablet.
ration I)IIP derivatives as anti atherosclerotic agents 2'-îYitrophenyl~-2,6-dimethyl-3,5-dicarbomethoxy-11,4-di,hydropyridiale SLY
I` No SHEA 2 C~¢~CO2 C~3 45 g of Z-nitrobenzaldehyde, 80 ml of methyl acetoacetate, 75 ml of methanol and 32 Al of ammonia are heated under reflex for several hours filtered, cooled S and, after filtering off with suction, 75 9 of yellow crystals of melting point 172 to 174C are obtained.
4-~3'-Nitrophenyl)-2,6-dimethyL-3,5-di-(carboxylicc acid 2 propcxyethyl ester)-1,4-dihydropyridjne NO
I/
SHEA KIWI, SHEA OCHl SHEA 2 C KIWI Cal Cal OOZE, C~2 SUE
lo IL
C~3 CX3 7u5 9 of 3-nitrobenza~dehydef 19 9 of 7--propoxy-ethyl acetoacetate and 5.5 ml of ammonia on 40 ml of alcohol are heated under reflex for 6 to 8 hours and, after cooling down, 21 9 of yellow crystals are obtained, which are recrystallized from ligroin with addition of a little Bunsen. Melting point 83 to 86C.
3-Methyl 5-ethyl 2,6-dimethyl-4-(3' nitrophenyl~-1,4-di-hydropyr;dine-3,5-dicarboxylate NO
of EKE, C~¢~CO2C~
lo A 21 534 us After boiling a solution of 13.4 9 of ethyl 3'-nitrobenzylideneacetoacetate and 5.8 9 of methyl Amman-crotonate on 50 ml of ethanol for 10 hours, the 3-methyl 5-ethyl 2,6-dimsthyl-4-(3'-nitrophenyl)~1,4-dihydropyri-Dunn dicarboxylate, of melting point 158C (ethanols obtained. Yield: 67~ of theory.
Example 4 Decal ethyl dodders dimethyl-4-(2-nitrophenyl~-pyridine-3,5-dicarboxylate H~C2O~C CO2-(C~2)9-CX
N
I C~3 A solution of 263 9 (1 molt of ethyl 2-(3-n;tro-benzyl;dene)-acetoacetate end 241 9 (1 molt of decal I-am;nocrotonate in 2~4 liters of absolute ethanol was heated to bullying under nitrogen for 18 hours. It was then filtered hot and evaporated to about one half of the volume in vacua. The concentrated solution was cooled in ice, whereupon a thick mass of crystals precipitated out.
This was filtered off with suction, recrystallized from ethanol and, after washing with 0.5 lithe of Nixon, Z0 dried in a vacuum oven at 60C~ Melting point 1û6 to 108C, yield: 337 9 (69.5~).
Example 5 Isobutyl2,6-d;methyl-3-methoxycarbonyl-4-~Z'~nitroph~nyl~--1,4-d;hydropyr;d;ne-5~carboxylate H, C
HO - H C -COO I,,, ~,~ C I C I, I HO N CEIL
lo A Z1 53~_ Jo 2~35~
14.6 9 (50 Melissa) of isobutyl 2'-nitrobenzylidene-acetoacetate, together with 5.8 g (50 Melissa) of methyl I-aminocrotonate, were heated in 80 ml of ethanol under reflex for 20 hours. After cooling the reaction mixture, the solvent was distilled off in vacua and the oily nest-due was thoroughly mixed with a little ethanol. The pro-duct crystallized completely after a short time, and was filtered off with suction and recrystallized from ethanol.
Melting point 151 to 152C, yield: 15.2 9 ~78X).
lo A 21 534
of EKE, C~¢~CO2C~
lo A 21 534 us After boiling a solution of 13.4 9 of ethyl 3'-nitrobenzylideneacetoacetate and 5.8 9 of methyl Amman-crotonate on 50 ml of ethanol for 10 hours, the 3-methyl 5-ethyl 2,6-dimsthyl-4-(3'-nitrophenyl)~1,4-dihydropyri-Dunn dicarboxylate, of melting point 158C (ethanols obtained. Yield: 67~ of theory.
Example 4 Decal ethyl dodders dimethyl-4-(2-nitrophenyl~-pyridine-3,5-dicarboxylate H~C2O~C CO2-(C~2)9-CX
N
I C~3 A solution of 263 9 (1 molt of ethyl 2-(3-n;tro-benzyl;dene)-acetoacetate end 241 9 (1 molt of decal I-am;nocrotonate in 2~4 liters of absolute ethanol was heated to bullying under nitrogen for 18 hours. It was then filtered hot and evaporated to about one half of the volume in vacua. The concentrated solution was cooled in ice, whereupon a thick mass of crystals precipitated out.
This was filtered off with suction, recrystallized from ethanol and, after washing with 0.5 lithe of Nixon, Z0 dried in a vacuum oven at 60C~ Melting point 1û6 to 108C, yield: 337 9 (69.5~).
Example 5 Isobutyl2,6-d;methyl-3-methoxycarbonyl-4-~Z'~nitroph~nyl~--1,4-d;hydropyr;d;ne-5~carboxylate H, C
HO - H C -COO I,,, ~,~ C I C I, I HO N CEIL
lo A Z1 53~_ Jo 2~35~
14.6 9 (50 Melissa) of isobutyl 2'-nitrobenzylidene-acetoacetate, together with 5.8 g (50 Melissa) of methyl I-aminocrotonate, were heated in 80 ml of ethanol under reflex for 20 hours. After cooling the reaction mixture, the solvent was distilled off in vacua and the oily nest-due was thoroughly mixed with a little ethanol. The pro-duct crystallized completely after a short time, and was filtered off with suction and recrystallized from ethanol.
Melting point 151 to 152C, yield: 15.2 9 ~78X).
lo A 21 534
Claims (13)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition in dosage unit form suitable for oral administration to a mammal for countering the formation of fibromusculo elastic plaques produced by intimal proliferation in mammals, which composition comprises as active ingredient 1,4-dihydropyridine of the general formula (I) (I) in which R1 and R2 are identical or different and each represent alkyl or alkoxyalkyl having up to 12 C atoms, the alkyl radical optionally being substituted by fluorine or chlorine, and R3 represents 1 or 2 identical or different substituents from the group comprising nitro, trifluoromethyl, halogen or cyano, in an amount suitable to counter the formation of fibro-musculo elastic plaques produced by intimal proliferation in a mammal, in admixture with a suitable pharmaceutically acceptable carrier or diluent.
2. A composition according to claim 1 wherein in the 1,4-dihydropyridine R1 and R2 are identical or different and each represent alkyl having 1 to 4 C atoms or alkoxy-alkyl having up to 6 carbon atoms, and R3 represents 1 or 2 substituents in the ortho or meta position from the group comprising nitro, chlorine or trifluoro-methyl.
3. A composition according to claim 1 wherein in the 1,4-dihydropyridine R1 and R2 represent alkyl having 1 to 4 carbon atoms and R3 represents nitro.
4. A composition according to claim 1 wherein the 1,4-dihydropyridine is 3-methyl 5-ethyl 2,6-dimethyl-4-(3'-nitro-phenyl)-1,4-dihydropyridine-3,5-dicarboxylate of formula
5. A composition according to claim 1 wherein the weight of the 1,4-dihydropyridine is from 1 to 150 mg per dosage unit.
6. A composition according to claim 2, 3 or 4 wherein the weight of the 1,4-dihydropyridine is from 1 to 150 mg per dosage unit.
7. A composition according to claim 1 wherein the weight of the 1,4-dihydropyridine is from 10 to 100 mg per dosage unit.
8. A composition according to claim 2, 3 or 4 wherein the weight of the 1,4-dihydropyridine is from 10 to 100 mg per dosage unit.
9. A composition according to claim 1, 2 or 3 in the form of tablets, pills, dragees or capsules.
10. A composition according to claim 4, 5 or 7 in the form of tablets, pills, dragees or capsules.
11. A composition according to claim 1, 2 or 3 in the form of tablets.
12. A composition according to claim 4, 5 or 7 in the form of tablets.
13. A process for preparing a therapeutic agent for countering the formation of fibromusculo elastic plaques produced by intimal proliferation in a mammal, in ready-to-use drug form, character-ized in that the therapeutic agent includes as active ingredient a compound of formula (I) as defined in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823222367 DE3222367A1 (en) | 1982-06-15 | 1982-06-15 | Use of 1,4-dihydropyridines in antiarteriosclerotics and preparation thereof |
| DEP3222367.6 | 1982-06-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1228549A true CA1228549A (en) | 1987-10-27 |
Family
ID=6166052
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000430227A Expired CA1228549A (en) | 1982-06-15 | 1983-06-13 | Use of 1,4-dihydropyridines in antiarteriosclerotic agents and their preparation |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS595114A (en) |
| BE (1) | BE897035A (en) |
| CA (1) | CA1228549A (en) |
| DE (1) | DE3222367A1 (en) |
| ES (1) | ES8403456A1 (en) |
| FR (1) | FR2528425B1 (en) |
| IL (1) | IL68970A0 (en) |
| IT (1) | IT1175920B (en) |
| ZA (1) | ZA834344B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IE57810B1 (en) * | 1984-03-27 | 1993-04-21 | Delagrange Lab | 1,4-dihydropyridine derivatives,their preparation and their use |
| GB8428552D0 (en) * | 1984-11-12 | 1984-12-19 | Sandoz Ltd | Organic compounds |
| US5260321A (en) * | 1984-11-12 | 1993-11-09 | Sandoz Ltd. | Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins |
| GB8431119D0 (en) * | 1984-12-10 | 1985-01-16 | Fujisawa Pharmaceutical Co | Anti-arteriosclerotic composition |
| GB2180532B (en) * | 1985-09-17 | 1989-08-23 | Inst Organicheskogo Sinteza Ak | Alkoxy-and phenoxy-alkyl-esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid |
| DE4222770A1 (en) * | 1992-07-10 | 1994-01-13 | Bayer Ag | Light-activated 1- (2-nitrobenzyl) -substituted 1,4-dihydropyridines |
| DE4328884A1 (en) * | 1993-08-27 | 1995-03-02 | Bayer Ag | Use of N-alkylated 1,4-dihydropyridinecarboxylic acid esters as medicaments |
| CA2470813A1 (en) * | 2001-12-20 | 2003-07-03 | Bayer Healthcare Ag | 1,4-dihydro-1,4-diphenylpyridine derivatives |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670827C3 (en) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridine |
| DE2117573C3 (en) * | 1971-04-10 | 1978-07-27 | Bayer Ag, 5090 Leverkusen | Process for the preparation of asymmetrical 1,4-dihydropyridine-3,5dicarboxylic acid esters, and their use as medicaments |
| 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 |
| DE2335466A1 (en) * | 1973-07-12 | 1975-01-30 | Bayer Ag | ALCOXY ALKYL-1,4-DIHYDROPYRIDINE, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINAL PRODUCT |
| DE2549568C3 (en) * | 1975-11-05 | 1981-10-29 | Bayer Ag, 5090 Leverkusen | 2,6-Dimethyl-3-methoxycarbonyl-4- (2'-nitrophenyl) -1,4-dihydropyridine-5-carboxylic acid isobutyl ester, several processes for its preparation and pharmaceuticals containing it |
| DE3033919A1 (en) * | 1980-09-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | SOLID PHARMACEUTICAL PREPARATIONS CONTAINING NIFEDIPINE AND METHOD FOR THE PRODUCTION THEREOF |
-
1982
- 1982-06-15 DE DE19823222367 patent/DE3222367A1/en active Granted
-
1983
- 1983-06-03 IT IT21465/83A patent/IT1175920B/en active
- 1983-06-10 JP JP58103003A patent/JPS595114A/en active Granted
- 1983-06-13 BE BE0/210988A patent/BE897035A/en not_active IP Right Cessation
- 1983-06-13 IL IL68970A patent/IL68970A0/en not_active IP Right Cessation
- 1983-06-13 CA CA000430227A patent/CA1228549A/en not_active Expired
- 1983-06-14 ZA ZA834344A patent/ZA834344B/en unknown
- 1983-06-14 ES ES523244A patent/ES8403456A1/en not_active Expired
- 1983-06-14 FR FR8309798A patent/FR2528425B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE3222367A1 (en) | 1983-12-15 |
| DE3222367C2 (en) | 1992-02-13 |
| IT1175920B (en) | 1987-08-12 |
| ES523244A0 (en) | 1984-03-16 |
| BE897035A (en) | 1983-12-13 |
| IT8321465A0 (en) | 1983-06-03 |
| FR2528425A1 (en) | 1983-12-16 |
| FR2528425B1 (en) | 1987-02-06 |
| ZA834344B (en) | 1984-03-28 |
| JPH0553774B2 (en) | 1993-08-10 |
| ES8403456A1 (en) | 1984-03-16 |
| IL68970A0 (en) | 1983-10-31 |
| JPS595114A (en) | 1984-01-12 |
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| MKEX | Expiry |