CA2170285A1 - Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments - Google Patents
Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicamentsInfo
- Publication number
- CA2170285A1 CA2170285A1 CA002170285A CA2170285A CA2170285A1 CA 2170285 A1 CA2170285 A1 CA 2170285A1 CA 002170285 A CA002170285 A CA 002170285A CA 2170285 A CA2170285 A CA 2170285A CA 2170285 A1 CA2170285 A1 CA 2170285A1
- Authority
- CA
- Canada
- Prior art keywords
- general formula
- carbon atoms
- compounds
- methyl
- atherosclerotic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- 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
-
- 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
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the use of N-alkylated 1,4-dihydropyridinecarboxylic acid esters of the general formula (I), <IMG> (I) some of which are known and in which R1 to R6 have the meanings given in the description, as antiatherosclerotic medicaments, in particular to their use for the prophylaxis of restenoses following angioplasties s and vascular surgery.
Description
~17028~
~ T ~ 5 The present invention relates to the use of N-alkylated 1,4-dihydropyri~;ne~;carboxylic acid esters, some of which are known, as anti-atherosclerotic medicaments, in particular to their use $or the prophylaxis of restenoses following angioplasties and vascular surgery.
It is already known that 4-nitrophenyl-substituted 1,4-dihydropyridines also bring about inhibition of the formation of fibromuscular plaques [cf. DE 32 22 367l.
It has now been found that N-alkylated 1,4-dihydropyri-dinedicarboxylic acid esters of the general formula (I) ~R
Rso2C ~ CO2R4 (I) in which R1 represents hydrogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen or methyl, R2 represents hydrogen, halogen, nitro, hydroxyl, trifluoromethyl or methyl, Le A 29 900 - 1 -~1702&~
R3 represents hydrogen or cyano, or R2 and R3 together form a fused-on benzo ring, R~ and R5 are identical or different and represent straight-chain or br~nche~ alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms, R6 represents straight-chain or br~nch~ alkyl having up to 6 carbon atoms, or represents cycloalkyl having 3 to 7 carbon atoms, surprisingly po~sess, in addition to their haemorheologi-cal effect, a strong inhibitory effect on the prolifera-tion of smooth muscle cell~ and are consequently suitable for use in controlling atherosclerosi~, in particular for the prophylaxis of restenoses following angioplasties and va~cular surgery.
Dimethyl 1,2,6-trimethyl-4-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and dimethyl 4-(4-chloro-3-trifluoromethylphenyl)-1-cyclopropyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate are particularly preferred in the control of atherosclerosis, in particular for the prophylaxis of restenoses following angioplasties and ~a~cular surgery.
Le A 29 900 - 2 -The compounds according to the invention thus exhibit a valuable spectrum of pharmacological activity which was not to be foreseen.
The compounds according to the invention inhibit the proliferation of smooth muscle cells. Injuries to the vessel wall lead to neoint;m~l cell growth and consequently to constriction of the free vessel lumen.
This process is the principal cause of restenosis prob-lems following vessel-opening procedures, such as percutaneous angioplasties, endarterectomies or bypass operations.
They can therefore be employed in medicaments for the treatment and prophylaxis of restenosis, e.g. following angioplasties and vascular surgery. In addition to this, the compounds according to the invention can also be ployed for treating atherosclerosis.
Some of the compounds according to the invention are known [cf. DOS 40 11 695].
In order to ascertain the antiproliferative effect of the compounds according to the invention, balloon catheters are inserted into the carotid arteries of rats, and these catheters are then inflated and the inner side of the blood vessel i~ damaged by moving the catheter [Clowes A.W, et al., Lab. Invest. Vol. 49, No. 3, p. 327, 1983]. This damage brings about neointimal proliferation of the smooth muscle, causing stenoses. The extent of Le A 29 900 - 3 -217028~
vessel constriction in the animals is determined after about 2 weeks by histological processi~g of the blood vessels, involving measurement of the area of prolifera-ted tissue in vessel cross sections. Surprisingly, the compounds according to the invention significantly inhibit the vessel constrictions, as i8 evident from the following table.
Example Proliferated tissue in ~m2 x 1000 (%) No. Control 10 mg/kg p.o.
1 129 (100%) 76 (59%) 2 125 (100%) 56 (45%) The novel active compounds can be converted, in a known ~anner, into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable, excipients or solvents.
In this connection, the therapeutically active compound should in each case be present at a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in quantities which are sufficient to achieve the given dosage scope.
The formulations are prepared, for example, by ext~n~ing the active compounds with solvents and/or excipients, optionally using emulsifiers and/or dispersants, it being possible, where appropriate, for example when u~ing water as a diluent, to use organic solvents as auxiliary 801-vents.
Le A 29 900 - 4 -~170285 Administration is effected in a customary manner, prefer-ably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral use, solutions of the active compound can be employed using suitable liquid carrier materials.
In general, it has proved ad~antageous to A~;n;ster quantities of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight in order to achieve effective results in the case of intravenous a~inistra-tion, and the dosage is about 0.01 to 20 mg/kg, prefer-ably 0.1 to 10 mg/kg, of body weight in the case of oral administration.
Despite this, it can, where appropriate, be necessary to diverge from the said quantities, specifically dep~n~;ng on the body weight and the nature of the route of admini-stration, on the individual response to the medicament, on the nature of its formulation, and on the time or interval at which administration is effected. Thus, it can, in some cases, be sufficient to make do with less than the aforesaid lowesk quantity, while, in other cases, the said upper limit must be exceeded. When larger quantities are being administered, it can be advisable to divide these into several smaller doses which are given over the day.
Le A 29 900 . - 5 -~1702~5 Example 1 Dimethyl 1,2,6-trimethyl-4-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dic~nhoYylate (~ ' H3CO2C ~ CO2CH3 A mixture consisting of 5.22 g (0.03 mol) of 4-trifluoro-methylbenzaldehyde, 7.04 g (0.06 mol) of methyl aceto-acetate and 2.07 g (0.03 mol) of methyl~_; ne hydrochloride in 20 ml of pyridine iR stirred under reflux for 5 hours. After the pyridine has been distilled off, partitioning takes place between water and methylene chloride, and the organic phase is then w~h~A with water, dried over sodium sulphate and e~aporated. The re~idue is recrystallized from methanol.
M.p.: 154-155C
Yield: 7.88 g (68.5% of theory) Example 2 Dimethyl 4-(4-chloro-3-trifluoromethylphenyl)-1-cyclopro-pyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Le A 29 900 - 6 -~ CF~
H3CO2C ~1, CO2CH3 J~ ~
A
Process A
A solution of 23.3 g (0.15 mol) of methyl 3-cyclopropyl-aminocrotonate, 46.0 g (0.15 mol) of methyl (4-chloro-3-trifluoromethylbenzylidene)acetoacetate and 17.7 g (0.15 mol) of pyridine hydrochloride in 100 ml of pyridine is stirred under reflux for 7.5 h. Following evaporation in vacuo, the residue is partitioned between 120 ml of methylene chloride and 150 ml of water. After having been evaporated down, the organic phase yields a resinous crude product which is recrystallized from 100 ml of cyclohexane.
M.p.: 131-135C
Yield: 35.0 g (52.6% of theory) Process B
A solution of 4.17 g (0.02 mol) of 4-chloro-3-trifluoro-methylbenzaldehyde, 4.65 g (0.04 mol) of methyl aceto-acetate and 1.96 g (0.021 mol) of cyclopropylamine Le A 29 900 - 7 -21702~
hydrochloride in 20 ml of pyridine i8 stirred under refluY. for 4 h. Following evaporation, the residue is partitioned between 40 ml of methylene chloride and 50 ml of water. Evaporation of the organic phase yields an oily crude product which is crystallized using cycloh~Y~ne and n-pentane.
M.p.: 131-134C
Yield: 3.33 g (37.5% of theory) Le A 29 900 - 8 -
~ T ~ 5 The present invention relates to the use of N-alkylated 1,4-dihydropyri~;ne~;carboxylic acid esters, some of which are known, as anti-atherosclerotic medicaments, in particular to their use $or the prophylaxis of restenoses following angioplasties and vascular surgery.
It is already known that 4-nitrophenyl-substituted 1,4-dihydropyridines also bring about inhibition of the formation of fibromuscular plaques [cf. DE 32 22 367l.
It has now been found that N-alkylated 1,4-dihydropyri-dinedicarboxylic acid esters of the general formula (I) ~R
Rso2C ~ CO2R4 (I) in which R1 represents hydrogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen or methyl, R2 represents hydrogen, halogen, nitro, hydroxyl, trifluoromethyl or methyl, Le A 29 900 - 1 -~1702&~
R3 represents hydrogen or cyano, or R2 and R3 together form a fused-on benzo ring, R~ and R5 are identical or different and represent straight-chain or br~nche~ alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms, R6 represents straight-chain or br~nch~ alkyl having up to 6 carbon atoms, or represents cycloalkyl having 3 to 7 carbon atoms, surprisingly po~sess, in addition to their haemorheologi-cal effect, a strong inhibitory effect on the prolifera-tion of smooth muscle cell~ and are consequently suitable for use in controlling atherosclerosi~, in particular for the prophylaxis of restenoses following angioplasties and va~cular surgery.
Dimethyl 1,2,6-trimethyl-4-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and dimethyl 4-(4-chloro-3-trifluoromethylphenyl)-1-cyclopropyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate are particularly preferred in the control of atherosclerosis, in particular for the prophylaxis of restenoses following angioplasties and ~a~cular surgery.
Le A 29 900 - 2 -The compounds according to the invention thus exhibit a valuable spectrum of pharmacological activity which was not to be foreseen.
The compounds according to the invention inhibit the proliferation of smooth muscle cells. Injuries to the vessel wall lead to neoint;m~l cell growth and consequently to constriction of the free vessel lumen.
This process is the principal cause of restenosis prob-lems following vessel-opening procedures, such as percutaneous angioplasties, endarterectomies or bypass operations.
They can therefore be employed in medicaments for the treatment and prophylaxis of restenosis, e.g. following angioplasties and vascular surgery. In addition to this, the compounds according to the invention can also be ployed for treating atherosclerosis.
Some of the compounds according to the invention are known [cf. DOS 40 11 695].
In order to ascertain the antiproliferative effect of the compounds according to the invention, balloon catheters are inserted into the carotid arteries of rats, and these catheters are then inflated and the inner side of the blood vessel i~ damaged by moving the catheter [Clowes A.W, et al., Lab. Invest. Vol. 49, No. 3, p. 327, 1983]. This damage brings about neointimal proliferation of the smooth muscle, causing stenoses. The extent of Le A 29 900 - 3 -217028~
vessel constriction in the animals is determined after about 2 weeks by histological processi~g of the blood vessels, involving measurement of the area of prolifera-ted tissue in vessel cross sections. Surprisingly, the compounds according to the invention significantly inhibit the vessel constrictions, as i8 evident from the following table.
Example Proliferated tissue in ~m2 x 1000 (%) No. Control 10 mg/kg p.o.
1 129 (100%) 76 (59%) 2 125 (100%) 56 (45%) The novel active compounds can be converted, in a known ~anner, into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable, excipients or solvents.
In this connection, the therapeutically active compound should in each case be present at a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in quantities which are sufficient to achieve the given dosage scope.
The formulations are prepared, for example, by ext~n~ing the active compounds with solvents and/or excipients, optionally using emulsifiers and/or dispersants, it being possible, where appropriate, for example when u~ing water as a diluent, to use organic solvents as auxiliary 801-vents.
Le A 29 900 - 4 -~170285 Administration is effected in a customary manner, prefer-ably orally or parenterally, in particular perlingually or intravenously.
In the case of parenteral use, solutions of the active compound can be employed using suitable liquid carrier materials.
In general, it has proved ad~antageous to A~;n;ster quantities of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg, of body weight in order to achieve effective results in the case of intravenous a~inistra-tion, and the dosage is about 0.01 to 20 mg/kg, prefer-ably 0.1 to 10 mg/kg, of body weight in the case of oral administration.
Despite this, it can, where appropriate, be necessary to diverge from the said quantities, specifically dep~n~;ng on the body weight and the nature of the route of admini-stration, on the individual response to the medicament, on the nature of its formulation, and on the time or interval at which administration is effected. Thus, it can, in some cases, be sufficient to make do with less than the aforesaid lowesk quantity, while, in other cases, the said upper limit must be exceeded. When larger quantities are being administered, it can be advisable to divide these into several smaller doses which are given over the day.
Le A 29 900 . - 5 -~1702~5 Example 1 Dimethyl 1,2,6-trimethyl-4-(4-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dic~nhoYylate (~ ' H3CO2C ~ CO2CH3 A mixture consisting of 5.22 g (0.03 mol) of 4-trifluoro-methylbenzaldehyde, 7.04 g (0.06 mol) of methyl aceto-acetate and 2.07 g (0.03 mol) of methyl~_; ne hydrochloride in 20 ml of pyridine iR stirred under reflux for 5 hours. After the pyridine has been distilled off, partitioning takes place between water and methylene chloride, and the organic phase is then w~h~A with water, dried over sodium sulphate and e~aporated. The re~idue is recrystallized from methanol.
M.p.: 154-155C
Yield: 7.88 g (68.5% of theory) Example 2 Dimethyl 4-(4-chloro-3-trifluoromethylphenyl)-1-cyclopro-pyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Le A 29 900 - 6 -~ CF~
H3CO2C ~1, CO2CH3 J~ ~
A
Process A
A solution of 23.3 g (0.15 mol) of methyl 3-cyclopropyl-aminocrotonate, 46.0 g (0.15 mol) of methyl (4-chloro-3-trifluoromethylbenzylidene)acetoacetate and 17.7 g (0.15 mol) of pyridine hydrochloride in 100 ml of pyridine is stirred under reflux for 7.5 h. Following evaporation in vacuo, the residue is partitioned between 120 ml of methylene chloride and 150 ml of water. After having been evaporated down, the organic phase yields a resinous crude product which is recrystallized from 100 ml of cyclohexane.
M.p.: 131-135C
Yield: 35.0 g (52.6% of theory) Process B
A solution of 4.17 g (0.02 mol) of 4-chloro-3-trifluoro-methylbenzaldehyde, 4.65 g (0.04 mol) of methyl aceto-acetate and 1.96 g (0.021 mol) of cyclopropylamine Le A 29 900 - 7 -21702~
hydrochloride in 20 ml of pyridine i8 stirred under refluY. for 4 h. Following evaporation, the residue is partitioned between 40 ml of methylene chloride and 50 ml of water. Evaporation of the organic phase yields an oily crude product which is crystallized using cycloh~Y~ne and n-pentane.
M.p.: 131-134C
Yield: 3.33 g (37.5% of theory) Le A 29 900 - 8 -
Claims (7)
1. Use of N-alkylated 1,4-dihydropyridinedicarboxylic acid esters of the general formula (I) (I) in which R1 represents hydrogen, nitro, cyano, trifluoro-methyl, trifluoromethoxy, halogen or methyl, R2 represents hydrogen, halogen, nitro, hydroxyl, trifluoromethyl or methyl, R3 represents hydrogen or cyano, or R2 and R3 together form a fused-on benzo ring, R4 and R5 are identical or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by alkoxy having up to 4 carbon atoms, R6 represents straight-chain or branched alkyl having up to 6 carbon atoms, or represents cycloalkyl having 3 to 7 carbon atoms, in the control of atherosclerotic diseases.
2. Use of compounds of the general formula (I) according to Claim 1 for the treatment and prophylaxis of restenoses.
3. Use of compounds of the general formula (I) accord-ing to Claim 1 for inhibiting intima proliferation in smooth muscle cells following vessel wall injuries.
4. Use of compounds of the general formula (I) accord-ing to Claim 1 for preparing medicaments for the control of atherosclerotic diseases.
5. Use of compounds of the general formula (I) accord-ing to Claim 1 for preparing medicaments for the prophylaxis and control of restenoses following vessel injuries.
6. Anti-atherosclerotic medicament containing at least one compound of the general formula (I) according to Claim 1.
7. Process for preparing anti-atherosclerotic medi-caments, characterized in that at least one compound of the general formula (I) according to Claim 1 is converted into a suitable form for administration, optionally using customary auxiliary substances and excipients.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4328884A DE4328884A1 (en) | 1993-08-27 | 1993-08-27 | Use of N-alkylated 1,4-dihydropyridinecarboxylic acid esters as medicaments |
| DEP4328884.7 | 1993-08-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2170285A1 true CA2170285A1 (en) | 1995-03-02 |
Family
ID=6496196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002170285A Abandoned CA2170285A1 (en) | 1993-08-27 | 1994-08-16 | Use of n-alkylated 1,4-dihydropyridine dicarboxylic acid esters as medicaments |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0714301A1 (en) |
| JP (1) | JPH09501923A (en) |
| KR (1) | KR960703594A (en) |
| CN (1) | CN1129906A (en) |
| AU (1) | AU7613594A (en) |
| BG (1) | BG100367A (en) |
| CA (1) | CA2170285A1 (en) |
| CZ (1) | CZ43896A3 (en) |
| DE (1) | DE4328884A1 (en) |
| HU (1) | HUT75302A (en) |
| NO (1) | NO960777L (en) |
| PL (1) | PL313116A1 (en) |
| WO (1) | WO1995005823A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19741694C2 (en) * | 1997-09-18 | 2002-10-31 | Schering Ag | Use of complexes whose ligand is a bis-amine oxime derivative or an N¶2¶S¶2¶ derivative and whose central atom is a radionuclide |
| DE60214428T2 (en) * | 2001-12-20 | 2007-09-20 | Bayer Healthcare Ag | 1, 4-DIHYDRO-1, 4-DIPHENYLPYRIDINE DERIVATIVES |
| US10258498B2 (en) * | 2011-11-24 | 2019-04-16 | Richter Gedeon Nyrt. | 1,4-dihydropyridine derivatives with Hsp modulating activity |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3222367A1 (en) * | 1982-06-15 | 1983-12-15 | Bayer Ag, 5090 Leverkusen | Use of 1,4-dihydropyridines in antiarteriosclerotics and preparation thereof |
| EP0169009A3 (en) * | 1984-07-17 | 1988-08-31 | FISONS plc | Novel dihydropyridine derivatives and their production, formulation and use as pharmaceuticals |
| DE4011695A1 (en) * | 1990-04-11 | 1991-10-17 | Bayer Ag | USE OF N-ALKYLATED 1,4-DIHYDROPYRIDE INDICARBOXIC ACID ESTERS AS DRUGS, NEW COMPOUNDS AND METHOD FOR THEIR PREPARATION |
-
1993
- 1993-08-27 DE DE4328884A patent/DE4328884A1/en not_active Withdrawn
-
1994
- 1994-08-16 EP EP94926199A patent/EP0714301A1/en not_active Withdrawn
- 1994-08-16 WO PCT/EP1994/002723 patent/WO1995005823A1/en not_active Application Discontinuation
- 1994-08-16 JP JP7507325A patent/JPH09501923A/en not_active Ceased
- 1994-08-16 CA CA002170285A patent/CA2170285A1/en not_active Abandoned
- 1994-08-16 KR KR1019960700944A patent/KR960703594A/en not_active Application Discontinuation
- 1994-08-16 CZ CZ96438A patent/CZ43896A3/en unknown
- 1994-08-16 HU HU9600472A patent/HUT75302A/en unknown
- 1994-08-16 CN CN94193170A patent/CN1129906A/en active Pending
- 1994-08-16 PL PL94313116A patent/PL313116A1/en unknown
- 1994-08-16 AU AU76135/94A patent/AU7613594A/en not_active Abandoned
-
1996
- 1996-02-19 BG BG100367A patent/BG100367A/en unknown
- 1996-02-26 NO NO960777A patent/NO960777L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG100367A (en) | 1996-07-31 |
| HUT75302A (en) | 1997-05-28 |
| PL313116A1 (en) | 1996-06-10 |
| KR960703594A (en) | 1996-08-31 |
| HU9600472D0 (en) | 1996-04-29 |
| NO960777L (en) | 1996-04-10 |
| JPH09501923A (en) | 1997-02-25 |
| EP0714301A1 (en) | 1996-06-05 |
| DE4328884A1 (en) | 1995-03-02 |
| CN1129906A (en) | 1996-08-28 |
| NO960777D0 (en) | 1996-02-26 |
| AU7613594A (en) | 1995-03-21 |
| WO1995005823A1 (en) | 1995-03-02 |
| CZ43896A3 (en) | 1996-05-15 |
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| EP0463407B1 (en) | Use of dihydropyridins in cardiotonic pharmaceutical compositions |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |