US 4,849,433 AGrant
The Compound, (.Revreaction.)1,4-Dihydro-2,6-Dimethyl-4-(2'-Nitrophenyl)-Pyridine-3,5- Dicarboxylic Acid, Methyl Isobutyl Ester, Compositions Containing Same and a Method for Effecting Coronary Dilation
Issue Date:1989-07-18
•9 Claims
Abstract
The invention relates to optically active 1,4-dihydropyridine compounds of Formulas Ia and Ib as defined hereinabove which are effective for influencing circulation. Also included in the invention are compositions containing said optically active compounds and methods for the use of said compounds and compositions.
Metadata
Assignee
- Bayer Aktiengesellschaft
Inventors
- Egbert Wehinger
- Horst Meyer
- Friedrich Bossert
- Wulf Vater
- Robertson Towart
- Kurt Stoepel
- Stanislav Kazda
Application Information
Application Number:US 0125156
Filing Date:1987-02-09
Priority Date:1979-09-01
Art Unit:121
Classifications
IPC:
C07D 2190A61K 3144
Field of Search:
546514321356
Patent Drawings
This patent does not have any drawings.
Description
The following Preparative Examples illustrate the preparation of compounds of the present invention.
Preparative Examples (according to process variant (c))
(A) Preparation of (+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound A) ##STR8##
A solution of 14.5 g (96 mmols) of 3-nitrobenzaldehyde, 13.7 g (96 mmols) of .beta.-aminocrotonic acid isopropyl ester and 22.8 g (96 mmols) of acetoacetic acid 2-methoxy-2-phenylethyl ester in 150 ml of isopropanol is heated to the boiling point under nitrogen for 12 hours.
The solvent is then distilled off in vacuo and the oily residue is triturated with a little ether, whereupon the reaction product partly solidified. The crystals which has precipitated was filtered off and recrystallised from ethanol. Melting point: m.p. =173.degree. C., yield: 19 g (40%)
This crystalline fraction is a single configuration and the specific optical rotation [.alpha.].sub.D.sup.20 =+53.82.degree. (c=1,1% w/v.sup.*, ethanol)
(B) Preparation of (-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound (b) ##STR9##
A solution of 27.7 g (0.1 mol) of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 23.5 g (0.1 mol) of .beta.-aminocrotonic acid 2-methoxy-2-phenyl-ethyl ester in 160 ml of methanol is heated to the boiling point under nitrogen for 12 hours. The solvent is then distilled off in vacuo and the oily residue is triturated with a little ether. The reaction product thereby solidified and is filtered off and recrystallised from ethanol.
Melting point: m.p. =173.degree. C., yield: 11.8 (24%)
The product has a single configuration and the specific optical rotation [.alpha.].sub.D.sup.20 =-53.3.degree. (c=1.04% w/v, ethanol).
Example 1
(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl methyl ester ##STR10##
19 g (38 mmols) of (+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound A) in a solution of 0.87 g (38 mmols) of sodium in 50 ml of methanol and 50 ml of 1,2-dimethoxyethane are heated to the boiling point under nitrogen for 5 hours. The solution is then concentrated to half the volume in vacuo and acidified with dilute hydrochloric acid. After adding an equal part of water, the mixture is extracted several times with methylene chloride and the extracts are concentrated in vacuo, after drying over sodium sulphate. The solid residue is recrystallized from methanol (crude yield: 5.5 g (3.%), melting point: 134.degree.-136.degree. C.) and the product is then purified by high performance liquid chromatography on a preparative RP8 column (10.mu.), internal diameter 16 mm, length 250 mm, using acetonitrile/water =45/55 as the eluting agent.
Melting point: m.p. =136.degree. C.
Specific optical rotation: [.alpha.].sub.D.sup.20 =+24.97 (c=0.93% w/v, ethanol).
Example 2
(-)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl methyl ester ##STR11##
16.5 g (33.4 mmols) of (-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound B) in a solution of 0.87 g (38 mmols) of sodium in 100 ml of methanol are heated to the boiling point under nitrogen for 24 hours. After cooling, the solution is concentrated to about half the volume in vacuo and acidified with dilute hydrochloric acid. After adding an equal part of water, the mixture is extracted several times with methylene chloride and the extracts are concentrated in vacuo, after drying over sodium sulphate. The residue crystallized completely and is filtered off and recrystallized from methanol (crude yield: 4.2 g (34%), melting point: 132.degree.-134.degree. C.), and the product is purified by high performance liquid chromatography, as described under Example 1.
Melting point: m.p. =136.degree. C.
Specific optical rotation: [60 ].sub.D.sup.20 =-24.60.degree. (c =1.07% w/v, ethanol).
Example 3
(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid ethyl isopropyl ester ##STR12##
19 g (38 mmols) of (+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-carboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound A) in a solution of 0.87 g (38 mmols) of sodium in 100 ml of ethanol are heated to the boiling point under nitrogen for 8 hours. The solvent is then distilled off in vacuo, the residue is taken up in water and the mixture is acidified with dilute hydrochloric acid and extracted several times with methylene chloride. The extracts are concentrated in vacuo, after drying over sodium sulphate. The residue crystallised completely and is filtered off and recrystallised from methanol (crude yield: 4.1 g (2,%), melting point: 143.degree.-146.degree. C.), and the product is purified by high performance liquid chromatography, as described under
Example 1.
Melting point: m.p. =140.degree. C.
Specific optical rotation: [.alpha.].sub.D.sup.20 =+4.61 (c =0.46% w/v, ethanol).
Example 4
(-)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid ethyl isopropyl ##STR13##
18.6 g (27.6 mmols) of (-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxy-2-phenylethyl ester (compound (B) in a solution of 0.86 g (3m.6 mmols) of sodium in 100 ml of ethanol are heated to the boiling point under nitrogen for 8 hours. The solution is then concentrated to about half the volume in vacuo, acidified with dilute hydrochloric acid and, after adding an equal part of water, extracted several times with methylene chloride. The extracts are concentrated in vacuo, after drying over sodium sulphate. The residue initially obtained as an oil soon crystallized completely and is filtered off and recrystallised from methanol (crude yield: 2.8 g (19,2%), melting point: 146.degree.-149.degree. C.), and the product is purified by high performance liquid chromatography, as described under
Example 1.
Melting point: m.p. =140.degree.
Specific optical rotation: [.alpha.].sub.D.sup.20 =-4.75 (c =0.51% w/v, ethanol).
Example 5
(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxyethyl ester ##STR14## 24.7 g (50 mmols) of (+)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl-2-methoxy-2-phenylethyl ester (compound A) are stirred in a solution of 1.4 g (61 mmols) of sodium in 230 ml of freshly distilled glycol monomethyl ether at 85.degree. C. under nitrogen for 8 hours. After cooling, the solvent is distilled off in vacuo, the residue is taken up in water and the mixture is acidified with dilute hydrochloric acid and extracted several times with methylene chloride. The organic extracts are concentrated, after drying over sodium sulphate, and the oily residue is triturated with a little ether, where-upon the substance rapidly crystallizes completely. The solid reaction product is filtered off (crude
yield: 15.1 g (72%),
melting point: 126.degree.-129.degree. C.) and recrystallized twice from ethanol.
Melting point: m.p. =134.degree. C.
Specific optical rotation: [.alpha.].sub.D.sup.20 =+17.10.degree. (c==0.96% w/v, ethanol).
Example 6
(-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-methoxyethyl ester ##STR15##
8.2 g (16.6 mmols) of (-)-1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl-2-methoxy-2-phenylethyl ester (compound B) are stirred in a solution of 0.5 g (21.8 mmols) of sodium in 80 ml of freshly distilled gylcol monomethyl ether at 85.degree. C. under nitrogen for 8 hours. After cooling, the solvent is distilled off in vacuo, the residue is taken up in water and the mixture is acidified with dilute hydrochloric acid and extracted several times Le A 19 861 with methylene chloride. The organic extracts are concentrated, after drying over sodium sulphate. The oily residue soon crystallizes completely and, after adding a little ether, is filtered off (crude yield: 5.1 g (73%)) and recrystallized twice from ethanol.
Melting point: m.p. =134.degree. C.
Specific optical rotation: [.alpha.].sub.D.sup.20 =-16.9 (c=1.5% w/v, ethanol).
Example 7
(-)-1,4dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid ethyl methyl ester ##STR16## 7,5 g (16 mmoles) of (-)-1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylic acid ethyl 2-(S)-methoxy-2-phenylethyl) ester (compound B) in a solution of 0,41 g (18 mmoles) of sodium in 75 ml of methanol heated to the boiling point under nitrogen for 5 hours. The solvent is then distilled off in vacuo, the residue is taken up in water and the mixture is acidified with dilute hydrochloride acid and extracted several times with methylene chloride. The organic extracts are concentrated in vacuo, after drying over sodium sulphate. The only residue crystallised completely (crude yield: 3,5 g) and the product is then purified by higher performance liquid chromatography as described in example 1.
Melting point: m.p. =159.degree.-160.degree. C.
Specific optical rotation [.alpha.].sub.D.sup.20 =-15.02.degree. C. (c=0,49 w/v, ethanol).
Example 8
(+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)pyridine-3,5-dicarboxylic acid isobutyl methyl ester ##STR17## is obtained analogeously to the method described in example 7 by selective alcoholyse of the compond of the formula D by using isobutanole.
Melting point: m.p. =138.degree. C.
Specific optical rotation: [.alpha.].sub.D.sup.20 =+25,9.degree. C. (c=0.50 ethanol)
Example 9
The compound (+)-1,4-Dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl neopentyl ester of the formula ##STR18## is obtained analogeously to the method described in example 7 by selective alcoholyse of the compound of the formula D with neopentyl alcohol.
Melting point: m.p. =131.degree. C.
Specific optical rotation: [.alpha.].sup.D.sup.20 =+53.4.degree. (c=0,51 ethanol
Example 10
The compound (=)-1,4-Dihydro-2,6-dimethyl-4-(2'-nitriphenyl)-pyridine-3,5-dicarboxylic acid isobutyl methyl ester of the formula ##STR19## is obtained as a yellowish oil which builds an amorpheous product after drying in vacuo. Specific optical rotation: [.alpha.].sub.D.sup.20 =+165.93.degree. C. (c=0,512, ethanol).
Among the new optically active 1,4-dihydro-pyridine salts of the invention, those salts that are pharmaceutically acceptable are particularly important and are preferred.
The new free optically active 1,4-dihydro-pyridine compounds of the general formula (Ia) and their salts can be interconverted in any suitable manner; methods for such interconversion are known in the art.
The present invention also comprises pharmaceutically acceptable bioprecursors of the active compounds of the present invention.
For the purpose of this specification the term pharmaceutically acceptable bioprecursor` of an active compound of the invention means a compound having a structural formula different from the active compound but which nonetheless, upon administration to a warm-blooded animal is converted in the patient's body to the active compound.
Claims
What is claimed is:
1. The compound (+)-1,4-dihydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl isobutyl ester.
2. A pharmaceutical composition comprising, as an active ingredient, a coronary dilator effective amount of a compound according to claim 1 in admixture with an inert pharmaceutical carrier.
3. A pharmaceutical composition of claim 2 in the form of a sterile or physiologically isotonic aqueous solution.
4. A composition according to claim 2 or 3 containing from 0.5 to 90% by weight of the said active ingredient.
5. A medicament in dosage unit form comprising an amount of a compound according to claim 1 as a coronary dilator together with an inert pharmaceutical carrier.
6. A medicament of claim 5 in the form of tablets, pills, dragees, capsules, ampoules or suppositories.
7. A method of effecting coronary dilation in warm-blooded animals which comprises administering to the animals a coronary dilation influencing amount of an active compound according to claim 1 either alone or in admixture with an inert pharmaceutical carrier or in the form of a medicament.
8. A method according to claim 7 in which the active compound is administered intravenously in an amount of 0.05 to 1 mg per kg body weight per day.
9. A method according to claim 7 in which the active compound is administered orally in an amount of 0.1 to 5 mg per kg body weight per day.