NZ226717A - Substituted pyrrolidine-alkyl 1,4-dihydropyridine carboxylate derivatives and medicaments - Google Patents
Substituted pyrrolidine-alkyl 1,4-dihydropyridine carboxylate derivatives and medicamentsInfo
- Publication number
- NZ226717A NZ226717A NZ226717A NZ22671788A NZ226717A NZ 226717 A NZ226717 A NZ 226717A NZ 226717 A NZ226717 A NZ 226717A NZ 22671788 A NZ22671788 A NZ 22671788A NZ 226717 A NZ226717 A NZ 226717A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
-
- 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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- Heart & Thoracic Surgery (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £26717
MO DfcAlOlkiGS
Patents Form No,
NEW ZEALAND
PATENTS ACT 1953
COMPLETE SPECIFICATION
NEW PYRROLIDINES
O'
%/we, BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH,
a German Company of Byk-Gulden-Strabe 2, D-7750 Konstanz, FEDERAL REPUBLIC OF GERMANY
hereby declare the invention, for which %/we pray that a patent may be granted to nj^/us, and the method by which it is to be performed, to be particularly described in and by the following statement:
(followed by page la)
3 6 SEN
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New pyrrolidines
Field of use of the invention
The invention relates to novel pyrrolidines, processes for their preparation, their use and medicaments which contain them. The compounds according to the invention are used in the pharmaceutical industry for the preparation of medicaments.
Prior art
It is known that certain 1,4-dihydropyridine derivatives which are substituted in various ways have pharmacologically useful properties. Surprisingly, it has been found that the novel compounds described in detail below have particularly interesting pharmacological properties which distinguish them in an advantageous manner from the compounds of the prior art.
Description of the invention
The invention relates to novel pyrrolidines of the formula I
(I)
H
where Cy represents a cyclic structure
R4
in which Y denotes oxygen (O), sulphur (S), vinylene (-CH=CH-), azometnine (-CH=N-) or a group of the formula
363EN
3
2&J 7 1
/ Y
or
R1 denotes l-6C-alkyl or 3-7C-alkoxyalkyl,
R2 denotes l-6C-alkyl or 3-7C-alkoxyalkyl,
R3 denotes hydrogen, l-6C-alkyl or 3-7C-alkoxyalkyl,
R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, l-4C-alkyl,
1-4C-alkoxy or l-4C-alkoxy which is completely or partially substituted by fluorine, or denote l-4C-alkoxycarbonyl,
2-5C-acyl, amino or mono- or di-l-4C-alkylamino,
R6 denotes phenyl or substituted phenyl having one, two or three identical or different substituents from the group consisting of halogen, hydroxyl, nitro, cyano, trifluoromethyl, l-4C-alkyl,
l-4C-alkoxy, l-4C-alkoxycarbonyl, 2-5C-acyl, amino and mono- or di-l-4C-alkylamino and
E denotes 2-5C-alkylene,
and the salts of these compounds.
1-6C-alkyl is straight-chain or branched and denotes, for example, a hexyl, neopentyl, isopentyl, butyl, i-buytl, sec.-butyl, t-butyl, propyl, isopropyl or, in particular, ethyl or methyl radical.
3-7C-alkoxyalkyl represents, for example, an ethoxyethyl, propoxyethyl, isopropoxyethyl, butoxyet'nyl, methoxyethyl,
2-methoxy-l-methylethyl, 2-ethoxy-l-methylethyl or, in particular , methoxyethyl radical.
For the purposes of the invention, halogen denotes bromine, fluorine and, in particular, chlorine.
l-4C-alkyl is straight-chain or branched and denotes, for example, a butyl, i-but.yl, sec.-butyl, t-butyl, propyl, isopropyl, ethyl or, in particular, methyl radical.
fc«*3 68EN
i
4
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l-4C-alkoxy contains, in addition to the oxygen atom, one of the above-mentioned l-4C-alkyl radicals. The methoxy radical and the ethoxy radical are preferred.
%
l-4C-alkoxy which is completely or partially substituted by fluorine is, for example, 1,1,2,2-tetrafluoroethoxy, trifluoro-methoxy, 2,2,2-trifluoroethoxy or, in particular, difluorometh-oxy.
1-4C-alkoxycarbonyl contains, in addition to the carbonyl group, one of the above-mentioned l-4C-alkoxy radicals. The methoxy-carbonyl radical and the ethoxycarbonyl radical are preferred.
2-5C-acyl contains, in addition to the carbonyl group, one of the above-mentioned l-4C-alkyl radicals. The acetyl radical is preferred.
Mono- or ai-l-4C-alkylamino contains, in addition to the nitrogen atom, one or two of the above-mentioned l-4C-alkyl radicals. Di-l-4C-alkylamino is preferred, and in particular dimethyl-, diethyl- or diisopropylamino.
2-5C-alkylene is straight-chain or branched and represents, for example, ethylene (-CH^-CI^-) , trimethylene (r tetramethylene (), pentamethylene (, 1, 2-dimethylethylene, 1,1-dimethyl-ethylene, 2,2-dimethylethylene, isopropylidene, 1-methylethylene and 2-ethylpropylene, ethylene and trimethylene being preferred.
Suitable salts are all salts with acids. The pharmacologically tolerated salts of the inorganic and organic acids usually used in the pharmaceutical industry may be mentioned in particular. Pharmacologically non-tolerated salts, which, for example, can be obtained as products in the preparation of the compounds according to the invention on an industrial scale, are converted
22 67
363EN 5 10881
into pharmacologically tolerated salts by methods familiar to those skilled in the art- Suitable salts of this type are, for example, water-soluble and water-insoluble acid addition salts, such as the hydrochloride, hydrobromide, hydriodide, phosphate, nitrate, sulphate, acetate, citrate, gluconate, benzoate, hibenzate, fendizoate, butyrate, sulphosalicylate, maleate, laurate, malate, fumaratfe, succinate, oxalate, tartrate, amsonate, metembonate, stearate, tosylate, 2-hydroxy-3-naph-thpate, 3-hydroxy-2-naphthoate or mesylate, but also salts with bumetanide, furosemide, azosemide, galosemide, besunide, piretanide, etacrynic acid, tienilic acid or 4-chlorosulpha-moylbenzoic acid.
Noteworthy compounds according to the invention are those of the formula I,
where
Cy denotes phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl, 3-(1,1,2,2-tetraf luoroethoxy)-phenyl, 2-difluoromethoxyphenyl,
3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl,
2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-tri-fluoromethylphenyl, 3-trifluoromethylphenyl or benzoxdiazolyl, R1 denotes methyl, ethyl or methoxyethyl,
R2 denotes methyl, ethyl or methoxyethyl,
R3 denotes methyl, ethyl or methoxyethyl,
R6 denotes phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chloro-phenyl, 2,3-dichlorophenyl, 3,4-dichloropheny.l, 2,4-dichloro-phenyl, 4-bromophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimeth-oxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methyl-phenyl, 3-chloro-4-methylphenyl, 3,4-dimethylphenyl, 4-amino-phenyl, 2,4-diaminophenyl, 4-nitrophenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 3 , 4-dihydroxyphen^1 or 3,4,5-trihydroxyphenyl and
? 9
o
*^68EN 6 10881
E denotes ethylene trimethylene ( -Cfc^-CK^-C^-) ,
tetramethylene (-CI^-CE^-CHj-CI^-) or Pentamet^y^ene
(-ch2-ch2-ch2-ch2-ch2-),
and the salts of these compounds.
Particularly noteworthy compounds according to the invention are those of the formula I, where
Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2-trifluoromethylphenyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
R6 denotes 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 4-nitrophenyl and
E denotes ethylene trimethylene (),
and the salts of these compounds.
Preferred compounds according to the invention are those of the formula I, wherein
Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl,
R1 denotes methyl or ethyl,
R2 denotes methyl or ethyl,
R3 denotes methyl or ethyl,
R6 denotes 4-chlorophenyl or 4-nitrophenyl and
E denotes ethylene (-CE^-CI^-) or trimethylene (-Cl^-CI^-Cf^-), and their salts.
Particularly preferred compounds according to the invention are those of the formula I, where
Cy denotes 3-nitrophenyl,
R1 denotes methyl,
R2 denotes methyl,
R3 denotes methyl or ethyl,
R6 denotes 4-chlorophenyl and
E denotes ethylene (-C^-CI^-) or trimethylene (-C^-Cf^-CI^-) , and their salts.
■ft 6 SEN
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10881
The compounds of the formula I possess a centre of chirality at the 4-position in the 1f4-dihydropyridine and at the 2-position in the pyrrolidine ring. The invention therefore relates both to the enantiomers and to the diastereomers, as well as their mixtures and racemates. Particularly preferred in this connection are the diastereomers which have the same configuration in the 4-position in the dihydropyridine as quinchonidine (—)—1— ethoxymethyl-1,4-dihydro-5-methoxycarbonyl~2,6-dimethyl-4--(3-nitrophenyl)-pyridine-3-carboxylate, which is used as a starting compound and rotates linearly polarized light of
22
wavelength 589 nm through [cc.]^ = + 63.4° (c = 1, chloroform); other preferred diastereomers are those which have the same configuration in the 2-position at the pyrrolidine ring as (-)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride, which is used as a starting compound and rotates linearly polarized light of wavelength 589 nm through [o.]^2 = - 31.7° (c = 1,
methanol).
The following may be mentioned as examples of preferred compounds according to the invention:
3-methyl 5—[3—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-di-carboxylate
3-ethyl 5-[3-(2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-di-carboxylate
3-(2-methoxyethyl) 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl ]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylate
3-(prop-2-yl) 5—[3—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridi-ne-3,5-dicarboxylate
3-methyl-5-[2-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-di-carboxylate
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3-ethyl 5-[2-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-dicarboyxlate
3-(2-methoxyethyl) 5-[2-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl ]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylate
3-(prop-2-yl) 5—[2—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 ,5-dicarboyxlate
3-methyl-5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl]
4-(+)-(2,3-dichlorophenyl)-l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
3-ethyl 5—[3—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
3-(2-methoxyethyl) 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboyxlate
3-(prop-2-yl)—5—[3 — [2—(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl ] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridi-ne-3,5-dicarboxylate
3-methyl 5—[2—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
3-ethyl 5—[2—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate
3-(2-methoxyethyl) 5-[2-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl ]-ethyl] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate
3-(prop-2-yl) 5—[2—[2—(-)—(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 4-(+)-2,3-dichlorophenyl)-l,4-dihydro-2,6-dimethylpyri-dine-3,5-dicarboxylate
3-methyl 5-[3 — [2-( — >-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl]
4-( + )- (2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyri-dine-3,5-dicarboxylate
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3-methyl 5—[2—£2—(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyri-dine-3,5-dicarboxylate
3-methyl 5-[3-[2-( +)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-di-carboxylate
3-ethyl 5-[3-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
3- ( 2-methoxyethyl) 5-[3-[2-( + )- (4-chlorobenzyl)-pyrrolidin-l-yl ]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pv-ridine-3 ,5-dicarboxylate
3-(prop-2-yl) 5-[3-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] l,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 ,5-dicarboyxlate
3-methyl 5—[2—[2—(+)—(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyri-dine-3,5-dicarboxylate
3-ethyl 5-[2-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
1.4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
3- (2-methoxyethyl) -5-[ 2-[2- (+ ) - (4-chlorobenzyl) -pyrrolidin-1 -yl|-ethyl] 1r4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylate
3-(propy-2-yl) 5-[2-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-
3.5-dicarboxylate
3-methyl 5-[3-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-ethyl 5 — [3—[2—(+-) — ( 4-chlorobenzyl)-pyrrolidin-l-yl]-propyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3- ( 2-methoxyethyl) 5-[3-[2-{ + )- (4-chlorobenzyl)-pyrrolidin-l-yl ]-propyl] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxyldte
3 6 SEN
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3-(prop-2-yl) 5-[3-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate
3-methyl 5-[2-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-ethyl 5-[2-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-(2-methoxyethyl) 5-[2-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl] -ethyl ] 4-(f)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate
3-(prop-2-yl) 5-[2-[2-(+ )-(4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyri-dine-3, 5-dicarboxylate
3-methyl 5-[3-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl]
4—( + ) — £2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridi-ne-3,5-dicarboxylate
3-methyl 5-[2-[2-( + )- (4-chlorobenzyl)-pyrrolidin-l-yl]-ethyl]
4—(+)—(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridi-ne-3,5-dicarboxylate
3-me thy1 5-[3-[2-(+)-(4-nitrobenzy1)-pyrrolidin-1-y1]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-di-carboxylate
3-ethyl 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl]
1.4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-di-carboxylate
3-(2-methoxyethyl) 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl ]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylate
3-(prop-2-yl)-5-[3 -[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl ] 1, 4-dihydro-2 ,6-dimethyl-4- (-t-) - ( 3-nitrophenyl)-pyridine-
3.5-dicarboxylate
3-methyl 5-[2-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
3 6 SEN
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3-ethyl 5-[2-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-dicarboxylate
3-(2-methoxyethyl 5-[2-[2-( + )-(4-nitrobenzyl)-pyrrolidin-l-yl ]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyri-dine-3,5-dicarboxylate
3-(prop-2-yl) 5-[2-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-ethyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyri-dine-3,5-dicarboxylate
3-methyl 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl] 4 - ( + )-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-ethyl 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-(2-methoxyethyl)-5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl] -propyl ] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate
3-(prop-2-yl) 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpy-ridine-3,5-dicarboxylate
3-methyl 5-[2-[2-(+)-(4-nitrobenzyl) -pyrrolidin-l-yl]-ethyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-ethyl 5-[2-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5--dicarboxylate
3-(2-methoxyethyl) 5-[2-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl] -ethyl ] 4-(+)-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate
3-(prop-2-yl) 5-[2-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-ethyl] 4- (-r) - ( 2 , 3-dichlorophenyl) -1, 4-dihydro-2, 6-dimethylpyri-dine-3,5-dicarboxylate
3-methyl 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl]
4-(+)-(2,1,3-benzoxdiazol-4-yl)-1,4-dihydro-2,6-dimethylpyridi-ne-3,5-dicarboxylate
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3-methyl 5-[2-[2- (+ )-(4-nitrobenzyl)-pyrrolidin-l-yl]-ethyl]
4-(+)-(2,1,3-benzoxdiazol-4-yl)-l,4-dihydro-2,6-dimethylpyridi-ne-3,5-dicarboxylate and the salts of these compounds.
The invention furthermore relates to a process for the preparation of the compounds according*to the invention and their salts. The process is characterized in that a) 1,4-dihydropyridine derivatives of the formula II
Cy H
(II)
R2 R1
J
are reacted with amines of the formula III
(HI)
or b) enamines of the formula IV
R300C H
R2 NHZ
(IV)
foil T\
j63en
13
1 2 Re7i 1
W
are reacted with benzylidenecarboxylic acid derivatives of the formula V
COO—E—N'
(V),
or c) enamine derivatives of the formula VI
✓COO—E—N.
H2N
R1
(VI),
are reacted with cinnamic acid derivatives of the formula VII
Cy
R300C
(VII),
as such or in the form of their salts and, if desired, the salts obtained are then converted into the free bases or the bases obtained are then converted into the salts, where Cy, Rl, R2, R3, R4, R5, R6 and E have the above-mentioned meanings and X represents a leaving group.
Embodiments of the process are those in which, in the formulae II to VII, the substituents or symbols Cy, Rl, R2, R3, R4, R5, R6 and E have the meanings stated in the Subclaims and independent Claims and X represents a leaving group.
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The reaction of II with III is carried out in the manner known for the preparation of tertiary amines. Depending on the leaving group X, which is preferably a halogen atom, in parti-_____ cular a chlorine or bromine atom, the reaction can, if desired, be carried out in the presence of a base (for example of an inorganic carbonate, such as potassium carbonate) or with the use of an excess of amine III.
The reaction of IV with V or of VI with VII is carried out in a manner known to the expert, for example as it is described in the European patent application 0 176 956.
The reaction of II with III, of IV with V or of VI with VII is carried out in suitable, preferably inert organic solvents. Hydrocarbons, such as toluene or xylene; ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monoethyl ether or glycol dimethyl ether; or ketones, such as acetone or ethyl methyl ketone, chlorinated hydrocarbons, such as methylene chloride, chloroform, tetrachloroethylene or dichloroethane; or other suitable solvents, such as dimethylformamide, may be mentioned as examples.
Depending on the reactivity of the educts, the reaction tempe-ratures can vary within a wide range. In general, the reaction is carried out at temperatures between 20°C and 150°C, preferably between 20°C and 100°C, in particular at the boiling point of the solvent used.
The pure diastereomeric compounds of the formula I and their salts, which form a preferred subject of the invention, are obtained, on the one hand, starting from racemic mixtures of the compounds II, by reacting the latter with a pure enantiomeric amine III and separating the resulting diastereomers in the usual manner.
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Alternatively, the pure diastereomeric compounds according to the invention are obtained by starting from racemic amines III and pure enantiomeric 1,4-dihydropyridine derivatives of the formula II and then resolving the diastereomers, or by starting from pure enantiomeric amines III and pure enantiomeric 1,4-dihydropyridine^derivatives of the formula II.
The pure diastereomeric compounds according to the invention are furthermore obtained by process variants b or c, by starting from pure enantiomeric benzylidene-carboxylic acid derivatives V or enamine derivatives VI. After reaction of pure entantiomeric V or VI with an enamine IV or a cinnamic acid derivative VII, a diastereomer mixture is obtained and can be resolved in the usual manner.
Pure enantiomeric 1,4-dihydropyridine derivatives of the formula II are obtained starting from pure enantiomeric N-protected 1,4-dihydropyridine- carboxylic acids which are known or can be prepared in an analogous manner by a known route [Chem. Pharm. Bull. 2_8 2809 (1980)], by reaction with bifunctional alkylene derivatives X-E-X, wherein E has the above-mentioned meanings and X represents a leaving group, in particular halogen atoms, preferably a bromine atom.
The reaction of the N-protected dihydropyridinecarboxylic acids, for example with dibromoalkylene derivatives Br-E-Br, is preferably carried out under basic conditions in the presence of a phase-transfer catalyst. In addition to onium salts, for example tetrabutylammonium bromide or benzyltriethylammonium chloride, in particular.crown ethers, such as dibenzo-[18]-crown-6, dicyclohexyl-[18]-crown-6 and especially [18]-crown-6, may be mentioned as catalysts.
Suitable bases, which are used in at least a molar ratio, preferably in excess, are inorganic bases, such as alkali metal hydroxides (for example sodium hydroxide or potassium hydro- s
I
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xide), or, in particular, alkali metal carbonates (for example sodium carbonate or, preferably, potassium carbonate). When an anhydrous solvent is employed, the hydroxides or carbonates used are preferably employed in finely powdered form.
The reaction is carried out (depending on the type of phase-transfer catalyst and of base used) in water-containing or anhydrous organic solvents, or in a mixture of water and an organic solvent which is immiscible or scarcely miscible with water. The mixtures of water with chloroform, dichloromethane or benzene may be mentioned as examples of water/solvent mixtures. Water-containing or anhydrous solvents which may be mentioned are, for example, dichloromethane, acetonitrile or acetone.
The choice of the reaction temperature depends on the other reaction conditions, preferred temperatures being, as a rule, between 20°C and the boiling point of the solvent used.
Pure enantiomeric amines III are obtained from their racemates by reaction with pure enantiomeric optically active acids, such as, for example, di-0,0'-p-toluoyltartaric acid or di-0,0'-benzoyltartaric acid, followed by separation of the diastereomeric salts in a conventional manner, for example by recry-stallization.
The diastereomeric salts having the same configuration and separated by these methods are converted into the optically active, pure enantiomeric compounds according to the invention by adding, preferably, inorganic bases, such as, for example, ammonium, or with the aid of basic ion exchangers.
The resulting substances according to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the resulting
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residue from a suitable solvent or subjecting the said residue to one of the conventional purification methods, such as, for example, column chromatography over a suitable carrier.
Acid addition salts are obtained by dissolving the free base in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol or isopropanol), which contains the desired acid or to which the desired acid is subsequently added.
The salts are obtained by filtration, reprecipitation, precipitation with a nonsolvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted into the free bases by treatment with an alkali, for example with aqueous ammonia solution, and the said bases can in turn be converted into acid addition salts. In this way, pharmacologically non-tolerated acid addition salts can be converted into pharmacologically tolerated acid addition salts.
The starting compounds II, III, IV, V, VI and VII are known from the literature or can be prepared analogously to methods known from the literature.
The starting compounds II used as a racemate can be prepared in a manner known per se, for example in accordance with the following reaction scheme:
0
(Rl-H)
+ HO-E-X
CyCHO
R300C H
V
(II)
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The amines of the formula III are disclosed in, for example, U.S. Patent 4,279,918.
The benzylidenecarboxylic acid derivatives V and the cinnamic acid derivatives VII can be prepared, for example, in analogy with G. Jones ["The Knoevenagel Condensation" in Org. Reactions Vol. XV, 204 et seq. (1387)]. The enamines IV and the enamine derivatives VI are obtainable, for example, in analogy with A.C Cope [J. Amer. Chem. Soc. 67_, 1017 (1945)].
The above preparation processes are merely mentioned by way of illustration, and the preparation of the compounds according to the invention, of the formula I is not restricted to these processes. Instead, any modification of these processes can also be used for the preparation of the compounds according to the invention. For example, the racemates of the compounds according to the invention can also be prepared from corresponding starting compounds by any of the processes mentioned in International Patent Application WO 86/03748.
The following preparation examples are intended to illustrate the invention in more detail without restricting it. Mp. denotes melting point, h represents hours, bp. represents boiling point and decomp. denotes decomposition.
'•"a
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Examples End products
1. 3-ethyl 5-C3-[2-(+)-(4-chlorobenzyl)-pyrrolidin-l-yl]-
propyl] 1,4-dihydro-2,6-dimethyl-4-(+)- ( 3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
According to process variant b, 3.30 g of 3-[2-(4-chlorobenzyl )-pyrrolidin-l-yl]-propyl (+)-2-acetyl-3-(3-nitrophenyl)-acrylate and 0.91 g of ethyl 3-aminocrotonate in 80 ml of 2-propanol and 0.46 g of acetic acid are refluxed for 4 h. The cooled solution is evaporated and the residue is extracted by shaking with water/dichloromethane. After the organic phase has been dried over sodium sulphate and evaporated, the oily residue is chromafcographed over a silica gel column using dichloromethane /methanol (95:5) as the eluant. The product fraction is evaporated, the residue is dissolved in methanol and hydrochloric acid in ether is added to the solution. After the solution has been evaporated again, the firm foamed yellowish residue is taken up in a small amount of dichloromethane and the title compound is precipitated in amorphous form by the dropwise addition of about 1 1 of petroleum ether/diethyl ether (2:1). 3.1 g of the title compound are obtained as a fine powder of m.p. 124-128°C (slow deliquescence).
2. 3-methyl 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyI-4- (+)-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
A mixture of 1.81 g of 3-methyl 5-(3-bromopropyl) (+)-l,4-di-hydro-2, 6-dimethyl-4- ( 3-nitrophenyl) -pyridine-3 ,5-dicarboxylate, 1.00 g of (-)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride and 1.8 g of potassium carbonate in 20 ml of toluene and 20 ml of water is refluxed for 20 h under a nitrogen atmosphere and with
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vigorous stirring according to process variant a. After the mixture has been cooled, the phases are separated and the organic phase is washed twice with water, dried over sodium sulphate and evaporated. The oily residue is chromatographed over a silica gel column (eluant: dichloromethane/methanol 98:2). After the amine obtained has been converted into the hydrochloride, the title compound is precipitated as a fine yellowish powder from petroleum ether/diethyl ether 3:1.
Melting range 100-116°C (slow deliquescence). Yield: 1.93 g.
3. 3-methyl 5-[3-[2-( + )-(4-chlorobenzyl)-pyrrolidin-l-yl1-propyl] 1,4-dihydro-2 ,6-dimethyl-4- (-f-) -(3-nitrophenyl) -pyridine-3,5-dicarboxylate hydrochloride
The title compound is obtained, analogously to Example 2, from 1.81 g of 3-methyl 5-(3-bromopropyl) (+)-l,4-dihydro-2,6-dime-thyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 1.00 g of (+)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride, in the form of a fine yellowish powder of melting range 125-140°C (slow deliquescence). Yield: 1.81 g.
4. 3-methyl 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride
The title compound is obtained, analogously to example 2, from 1.81 g of 3-methyl 5-(3-bromopropyl) (+)-l,4-dihydro-2,6-di-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 1.00 g of (-)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride, in the form of fine crystal platelets of m.p. 113-117°C (slow deliquescence, from 2-propanol); [o.]^2 = +45.9° (c = 1, methanol); yield: 1.87 g. The m.p. of the free base is 81 - 83°C (from dichlormetha-ne/diethylether); [a.]D = + 54.7° (c = 1, methanol); the furaarate has a m.p. of 105 - 111°C (slow deliquenscense, from ethyl acetate); [a-]22 = + 40.2° (c = 1, methanol).
"A
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The title compound is likewise obtained, when equimolar amounts of D-(+)-0,0'-dibenzoyltartaric acid are added to the free bases of the diastereomer mixture obtained in Example 2, and when the salt which crystallizes at first from acetone/methanol (1 + 1)
is recrystallized so many times from acetone/methanol, until the
D-(+)-0,0'-bibenzoyltartrate (hydrate) of the title compound
22
obtained has a specific rotation of [a]^ =+77,3° (c = 1, methanol); m.p. 153 - 154°C. Extraction of the salt with, dichloromethane/concentrated ammonia solution leads to the free base, from which the title compound is obtained with hydrochloric acid in diethyl ether.
. 3-methyl 5 — [2—[2 — ( —) — (4-chlorobenzyl)-pyrrolidin-l-yl3-ethyl] 1,4-dihydro-2,6-dimethyl-4-(±)-(3-nitropheny1)-pyridine-3 ,5-dicarboxylate hydrochloride
The title compound is obtained, analogously to example 2, from 8.80 g of 3-methyl 5-(2-bromoethyl) (+)-1,4-dihydro~2,6-dime-thyl-4-(3-nitrophenvl)-pyridine-3,5-dicarboxylate and 4.64 g of (-)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride, in the form of a fine yellowish powder of melting range 122-130°C (slow deliquescence). Yield: 3.61 g.
6. 3-ethyl 5—[3—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl ] 1, 4-dihydro-2,6-dimethyl-4- (±.) - ( 2-chlorophenyl) -pyridine-3 ,5-dicarboxylate hydrochloride
The title compound is obtained analogously to Example 2 from 3-ethyl 5-( 3-bromopropyl) ( + )-l,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate as fine yellowish powder of melting range 95 - 105°C (slow deliquescence); yield: 61 % of theory.
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7. 3-methyl 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl ] 1,4-dihydro-2 ,6-dimethyl-4- (±) - ( 2-trif luoromethylphenyl )-pyridine-3,5-dicarboxylate hydrochloride
Following the same procedure as described in Example 1, the title compound is obtained according to process variant c) from methyl 2-(2-trifluoromethylbenzylidene)-acetoacetate and 3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl 3-aminocroto-nate as fine yellowish powder of melting range 77 - 90°C (decomposition); yield: 41 % of theory.
8. 3-methyl 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl ] 1, 4-dihydro-2 , 6-dimethyl-4- (±) -2 , 3-dichlorophenyl) -pyridine-3,5-dicarboxylate hydrochloride
The title compound is obtained analogously to Example 7 from methyl 2-(2,3-dichlorobenzylidene)-acetoacetate as fine yellowish powder of melting range 120 - 132°C (decomposition); yield: 38 % of theory.
9. 3-methyl 5-[3-[2-(+)-4-methoxybenzyl)-pyrrolidin-l-yl]-propyl ] 1, 4-dihydro-2 , 6-dimethyl-4-(+ ) - (3-nitrophenyl) -pyridine-3 ,5-dicarboxylate hydrochloride
The title compound is obtained analogously to Example 4 from (+)-2-(4-methoxybenzyl)-pyrrolidine as fine yellowish powder of melting range 138 - 148°C (decomposition); yield: 69 % of theory.
. 3-methyl 5- [ 3- [ 2- (+) -3 , 4-dirnethoxybenzyl) -pyrrolidin-l-yl ] -propyl] 1,4-dihydro-2,6-dimethyl-4-( + )-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylate hydrochloride
The title compound is obtained analogously to Example 4 from
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(+)-2-(3,4-dimethoxybenzyl)-pyrrolidine as fine yellowish powder of melting range 115 - 126°C (slow deliquescence); yield: 56 % of theory.
11. 3-methyl 5-[3-[2-(+)-(4-nitrobenzyl)-pyrrolidin-l-yl]-propyl ] 1,4-dihydro-2,6-dimethyl-4-( + )- (3-nitrophenyl)-pyridine-3 , 5-dicarboxylate hydrochloride
The title compound is obtained analogously to Example 4 from (+)-2-(4-nitrobenzyl)-pyrrolidine as fine yellowish powder of melting range 111 - 125°C (slow deliquescence); yield: 48 % of theory.
Starting compounds t
A. 3 —[2 — (4-chlorobenzyl)-pyrrolidin-l-yl]-propyl ( + )-2-ace-tyl-3-(3-nitrophenyl)-acrylate a) 14.45 g of (+)-3-[2-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl acetoacetate, 6.46 g of 3-nitrobenzaldehyde, 3.0 ml of acetic acid and 0.5 ml of piperidine in 70 ml of benzene are heated to the boil under a water separator. After 0.8 ml of water has been separated off, the cooled solution is washed with saturated sodium bicarbonate solution and then with water.
After the organic phase has been dried with sodium sulphate, the clear solution is evaporated under a high vacuum until the weight remains constant. The title compound which forms as a viscous yellowish oil is used directly for the condensation, without further purification. Yield: 21 g of crude product.
b) 10.72 g of (+)-N-(3-hydroxypropyl)-2-(4-chlorobenzyl)-pyrrolidine are dissolved in 100 ml of absolute toluene, and 8.4 ml of a 50% strength diketene solution in acetone are added,
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while stirring. After standing for several days at room temperature (TLC check), the mixture is evaporated and the residue is dried under high vacuum. The (+)-3-[2-(4-chloro-benzyl)-pyrrolidin-l-yl]-propyl acetoacetate which remains as a -pale yellow viscous oil is used in stage a without further purification. Yield: 14.5 g.
c) 10.34 g of (+)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride, 6.9 g of 3-bromopropanol, 30 g of powdered potassium carbonate and 1 g of potassium iodide in 100 ml of a 1:1 mixture of dioxane and 1-butanol are refluxed for 48 h with vigorous stirring. After cooling, the mixture is filtered and the filtrate is evaporated. The oily residue is taken up in ethyl acetate and the solution is filtered again. After the filtrate has been evaporated to dryness, ( + ) -N-(3-hydroxypropyl)-2-(4-chlorobenzyl)-pyrrolidine is obtained in the form of a viscous oil, which is directly reacted further, without further purification, as described under b. Yield: 12 g.
B.# 3-methyl 5-(3-bromopropyl) (±)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate a) 100 g of 3-bromopropyl acetoacetate and 67.7 g of 3-nitrobenzaldehyde are dissolved in 450 ml of benzene, 22 ml of acetic acid and 2 ml of piperidine are added, and the mixture is then refluxed under a water separator until about 9.5 ml of water have been separated off. After cooling, the mixture is evaporated to dryness, the oil residue is taken up in 500 ml of isopropanol, and 51.6 g of methyl 3-aminocrotonate are then added. The mixture is heated at about 50-55°C for 4 h, while stirring, seeded with a few crystals of the title compound and then cooled very slowly. Finally, the mixture is stirred overnight at room temperature, after which the product is filtered off under suction, washed with isopropanol and dried. The product (146.5 g) is recrystallized from five times the amount of isopropanol (w/v), and 13 2 g of the title compound of
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m.p. 142-146°C are obtained. 3-methyl 5-(3-bromopropyl) (+)-l,4-dihydro-2,6-dimethyl~4-(2-chlorophenyl)-pyridine-3,5-dicarboxylate is obtained analogously, when 2-chlorbenzaldehyde is used instead of 3-nitrobenzaldehyde.
b) 1 g of 4-dimethylaminopyridine is added to a mixture of 210 g of 3-bromo-l-propanol and 1250 ml of anhydrous dichloromethane. Thereafter, 300 ml of 50% strength solution of diketene in acetone are added dropwise, while stirring vigorously, in such a way that the solvent boils moderately. The mixture is allowed to stand at room temperature, then extracted once by shaking with dilute hydrochloric acid, dried and evaporated. The residue is distilled at 0.03 mbar. 248 g of 3-bromopropyl acetoacetate of bp. 90°C/0.03 mbar are obtained.
C. ( + )- and (-)-2-(4-chlorobenzyl)-pyrrolidine hydrochloride
97.8 g of (+)-2-(4-chlorobenzyl)-pyrrolidine are dissolved in
200 ml of acetone. The clear solution is added dropwise, in the course of 20 minutes, to a boiling solution of 118.16 g of
L-(-)-0,0'-dibenzoyltartaric acid hydrate in 500 ml of acetone.
After the dropwise addition of 2/3 of the acetone solution,
precipitation of the first crystals begins. When the dropwise addition is complete, the suspension of crystals obtained is refluxed for a further 2 h, after which the suspension is allowed to cool to room temperature with thorough stirring.
22
Initial crystals with [a-lD = -90.7° (c = 1, methanol) are obtained; yield: 90.1 g. After further recrystallization from
600 ml of methanol and with the addition of 100 ml of diiso-
22
propyl ether, a second batch of crystals with [a]D = - 92.3°
(c = 1, methanol) is obtained on cooling; yield: 73 g. After recrystallization twice from methanol and with the addition of
22
% diisopropyl ether, a third batch of crystals with [cc.]^ = - 92.0° (c = 1, methanol) is obtained on cooling; yield: 23 g. The second and third batches of crystals (96 g) are stirred together for 30 minutes in 870 ml of 1 N sodium hydroxide
2 2 6 7 17
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solution until the crystals have completely dissolved. The resulting solution is extracted with three times 800 ml of dichloromethane, and the organic phases are combined and washed with twice 500 ml of water. After the organic phase has been dried over sodium sulphate, a solution of hydrochloric acid in ether is added, the solution is evaporated and the solid residue obtained is recrystallized from methanol/ diisopropyl ether.
38 g of (-)-2-(4-chlorobenzyl-pyrrolidine)-hydrochloride are
22
obtained as fine colourless needles of m.p. 222-223°C, [a]^ = - 31.7° (c = 1, methanol).
In an analogous manner, (+)-2-(4-chlorobenzyl-pyrrolidine) hydrochloride is obtained by crystallization of the racemate with D-(+)-OrO'-dibenzoyltartaric acid hydrate and working up as described above. Mp. : 220-221°C, = + 31.4° (c = 1,
methanol).
D. 3-methyl 5-(3-bromopropyl) (+)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3 ,5-dicarboxylate
36 g of the quinchonidine salt of (-)-1-ethoxymethyl-l,4-dihy-dro-5-methoxycarbonyl-2,6-dimethyl-4- (3-nitrophenyl)-pyridine-3-carboxylic acid [Chem. Pharm. Bull. 28(9) 2809-2812 (1980)] are dissolved in 250 ml of chloroform, 260 ml of 0.2 N hydrochloric acid solution are added and the mixture is stirred vigorously. The pH is adjusted to 2 by adding 2 N hydrochloric acid solution, after which the phases are separated. The organic phase is washed a total of four times with hydrochloric acid solution of pH 2 and then with water, dried over sodium sulphate and evaporated. The oily residue is dissolved in 200 ml of acetone. Thereafter, 16 g of finely powdered potassium carbonate, 80 ml of 1,3-di.bromopropane and 0.5 g of [18]-crown-6 are added. The mixture is stirred vigorously for 16 h at room temperature and then filtered under suction, and the filter cake is washed with acetone. The acetone is removed in a rotary
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evaporator under a slight vacuum, and the excess 1,3-dibromo-propane is distilled off at 0.02 mbar. 160 ml of concentrated formic acid are poured over the oily residue, while cooling with ice; stirring is then continued at room temperature until a clear solution has formed (about 15 minutes). The formic acid is distilled off in vacuo. After 50 ml of toluene has been added twice and distilled off twice, the residue is dissolved in dichloromethane. The solution is stirred with sodium bicarbonate solution (pH 8.5). The organic phase is dried over sodium sulphate and evaporated. The oily residue is then crystallized from methanol at room temperature. 18.9 g of the title compound of mp. 112-114°C and [a.]^2 = +13.8° (c = 1, methanol) are obtained.
E. 3-methyl 5-(2-bromoethyl) ( + )-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate a) 494 g of 2-bromoethyl 2-(3-nitrobenzylidene)-acetoacetate and 173.5 g of methyl 3-aminocrotonate are dissolved in 1750 ml of isopropanol at 75-80°C under a nitrogen atmosphere and while stirring. The mixture is then cooled very slowly in a heating bath. After seeding with the title compound, the mixture is stirred for 16 h at room temperature and then cooled, and the product is filtered off under suction, washed with ice-cold ether and dried. 481 g of the title compound of mp. 139-141°C are obtained.
b) 405 g of 2-bromoethyl acetoacetate are dissolved in 1500 ml of isopropanol. 293 g of 3-nitrobenzaldehyde, 4.6 g of acetic acid and 6.8 g of piperidine are added, while stirring. The mixture is stirred at 40°C until a clear solution has formed. The solution is allowed to cool slowly, seeded with a few crystals of the end product and stirred at room temperature for 48 h and then cooled, and the product is filtered off under suction, washed with cold isopropanol and dried at 50°C in
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vacuo. 495 g of 2-bromoethyl 2-(3-nitrobenzyli-dene)-acetoa-cetate of mp. 94.5-95.5°C are obtained.
c) 250 g of 2-bromoethanol are dissolved in 1.3 1 of dichloromethane, and 1.2 g of 4-dimethylaminopyridine are added. 400 ml of a 50% strength diketene solution in acetone are added dropwise, with vigorous stirring, in such a way that the solvent boils moderately. After the dropwise addition, stirring is continued for a further 1 h at the boiling point and the mixture is then allowed to stand overnight. After the solvent has been evaporated off in a rotary evaporator in vacuo, the residue is distilled. 402 g of 2-bromoethyl acetoacetate of bp. 80-83°C/0.04 mbar are obtained.
F. 3—[2—(—)—(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl 3-aminocrotonate
Ammonia is passed into a solution of 3-[2-(-)-(4-chlorobenzyl ) -pyrrolidinyl-1 ] -propyl acetoacetate in 2-propanol while cooling with ice and stirring, until the solution is saturated. The solution is left to stand at 0°C overnight and is then concentrated under a water-jet vacuum at a maximum bath temperature of 70°C to constant weight. The obtained yellowish oil is further reacted without additional purification.
22 6 7 1 7
3 6 SEN 29 10881
Susceptibility of industrial application
The compounds according to the invention, of the formula I, and their salts have valuable properties which make them industrially useful. They are in particular effective vasodilators having therapeutic properties in coronary medicine. The pharmacological efficacy of the compounds according to the invention, which is coupled with low toxicity, manifests itself in particular in a rapid, pronounced and optimally persistent reduction in blood pressure following oral administration. Moreover, the compounds according to the invention have an inhibitory action on the inflow of calcium into cells and promote the outflow of potassium from cells, have muscle-relaxant properties in smooth muscles and have vasodilatory properties in peripheral, coronary, cerebral and renal vessels and salidiuretic, antithrombotic, antiarteriosclerotic and advantageous haemorheological properties.
In their excellent efficacy, which is coupled with low toxicity and a lack of significant side effects, the compounds according to the invention differ in a surprising and advantageous manner from the compounds of the prior art.
Examples of advantageous properties of the compounds I are: the extent of reduction of blood pressure, the optimum persistence of the reduction in blood pressure, the good controllability of the reduction in blood pressure, the surprisingly small increase in heart rate, the excellent bioavailability, the high therapeutic index, the lack of central side effects, the lack of kinetic interactions with other substances, the failure to develop tolerance, the balanced physical properties and the high stability.
The excellent efficacy of the compounds according to the invention, of the formula I, and their salts permit their use in
368EN
226 7 17
10881
human medicine, possible indications being, in particular, primary (essential) and secondary, arterial and pulmonal hypertension of all severities, coronary heart diseases (coronary insufficiency, angina pectoris, myocardial infarction, etc.), peripheral and cerebral blood flow disturbances (cerebral apoplexy, temporary cerebral blood flow disturbances, migraines, giddiness, narrowing of renal arteries, etc.), hypertrophic cardiomyopathy, cardiac insufficiency, diseases based on increased water and sodium retention and diseases based on increased calcium inflow, such as, for example, spasms of smooth muscle organs (respiratory system, gastrointestinal tract, urogenital tract, etc.) and arrhythmia, arteriosclerosis and cell damage of various origins (for example hypoxia).
The invention therefore also relates to a method for the treatment of mammals, in particular humans, suffering from one of the above-mentioned diseases. The method is characterized in that the individual suffering from the disease is administered a therapeutically effective and pharmacologically tolerated amount of one or more compounds of the formula I.
The invention also relates to the compounds of the formula I for use in the treatment of the stated diseases.
The invention also relates to the use of compounds of the formula I in the preparation of medicaments which are used for the treatment of the stated diseases.
The invention also relates to medicaments which contain one or more compounds of the general formula I.
The medicaments are prepared by processes which are known per se and are familiar to those skilled in the art. The pharmacologically active compounds (= active ingredients) according to the invention are used as medicaments either as such or, preferably, in combination with suitable pharmaceutical excipients, in the
-s
363EN
31
2 6 7 1
10881
form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions, aerosols, sprays, ointments, creams, gels or solutions, the content of active ingredient advantageously being between 0.1 and 95%.
Excipients which are suitable for the desired medicament formulations are familiar to the skilled worker from his technical knowledge. In addition to solvents, gel formers, suppository bases, tablets, excipients and other vehicles for the active ingredient, it is also possible to use, for example, antioxidants, dispersants, emulsifiers, antifoams, flavour improvers, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex formers (for example cyclodextrins).
The active ingredients can be administered orally, rectally, by inhalation or parenterally (in particular perlingually, intravenously or percutaneously).
In the case of oral administration, it has in general proved advantageous in human medicine to administer the active ingredient or ingredients in a daily dose of about 0.01 to about 10, preferably 0.05 to 5, mg/kg body weight, if desired in the form of several, preferably 1 to 4, individual doses in order to achieve the desired result. In the case of parenteral treatment, similar or (in particular in the case of intravenous administration of the active ingredients) as a rule lower doses are used. In the case of slowly increasing doses, a low dose is administered at the beginning of the treatment, and this is then replaced by a higher dose. After the desired therapeutic success has been achieved, a low dose is used again.
The required optimum dose and mode of administration of the active ingredients in each case can be readily determined by anyone skilled in the art on the basis of his technical knowledge .
mm 368EN
32
22 6 7 1 :
10881
If the compounds according to the invention and/or their salts are used for the treatment of the stated diseases, the pharmaceutical formulations can also contain one or more other pharmacologically active constituents from other groups of ^ ^ medicaments, such as other vasodilators, antihypertensive agents, alpha-l-receptor blockers, alpha-2-receptor stimulators, beta-l-receptor blockers, beta-2-receptor stimulators, ACE inhibitors, nitro compounds, cardiotonic agents, diuretics, saluretics, alkaloids, analgesics, lipid-lowering agents, ' ^ anticoagulants, anticholinergic agents, methylxanthines,
antiarrhythmic agents, antihistamines, dopamine stimulators, serotonin receptor blockers, etc., such as nifedipine, dihydra-lazine, prazosin, clonidine, atenolol, labetalol, fenoterol, captopril, isosorbide dinitrate, digoxin, milrinone, mefruside, clopamide, spironolactone, chlorthalidone, furosemide, poly-thiazide, hydrochlorothiazide, reserpine, dihydroergocristine, rescinnamine, rauwolfia total alkaloids, acetylsalicylic acid, bezafibrate, warfarin, atropine, theophylline, lidocaine, astemizol^, broraocryptine, ketanserin, etc.
t
Pharmacology
The antihypertensive activity of the compounds according to the invention can be demonstrated using the model of the spontaneously hypertensive rat.
To determine the antihypertensive action, the compounds stated below are administered in the stated doses by means of a gastric tube, once daily on four successive days, to 6 male rats (strain SHR/N/lbm/Bm, 250-350 g) with genetic high blood pressure (systolic blood pressure > 180 mmHg). The blood pressure is measured in each case 6 hours and, if appropriate, 2 or 24 hours after administration of the substance.
3 63EN
33
22 67 1 7
10831
The blood pressure measurement is carried out in a heated chamber at 36°C in order to achieve better flow through the caudal artery. For this purpose, the animals are placed in perforated sheet metal cages and measurement is carried out 20-40 minutes after the beginning of the warming up period. To measure the systolic arterial pressure, an annular collar having an inflatable rubber membrane to suppress blood flow and an annular piezoelectric crystal transducer for measuring the pulse waves are pushed onto the tail. After blood flow in the caudal artery has been suppressed, the collar pressure is continuously reduced. The return of the pulse waves on pressure reduction is automatically recognized as systolic blood pressure and is printed out (Buhler, R. et al.: Microprocessor-based automation of blood pressure measurement in the conscious rat. Proceedings of the 4th International Symposium on rats with spontaneous hypertension and related studies, Rascherf R. et al. (Eds.), Schattauer Verlag, Stuttgart, New York, 1982, pages 410-413). Pulse signals and pressure curve are plotted graphically for evaluation.
For familiarization with the measuring process, the animals are trained for 14 days prior to testing of the substance. In the second week of training, preliminary blood pressure values are measured. Animal groups which receive the substance are tested against a control group.
In the Table below, the compounds investigated are identified by serial numbers which correspond to the particular example numbers.
Table I shows, for representatives of the compounds according to the invention, percentage reduction in the blood pressure (BP) following oral administration to the rat.
Claims (11)
1. Pyrtolidines of the formula I Cy H R300C COO—E N' R2 ^ N H H,-R6 (I) wherein Cy represents a cyclic structure of the formula R4 Y Y; 4-R5 J in which Y denotes oxygen (O), sulphur (S), vinylene (-CH=CH-), azomethine (-CH=N-) or a group of the formula /Sf or / v \.A Rl denotes l-6C-alkyl or 3-7C-alkoxyalkyl, R2 denotes l-6C-alkyl or 3-7C-alkoxyalkyl, R3 denotes hydrogen, l-6C-alkyl or 3-7C-alkoxyalkyl, R4 and R5 are identical or different and denote hydrogen, hydroxyl, halogen, nitro, cyano, trifluoromethyl, l-4C-alkyl/ l-4C-alkoxy, completely or partially fluorine-substituted ZZ 6 7 1 368en 36 10881 l-4C-alkoxy, l-4C-alkoxycarbonyl, 2-5C-acyl, amino or mono- or di-l-4C-alkylamino, R6 denotes phenyl or substituted phenyl having one, two or three identical or different substituents from the group consisting of halogen, hydroxyl, nitro, cyano, trifluoromethyl, l-4C-alkyl/ 1-4C-alkoxy, l-4C-alkoxycarbonyl, 2-5C-acyl, amino and mono- or di-l-4C-alkylamino, and E denotes 2-5C-alkylene, and the salts of these compounds.
2. Compounds of the formula I according to Claim 1, wherein Cy denotes phenyl, 2-nitrophenyl, 3-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl, 3-(1,1,2,2-tetrafluoroethoxy)-phenyl, 2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-trifluoromethylphenyl , 3-trifluoromethylphenyl or benzoxdiazolyl, Rl denotes methyl, ethyl or methoxyethyl, R2 denotes methyl, ethyl or methoxyethyl, R3 denotes methyl, ethyl or methoxyethyl, R6 denotes phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 2,4-dichloro-phenyl, 4-bromophenyl, 4-fluorophenyl, 3-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimeth-oxyphenyl, 3,4,5-trimethoxyphenyl, 2-methylphenyl, 3-methyl-phenyl, 3-chloro-4-ir.ethylphenyl, 3,4-dimethylphenyl, 4-amino-phenyl, 2,4-diaminophenyl, 4-nitrophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl or 3,4,5-trihydroxyphenyl and E denotes ethylene ( -CI^-CJ^- ), trimethylene ( -CH2-CH2-CH2-) , tetramethylene (-CH2-CH2-CH2-CH2-) or Pentame^ylene (-ch2-ch2-ch2-ch2-ch2-), and the salts of these compounds. 3 6 SEN 37 22 6 7 1 10882
3. Compounds of the formula I according to claim 1, wherein Cy denotes 3-nitrophenyl, 2-chlorophenyl, 2,3-dichlorophenyl or 2-trifluoromethylpheny1, Rl denotes methyl or ethyl, R2 denotes methyl or ethyl, R3 denotes methyl or ethyl, R6 denotes 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or 4-nitrophenyl and E denotes ethylene (-CH2-CH2~) or trimethylene (-CH2-CH2-CH2~), and the salts of these compounds.
4. Compounds of the formula I according to Claim 1, wherein Cy denotes 3-nitrophenyl or 2,3-dichlorophenyl, Rl denotes methyl or ethyl, R2 denotes methyl or ethyl, R3 denotes methyl or ethyl, R6 denotes 4-chlorophenyl or 4-nitropheynl and E denotes ethylene (-CH2-CH2~) or trimethylene (-CH2~CH2-CH2-)f^ and their salts.
5. Compounds of the formula I according to Claim 1, wherein Cy denotes 3-nitrophenyl, Rl denotes methyl, R2 denotes methyl, R3 denotes methyl or ethyl, R6 denotes 4-chlorophenyl and E denotes ethylene (-CH2~CH2-) or trimethylene (-CH2-CH2-CH2~), and their salts.
6. 3-methyl 5-[3-[2-(-)-(4-chlorobenzyl)-pyrrolidin-l-yl]-propyl] 1,4-dihydro-2,6-dimethyl-4-(+)-(3-nitrophenyl)-pyridine-3 , 5-dicarboxylate and its salts. 22 6 7 1 363EN 38 10882 O
7. Process for the preparation of compounds of the formula I according to Claim 1 and their salts, characterized in that a) 1,4-dihydropyridine derivatives of the formula II Cy H R300C R2' A COO—E—X Rl are reacted with amines of the formula III H—N or b) enamines of the formula IV R300C H R2 NH2 (II), (HI)', (IV), are reacted with benzylidenecarboxylic acid derivatives of the formula V W cy / ✓C00—E—N' Rl (V), 368EN 39 226717 10882 or c) enamine derivatives of the formula VI h2n ki (VI) are reacted with cinnamic acid derivatives of the formula VII Cy as such or in the form of their salts and, if desired, the salts obtained are then converted into the free bases or the bases obtained are converted into the salts, where Cy, Rl, R2, R3, R4, R5, R6 and E have the meanings stated in Claim 1 and X represents a leaving group.
8. Medicaments containing one or more compounds according to one or more of Claims 1 to 6 and/or their pharmacologically tolerated salts.
9. Compounds according to one or more of Claims 1 to 6 and their pharmacologically tolerated salts for use in the treatment and/or prophylaxis of hypertension, coronary heart diseases, peripheral and cerebral circulatory disturbances and/or diseases which are based on increased water or sodium retention. (VII) c 2 2 « 7 17 40
10. A compound as claimed in claim 1 as specifically set forth herewith.
11. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to any one of the examples. BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH i. 3y Their Attorneys ■'BALDWIN, SON & CAREY - CJ N z260CT1988 «|
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH422387 | 1987-10-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ226717A true NZ226717A (en) | 1990-04-26 |
Family
ID=4272097
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ226717A NZ226717A (en) | 1987-10-27 | 1988-10-26 | Substituted pyrrolidine-alkyl 1,4-dihydropyridine carboxylate derivatives and medicaments |
Country Status (8)
| Country | Link |
|---|---|
| EP (2) | EP0393074A1 (en) |
| JP (1) | JPH03500647A (en) |
| AU (1) | AU2614288A (en) |
| IL (1) | IL88161A0 (en) |
| NZ (1) | NZ226717A (en) |
| PT (1) | PT88869B (en) |
| WO (1) | WO1989003824A1 (en) |
| ZA (1) | ZA888010B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU7058991A (en) * | 1989-12-22 | 1991-07-24 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New dihydropyridines |
| GB9405833D0 (en) * | 1994-03-24 | 1994-05-11 | Pfizer Ltd | Separation of the enantiomers of amlodipine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1983003249A1 (en) * | 1982-03-17 | 1983-09-29 | Yoshitomi Pharmaceutical | 1,4-dihydropyridine-3,5-dicarboxylate derivatives |
| WO1984002702A1 (en) * | 1983-01-11 | 1984-07-19 | Takeda Chemical Industries Ltd | Dihydropyridine derivatives |
| CH663616A5 (en) * | 1983-06-21 | 1987-12-31 | Sandoz Ag | 1,4-DIHYDROPYRIDINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME. |
| EP0176956B1 (en) * | 1984-09-28 | 1994-06-15 | Byk Gulden Lomberg Chemische Fabrik GmbH | Diaryl derivatives |
| JPS62501972A (en) * | 1984-12-21 | 1987-08-06 | ビク・グルデン・ロムベルク・ヘミッシエ・フアブリ−ク・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | New piperazine derivatives |
-
1988
- 1988-10-24 WO PCT/EP1988/000951 patent/WO1989003824A1/en not_active Application Discontinuation
- 1988-10-24 EP EP88909530A patent/EP0393074A1/en active Pending
- 1988-10-24 EP EP88117660A patent/EP0314038A1/en not_active Withdrawn
- 1988-10-24 JP JP63508795A patent/JPH03500647A/en active Pending
- 1988-10-24 AU AU26142/88A patent/AU2614288A/en not_active Abandoned
- 1988-10-25 IL IL88161A patent/IL88161A0/en unknown
- 1988-10-26 NZ NZ226717A patent/NZ226717A/en unknown
- 1988-10-26 ZA ZA888010A patent/ZA888010B/en unknown
- 1988-10-27 PT PT88869A patent/PT88869B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT88869B (en) | 1993-01-29 |
| EP0314038A1 (en) | 1989-05-03 |
| AU2614288A (en) | 1989-05-23 |
| JPH03500647A (en) | 1991-02-14 |
| IL88161A0 (en) | 1989-06-30 |
| EP0393074A1 (en) | 1990-10-24 |
| WO1989003824A1 (en) | 1989-05-05 |
| ZA888010B (en) | 1989-06-28 |
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