EP0000150B1 - Dérivés de dihydropyridine, leur préparation et leur application dans des compositions pharmaceutiques. - Google Patents

Dérivés de dihydropyridine, leur préparation et leur application dans des compositions pharmaceutiques. Download PDF

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Publication number
EP0000150B1
EP0000150B1 EP78100165A EP78100165A EP0000150B1 EP 0000150 B1 EP0000150 B1 EP 0000150B1 EP 78100165 A EP78100165 A EP 78100165A EP 78100165 A EP78100165 A EP 78100165A EP 0000150 B1 EP0000150 B1 EP 0000150B1
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Prior art keywords
carbon atoms
compound
formula
alkyl
alkoxy
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EP78100165A
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German (de)
English (en)
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EP0000150A1 (fr
Inventor
Peter Dr. Neumann
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Novartis AG
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Sandoz AG
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Classifications

    • 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
    • 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
    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to dihydropyridine derivatives.
  • the present invention provides compounds of formula I, wherein
  • alkyl of 1 to 6 carbon atoms is preferably of 1 to 4 carbon atoms, especially of 1 to 2 carbon atoms.
  • Any alkyl, alkoxy, alkylthio or or alkylsulfonyl radical of 1 to 4 carbon atoms is preferably of 1 or 2 carbon atoms.
  • the alkyl moiety of cycloalkylalkyl or cycloalkyalkoxy is conveniently methyl.
  • Halogen means fluorine, chlorine or bromine and is especially chlorine.
  • Cycloalkyl or the cycloalkyl moiety of cycloalkylalkyl or cycloalkylalkoxy is conveniently cyclopropyl or cyclopentyl or cyclohexyl.
  • alkenyl, alkynyl, alkenyloxy, alkynyloxy or phenylalkenyl is preferably not in the ⁇ , ⁇ position.
  • Alkenyl, alkenyloxy, alkynyl or alkynyloxy preferably has 3 to 5 carbon atoms.
  • Alkenyl or the alkenyl moiety of alkenyloxy is conveniently allyl or 2-methylallyl.
  • Alkynyl or the alkynyl moiety of alkynyloxy is conveniently propynyl.
  • Phenylalkenyl preferably has the trans-configuration and is for example cinnamyl.
  • R is optionally substituted phenylalkyl
  • the phenyl group is preferably unsubstituted.
  • the phenyl group is di- or tri-substituted, preferably the substituents are the same.
  • R 3 and/or R 4 is alkoxy, this is preferably ethoxy or methoxy.
  • R 3 and/or R 4 is alkoxyalkoxy or hydroxyalkoxyalkoxy, preferably the carbon chain between the two ether oxygen atoms is of 2 carbon atoms.
  • the hydroxy group of hydroxyalkoxy or of hydroxyalkoxyalkoxy is preferably not attached to the carbon atom attached to an ether oxygen atom.
  • R is preferably hydrogen.
  • R 2 is conveniently identical to R 5 .
  • R 2 and/or R 5 is preferably methyl.
  • R 3 and/or R 4 is preferably alkoxy or alkoxyalkoxy, especially n-butyloxyethoxy.
  • R . is conveniently halogen, alkyl or alkoxy, or especially hydrogen.
  • R 6 is conveniently adjacent to the dihydropyridine moiety which in turn is conveniently in the 4-position.
  • the process may be effected in conventional manner for analogous dihydropyridine syntheses, e.g. according to Hantzsch.
  • R 2 is identical to R 5 and R 3 is identical to R 4
  • At least 2 moles of a compound of formula IV per mole of a compound of formula II are present.
  • a compound of formula II may be reacted with a compound of formula VI, wherein R 1 , R 4 and R 5 are as defined above.
  • At least 2 moles of a compound of formula VI per mole of a compound of formula II are present.
  • R is hydrogen.
  • a compound of formula VI may be formed as an intermediate during the reaction of a compound of formula IV and a compound of formula V.
  • R 2 , R 3 , R 4 and R 5 are not identical that more than one isomer of formula I may be formed. If so these may be separated in conventional manner, e.g. by thin layer chromatography.
  • the reaction is a ring cyclisation.
  • Z and Z' are both oxygen, then an amine of formula V should be present.
  • reaction may be effected conveniently in solution.
  • a suitable solvent is water, ethanol, dioxane, dimethyl formamide, dimethyl sulphoxide, pyridine or glacial acetic acid.
  • Suitable reaction temperatures may be from 20 to 160°C, preferably from 60 to 120°C.
  • the compounds of formula I exhibit pharmacological activity. In particular, they lead to a dilation of the coronary vessels as demonstrated by the results of tests measuring the blood flow to the myocardium of an anaesthetised cat by means of the microsphere method upon the administration of the active substance i.v. or i.d.
  • the compounds of formula I also possess a favourable effect against angina pectoris, as shown by the increase of the coronary flow of an anaesthetised cat upon administration of the active substance.
  • the compounds of formula 1 are therefore indicated for use in the treatment of coronary insufficiency.
  • an indicated daily dose is from about 5 to 100 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 1.25 to about 50 mg, or in sustained release form.
  • the compounds of formula I exhibit antihypertensive activity, as indicated in standard tests, e.g. in the Grollman rat test [see A. Grollman, Proc. Soc. Expt. Biol. and Med. 57, 104 (1944)J on s.c. administration of from 0.1 to 10 mg/kg animal body weight of the compounds.
  • an indicated daily dose is from about 5 to about 1000 mg, conveniently given in divided doses 2 to 4 times a day in unit dosage form containing about 1.25 mg to about 500 mg, or in sustained release form.
  • the compounds of formula I may be administered in the form of a pharmaceutical composition.
  • the present invention accordingly provides a pharmaceutical composition comprising a compound of formula I in association with a pharmaceutical carrier or diluent.
  • Such compositions may be prepared by conventional techniques to be in conventional forms, for example capsules or tablets.
  • the compounds of Examples 1 and 2 are the preferred compounds.
  • the coronary insufficiency utility is preferred utility.
  • R is hydrogen, alkyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms or phenylalkyl; the phenyl ring being unsubstituted or substituted by one, two or three substituents chosen from one or two halogen radicals, one or two alkyl groups of 1 to 4 carbon atoms, one to three alkoxy groups of 1 to 4 carbon atoms; R 3 and R 4 , indpendently, are alkyl, alkenyl, cycloalkyl of 3 to 6 carbon atoms, alkoxy, hydroxyalkoxy of 2 to 6 carbon atoms, alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4 to 8 carbon atoms, alkenyloxy, or cycloalkyloxy of 3 to 6 carbon atoms, and R 6 is other than alkylsulfonyl.
  • R is hydrogen
  • R 2 and R 5 are each alkyl, especially methyl
  • R 3 and R 4 are each alkoxy, especially ethoxy
  • R e is hydrogen or halogen, especially chlorine, especially in the 4 position
  • the dihydropyridine moiety is in the 4 or 5 position
  • X is S.
  • R is hydrogen
  • R 2 and R 5 are each alkyl, especially methyl
  • R 3 and R 4 are each alkyl or alkoxy, especially methyl, ethyl, tert. butyl, methoxy, ethoxy or tert. butyloxy
  • R- is hydrogen or halogen, especially chlorine, or alkoxy, especially methoxy
  • the dihydropyridine moiety is in the 4 or 5 position and R- is in the 4, 5 or 7 position.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (11)

1. Un Procédé de préparation d'un composé de formule I
Figure imgb0016
dans laquelle
R1 représente l'hydrogène, un groupe alkyle contenant de 1 à 6 atomes de carbone, alcényle ou alcynyle contenant de 3 à 6 atomes de carbone, cycloalkyle contenant de 3 à 7 atomes de carbone, cycloalkylalkyle contenant de 4 à 8 atomes de carbone, phénylalkyle contenant de 7 à 9 atomes de carbone ou phénylalcényle contenant de 9 à 12 atomes de carbone, le cycle phénylique étant non substitué ou mono-, di- ou trisubstitué indépendamment par de l'halogène, un groupe hydroxy ou un groupe alkyle ou alcoxy contenant de 1 à 4 atomes de carbone,
R2 et R5 signifient, indépendamment l'un de l'autre, l'hydrogène ou un groupe alkyle contenant de 1 à 6 atomes de carbone,
R3 et R2 signifient, indépendamment l'un de l'autre, un groupe alkyle contenant de 1 à 6 atomes de carbone, alcényle ou alcynyle contenant de 3 à 6 atomes de carbone, cycloalkyle contenant de 3 à 7 atomes de carbone, cycloalkylalkyle contenant de 4 à 8 atomes de carbone, alcoxy contenant de 1 à 6 atomes de carbone, hydroxyalcoxy contenant de 2 à 6 atomes de carbone, alcoxyalcoxy contenant de 3 à 6 atomes de carbone, hydroxyalcoxyalcoxy contenant de 4 à 8 atomes de carbone, alcényloxy ou alcynyloxy contenant de 3 à 6 atomes de carbone, cycloalkyloxy contenant de 3 à 7 atomes de carbone ou cycloalkylalcoxy contenant de 4 à 8 atomes de carbone,
R6 signifie l'hydrogène, un halogène, un groupe alkyle ou alcoxy ou alkylthio ou alkylsulfonyle contenant chacun de 1 à 4 atomes de carbone, trifluorométhyle, nitro ou hydroxy, et
X signifie l'oxygène ou le soufre,
lequel comprend la conversion chimique du reste -HC=Y présent dans un composé de formule Il
Figure imgb0017
dand laquelle R6 et X ont les significations donns ci-dessus, et
-HC=Y signifie
i) un groupe formyle,
ii) un radical de formule
Figure imgb0018
ou
iii) un radical de formule
Figure imgb0019
où et Z' représentent, indépendamment l'un de l'autre, un atome d'oxygène ou un reste NR, et R, à Rs ont les significations données ci-dessus, en un reste de formule III
Figure imgb0020
dans laquelle R, à R5 ont les significations données-ci-dessus.
2. Un composé de formule I, tel que défini à la revendication 1.
3. Un composé de la revendication 2, dans lequel R, signifie l'hydrogène.
4. Un composé de la revendication 2, dans lequel R2 et R5 signifient un groupe méthyle.
5. Un composé de la revendication 2, dans lequel l'un moins des symboles R4 et R4 signifie un groupe alcoxy ou alcoxyalcoxy.
6. Un composé de la revendication 2, dans lequel Re signifie l'hydrogène.
7. Un composé de la revendication 2, dans lequel R, signifie l'hydrogène, un groupe alkyle, alcényle, cycloalkyle contenant de 3 à 6 atomes de carbone ou phénylalkyle, le reste phénylique étant non substitué ou substitué par un, deux ou trois substituants choisis parmi 1 ou 2 radicaux halogène, un ou deux groupes alkyle contenant de 1 à 4 atomes de carbone, et un à trois groupes alcoxy contenant de 1 à 4 atomes de carbone, R3 et R4 signifient, indépendamment l'un de l'autre, un groupe alkyle, alcényle, cycloalkyle contenant de 3 à 6 atomes de carbone, alcoxy, hydroxyalcoxy contenant de 2 à 6 atomes de carbone, alcoxyalcoxy contenant de 3 à 6 atomes de carbone, hydroxyalcoxyalcoxy contenant de 4 à 8 atomes de carbone, alcényloxy ou cycloalkyloxy contenant de 3 à 6 atomes de carbone, et R6 a une signification autre que alkylsulfonyle.
8. Un composé de la revendication 7, dans lequel R, signifie l'hydrogène, R2 et R5 signifient chacun un groupe alkyle, R3 et R4 représentent chacun un groupe alkyle ou alcoxy, R6 représente l'hydrogène ou un halogène ou un groupe alcoxy, le reste dihydropyridine est en position 4 ou 5 et Re est en position 4, 5 ou 7.
9. L'ester diéthylique de l'acide 4-(2,1,3-benzoxadiazole-4-yl)-2,6-diméthyl-1,4-dihydropyridine-3,5-dicarboxylique.
10. Une composition pharmaceutique comprenant un composé de l'une quelconque des revendications 2 à 9 en association avec un excipient ou un diluant pharmaceutique.
11. Un composé de formule 1 tel que défini à l'une quelconque des revendications 2 à 9, pour l'utilisation comme médicament.
EP78100165A 1977-06-20 1978-06-15 Dérivés de dihydropyridine, leur préparation et leur application dans des compositions pharmaceutiques. Expired EP0000150B1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH752077 1977-06-20
CH7520/77 1977-06-20
CH2865/78 1978-03-16
CH286578 1978-03-16

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EP0000150A1 EP0000150A1 (fr) 1979-01-10
EP0000150B1 true EP0000150B1 (fr) 1981-05-20

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EP (1) EP0000150B1 (fr)
JP (1) JPS54103876A (fr)
AT (1) AT376220B (fr)
AU (1) AU524000B2 (fr)
CA (1) CA1105463A (fr)
CY (1) CY1239A (fr)
DE (1) DE2860708D1 (fr)
DK (1) DK149855C (fr)
ES (1) ES470917A1 (fr)
FI (1) FI64938C (fr)
HK (1) HK65184A (fr)
IE (1) IE47212B1 (fr)
IL (1) IL54948A (fr)
IT (1) IT1105364B (fr)
LU (1) LU88342I2 (fr)
MY (1) MY8500041A (fr)
NL (1) NL930126I2 (fr)
NZ (1) NZ187617A (fr)
PT (1) PT68191A (fr)
SG (1) SG20584G (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2316469A1 (fr) 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH639659A5 (de) * 1978-12-18 1983-11-30 Sandoz Ag Neue 1,4-dihydropyridinderivate, deren herstellung und verwendung.
FI793848A (fi) * 1978-12-18 1980-06-19 Sandoz Ag Benzoxadiazoler och benzothiadiazoler deras framstaellning och farmaceutiska kompositioner innehaollande dessa
BE886259A (fr) * 1979-11-23 1981-05-20 Sandoz Sa Nouveaux medicament a base de derives de la 1,4-dihydropyridine, pour le traitement de l'insuffisance cerebrovasculaire ou a action spamolytique
CH655658B (fr) * 1980-09-18 1986-05-15
FI813460L (fi) * 1980-11-10 1982-05-11 Sandoz Ag Nya 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-pyridinderivat deras framstaellningsfoerfarande och dessa innehaollande farmaceutiska kompositioner
EP0080220B1 (fr) * 1981-11-17 1986-02-19 FISONS plc Dihydropyridines, leur procédé de préparation, leurs compositions et leur application comme médicaments
DE3207982A1 (de) * 1982-03-05 1983-09-08 Bayer Ag, 5090 Leverkusen Neue 1,4-dihydropyridine, verfahren zu ihrer herstellung und ihrer verwendung in arzneimitteln
ZA83959B (en) * 1982-03-10 1984-09-26 Sandoz Ltd 1,4-dihydropyridine derivatives,their preparation and pharmaceutical compositions containing them
DE3208628A1 (de) * 1982-03-10 1983-09-22 Bayer Ag, 5090 Leverkusen Neue verbindungen, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel
FR2528431B1 (fr) * 1982-06-15 1986-01-10 Sandoz Sa Nouveaux derives de la 1,4-dihydropyridine, leur preparation et leur utilisation comme medicaments
FR2554109A1 (fr) * 1983-11-01 1985-05-03 Sandoz Sa Nouveaux derives de la 1,4-dihydropyridine, leur preparation et leur utilisation en therapeutique comme medicaments
IE57810B1 (en) * 1984-03-27 1993-04-21 Delagrange Lab 1,4-dihydropyridine derivatives,their preparation and their use
HU198844B (en) * 1984-06-14 1989-12-28 Sandoz Ag Process for producing new galenic pharmaceutical composition ensuring retarded release of active ingredient
US5260321A (en) * 1984-11-12 1993-11-09 Sandoz Ltd. Use of 1,4-dihydropyridine derivatives and combinations thereof with calcitonins
GB8428552D0 (en) * 1984-11-12 1984-12-19 Sandoz Ltd Organic compounds
GB8616047D0 (en) * 1986-07-01 1986-08-06 Sandoz Ltd A 1 4-dihydropyridine derivatives

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1552911A (en) * 1975-07-02 1979-09-19 Fujisawa Pharmaceutical Co 1,4 dihydropyridine derivatives and the preparation thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2316469A1 (fr) 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine
EP2316468A1 (fr) 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine

Also Published As

Publication number Publication date
CY1239A (en) 1984-06-29
LU88342I2 (fr) 1994-05-04
AU3725278A (en) 1980-01-03
FI781867A (fi) 1978-12-21
ATA443178A (de) 1984-03-15
EP0000150A1 (fr) 1979-01-10
AT376220B (de) 1984-10-25
IE47212B1 (en) 1984-01-25
JPS54103876A (en) 1979-08-15
HK65184A (en) 1984-08-31
MY8500041A (en) 1985-12-31
IT1105364B (it) 1985-10-28
CA1105463A (fr) 1981-07-21
IE781231L (en) 1978-12-20
ES470917A1 (es) 1979-10-01
DK262578A (da) 1978-12-21
IL54948A (en) 1982-01-31
JPS6360755B2 (fr) 1988-11-25
DK149855B (da) 1986-10-13
PT68191A (fr) 1978-07-01
FI64938B (fi) 1983-10-31
DK149855C (da) 1987-04-21
IL54948A0 (en) 1978-08-31
NL930126I2 (nl) 1995-02-16
NL930126I1 (nl) 1993-11-01
FI64938C (fi) 1984-02-10
IT7849939A0 (it) 1978-06-19
SG20584G (en) 1985-03-08
AU524000B2 (en) 1982-08-26
NZ187617A (en) 1980-12-19
DE2860708D1 (en) 1981-08-27

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