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.

Landscapes

• 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)

Applications Claiming Priority (4)

Publications (2)

Family

ID=25691589

Family Applications (1)

Country Status (20)

Cited By (1)

Families Citing this family (16)

Family Cites Families (1)

• 1978
  • 1978-06-12 DK DK262578A patent/DK149855C/da not_active IP Right Cessation
  • 1978-06-12 FI FI781867A patent/FI64938C/fi not_active IP Right Cessation
  • 1978-06-15 DE DE7878100165T patent/DE2860708D1/de not_active Expired
  • 1978-06-15 EP EP78100165A patent/EP0000150B1/en not_active Expired
  • 1978-06-15 CY CY1239A patent/CY1239A/xx unknown
  • 1978-06-19 NZ NZ187617A patent/NZ187617A/xx unknown
  • 1978-06-19 AT AT0443178A patent/AT376220B/de not_active IP Right Cessation
  • 1978-06-19 PT PT68191A patent/PT68191A/pt unknown
  • 1978-06-19 IL IL54948A patent/IL54948A/xx unknown
  • 1978-06-19 ES ES470917A patent/ES470917A1/es not_active Expired
  • 1978-06-19 JP JP7332778A patent/JPS54103876A/ja active Granted
  • 1978-06-19 AU AU37252/78A patent/AU524000B2/en not_active Expired
  • 1978-06-19 IE IE1231/78A patent/IE47212B1/en not_active IP Right Cessation
  • 1978-06-19 IT IT49939/78A patent/IT1105364B/it active Protection Beyond IP Right Term
  • 1978-06-19 CA CA305,727A patent/CA1105463A/en not_active Expired
• 1984
  • 1984-03-05 SG SG205/84A patent/SG20584G/en unknown
  • 1984-08-23 HK HK651/84A patent/HK65184A/xx not_active IP Right Cessation
• 1985
  • 1985-12-30 MY MY41/85A patent/MY8500041A/xx unknown
• 1993
  • 1993-06-30 LU LU88342C patent/LU88342I2/fr unknown
  • 1993-07-01 NL NL930126C patent/NL930126I2/nl unknown

Also Published As

Similar Documents

Legal Events