IE902409A1 - Pharmaceutical composition for use against hypertension and¹congestive heart failure - Google Patents
Pharmaceutical composition for use against hypertension and¹congestive heart failureInfo
- Publication number
- IE902409A1 IE902409A1 IE240990A IE240990A IE902409A1 IE 902409 A1 IE902409 A1 IE 902409A1 IE 240990 A IE240990 A IE 240990A IE 240990 A IE240990 A IE 240990A IE 902409 A1 IE902409 A1 IE 902409A1
- Authority
- IE
- Ireland
- Prior art keywords
- denotes
- hydroxy
- dihydro
- trans
- oxo
- Prior art date
Links
- 206010020772 Hypertension Diseases 0.000 title claims abstract description 20
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 206010007559 Cardiac failure congestive Diseases 0.000 claims abstract description 17
- 239000004036 potassium channel stimulating agent Substances 0.000 claims abstract description 13
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- -1 methoxy, hydroxy Chemical group 0.000 claims description 7
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 6
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052720 vanadium Inorganic materials 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- SFYOAZMZOYWKPH-CABCVRRESA-N (3s,4r)-3-hydroxy-2,2-dimethyl-4-[(5-oxo-2h-furan-3-yl)amino]-3,4-dihydrochromene-6-carbonitrile Chemical compound N([C@@H]1C2=CC(=CC=C2OC([C@H]1O)(C)C)C#N)C1=CC(=O)OC1 SFYOAZMZOYWKPH-CABCVRRESA-N 0.000 claims description 4
- PSSCYMQXPDCWDR-CVEARBPZSA-N (3s,4r)-4-[(2-bromo-3-oxocyclopenten-1-yl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydrochromene-6-carbonitrile Chemical compound N([C@@H]1C2=CC(=CC=C2OC([C@H]1O)(C)C)C#N)C1=C(Br)C(=O)CC1 PSSCYMQXPDCWDR-CVEARBPZSA-N 0.000 claims description 4
- PCCUKMRGFNYSMZ-CVEARBPZSA-N (3s,4r)-4-[(2-chloro-3-oxocyclopenten-1-yl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydrochromene-6-carbonitrile Chemical compound N([C@@H]1C2=CC(=CC=C2OC([C@H]1O)(C)C)C#N)C1=C(Cl)C(=O)CC1 PCCUKMRGFNYSMZ-CVEARBPZSA-N 0.000 claims description 4
- QXWQTZYZRKCDGD-CVEARBPZSA-N (3s,4r)-4-[(2-fluoro-3-oxocyclopenten-1-yl)amino]-3-hydroxy-2,2-dimethyl-3,4-dihydrochromene-6-carbonitrile Chemical compound N([C@@H]1C2=CC(=CC=C2OC([C@H]1O)(C)C)C#N)C1=C(F)C(=O)CC1 QXWQTZYZRKCDGD-CVEARBPZSA-N 0.000 claims description 4
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 3
- OMJFGZRQBBQSQA-SJORKVTESA-N N-[(3S,4R)-3-hydroxy-2,2-dimethyl-4-(3-oxocyclopenten-1-yl)oxy-3,4-dihydrochromen-6-yl]acetamide Chemical compound C(C)(=O)NC=1C=CC2=C([C@H]([C@@H](C(O2)(C)C)O)OC2=CC(CC2)=O)C=1 OMJFGZRQBBQSQA-SJORKVTESA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
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- XOKHARMGBGLZJE-CABCVRRESA-N (3s,4r)-3-hydroxy-2,2-dimethyl-4-[(5-oxo-2h-furan-3-yl)oxy]-3,4-dihydrochromene-6-carbonitrile Chemical compound O([C@@H]1C2=CC(=CC=C2OC([C@H]1O)(C)C)C#N)C1=CC(=O)OC1 XOKHARMGBGLZJE-CABCVRRESA-N 0.000 claims 2
- STEXHBOXTSJMKZ-MOPGFXCFSA-N (3s,4r)-3-hydroxy-4-(3-oxocyclopenten-1-yl)oxyspiro[3,4-dihydrochromene-2,1'-cyclohexane]-6-carbonitrile Chemical compound O([C@H]1[C@@H](C2(CCCCC2)OC2=CC=C(C=C21)C#N)O)C1=CC(=O)CC1 STEXHBOXTSJMKZ-MOPGFXCFSA-N 0.000 claims 2
- DEXFECVQHJPZGH-UHFFFAOYSA-N 3-hydroxy-4-(3-oxocyclopenten-1-yl)oxy-2H-chromene-6-carbonitrile Chemical compound OC=1COC2=C(C1OC1=CC(CC1)=O)C=C(C=C2)C#N DEXFECVQHJPZGH-UHFFFAOYSA-N 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims 1
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- 239000013543 active substance Substances 0.000 description 4
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- 102100030988 Angiotensin-converting enzyme Human genes 0.000 description 3
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- MADRIHWFJGRSBP-ROUUACIJSA-N benazeprilat Chemical compound C([C@H](N[C@H]1CCC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CC1=CC=CC=C1 MADRIHWFJGRSBP-ROUUACIJSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 230000003684 cardiac depression Effects 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960005025 cilazapril Drugs 0.000 description 1
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229960002680 enalaprilat Drugs 0.000 description 1
- LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229950009810 indolapril Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- IYNMDWMQHSMDDE-MHXJNQAMSA-N perindopril erbumine Chemical compound CC(C)(C)N.C1CCC[C@@H]2N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H](C(O)=O)C[C@@H]21 IYNMDWMQHSMDDE-MHXJNQAMSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003401 ramipril Drugs 0.000 description 1
- HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 description 1
- BSHDUMDXSRLRBI-JOYOIKCWSA-N rentiapril Chemical compound SCCC(=O)N1[C@H](C(=O)O)CS[C@@H]1C1=CC=CC=C1O BSHDUMDXSRLRBI-JOYOIKCWSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229960002769 zofenopril Drugs 0.000 description 1
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
-
- 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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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
A pharmaceutical composition for use against hypertension and congestive heart failure contains a) a potassium channel activator especially a benzopyran derivative of specified formula and b) an angiotensin-converting enzyme (ACE-) inhibitor, especially spirapril. A product comprising (a) and (b) for separate administration is also disclosed.
Description
PHARMACEUTICAL COMPOSITION FOR USB AGAINST HYPERTENSION AND CONGESTIVE HEART FAILURE This invention relates to novel pharmaceutical compositions effective against hypertension and congestive heart failure and to their production and use.
The present invention provides a pharmaceutical composition containing as active agents a) a Potassium Channel Activator and b) an Angiotensin-Converting Enzyme(ACE-) inhibitor The present invention also provides a method of treating hypertension or congestive heart failure in a subject which comprises co-administering a) a potassium channel activator and b) an angiotensin-convering enzyme(ACE-) inhibitor.
The potassium channel activator comprise a class of physiologically active substances characterised by increasing the potassium permeability of the smooth muscle cell membrane. A vide range of such compounds are now known and have found vide therapeutic application, in particular in the treatment of cardiovascular disturIE 902409 100-7516 bances or diseases, for example in the treatment of chronic cardiac insufficiency, further the treatment of asthma and obstructive disorders of the respiratory system, hypertension and in the treatment of disorders of the gastrointestinal tract. Typically the potassium channel activators are employed as vasodilators, e.g. in the treatment of hypertension.
Component b) are angiotensin-converting enzyme (ACE-) inhibitors. Little has been published on their pharmacological and biopharmaceutical properties. ACE inhibitors are known compounds that influence the transformation of angiotensin I in angiotensin II and that are useful in the lowering of elevated blood pressure when this is due to the action of angiotension II. ACE-inhibiting compounds when administered alone have to be used in relatively high dosages that may lead to unwanted side effects.
The pharmaceutical composition of the invention and also the co-administration of component a) and component b) possess surprisingly and unexpectedly advantageous pharmaceutical properties with an especially favourable or improved pharmacological/therapeutic profile. In particular it has been found that co-administration of a component a) and a component b) as aforesaid in conjunction results in unexpected enhancement of antihypertensive activity and in surprisingly potent activity against congestive heart failure.
The component a) induces increase in central venous pressure and consequently the increase in cardiac output is blunted in component b) pretreated animals. The increase of central venous pressure in the absence of cardiac depression (cardiac contractility was accurately assessed with a strain gauge sewn onto the myocardium) indicates an increased venous return caused by arteriolar dilatation. The blunted effect of component a) hence indicates an increased venous compliance after ACE inhibition. 100-7516 The potassium channel activator for use in the composition of invention as component a) is of the class of benzo[bjpyranes and pyranopyridines of formula * wherein either A) V denotes Rx-C, T denotes R2-C and V denotes H-C, wherein Rx signifies hydrogen, halogen, ethynyl, hydroxy, cyano or the groups of formulae -NR6R8-CO2Re or -C0NReR7 and R2 signifies hydrogen, halogen, (Cx_4)alkoxy, hydroxy or the group of formula -NReR8 - whereby R« and R7 independently of one another respectively denote hydrogen or a (Cx_4)alkyl group, and R8 signifies hydrogen, a (Cx_4) alkylgroup, a formyl-, an acetyl- or a trifuoroacetyl group - or one of Rx and R2 signifies nitro and the other of Rx and R2 is defined as above, or Β) V denotes N, T denotes R2-C wherein R2 has the significance 100-7516 given above and W denotes HC, or C) V denotes Ri'-C, T denotes H-C and W denotes N, wherein Rx signifies hydrogen, a cyano or nitro group or D) V denotes Ν, T denotes H-C and W denotes N, R3 and R< independently of one another, denote hydrogen or a (Ci_4)alkyl group or R3 and R4 together signify a group -(CHj)n-, whereby n is 2, 3, 4 or 5, R5 signifies hydrogen or 0R8, wherein Re is defined as above, R9 and Rio respectively denote hydrogen or methyl or together signify an oxo- or a thio-group, m is 1,2 or 3, X signifies 0 or NRn, whereby RX1 signifies hydrogen, a (C3_4)alkyl—, formyl-, acetyl- or hydroxymethyl group, Y = CH, C-halogen, N, C-formyl or C-hydroxymethyl and Z = CHj, 0, S, CH-halogen or NR$, wherein Re is defined as above, as well as their N-0xides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.
Of the compounds of formula I, preferred compounds possess formula Ia, - 5 - 100-7516 wherein either A*) V* denotes R3a-C, T* denotes R2a-C and V· denotes H-C, wherein Ri* signifies hydrogen, cyano, halogen, -NReRe ethynyl or a group -C02Re or -C0NReR7 and R2a signifies hydrogen, methoxy, hydroxy or a group of formula -NR6Re, wherein R6, R7 and Ra have the significance given above, or one of Rx· and R2b denotes nitro and the other of R3a and R2* is defined as above, or B*) V* denotes N, Ta denotes R2a-C wherein R2a has the significance given above and Wa denotes H-C, or Ca) V* denotes Rxa'-C, Ta denotes H-C and W* denotes N, wherein Rt*' signifies hydrogen, cyano or nitro or Da) V* denotes N, Ta denotes H-C and Wa denotes N R3a and R4* respectively signify hydrogen or (Ci_g)alkyl or R3a and Rg* together form a group of formula -(CH2)na, - 6 100-7516 wherein n* signifies 2,3 or 4 R9a and Rio* respectively signify hydrogen or methyl or together signify an oxo group, m* = 1 or 2 X* denotes 0 or NRn, wherein Rn possesses the definition given above, Y" denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Z* denotes 0, NRe, wherein R6 possesses the definition given above, CH2 , CH-halogen or S, as well as their N-0xides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.
Of the compounds of formula I, especially preferred compounds posses formula Ib, Ab) Vb denotes Rib-C, Tb denotes R2b-C, wherein Rib signifies hydrogen, ethynyl, cyano or a group of formula -NReRe, -CO2R6 or C0NR6R7 and R2b signifies hydrogen, hydroxy or a group of formula -NR«Rg wherein R«, R7 and Rg have the sigIE 902409 - 7 - 100-7516 nificances given above, or one of Rxb and R2b signifies nitro and the other of Rxb and R2b is defined as above, or Bb) Vb denotes N, Tb denotes R2b-C, wherein R2b has the significance given above, R3b and R4b respectively signify hydrogen or (Ci-4)alkyl, or R3b and R4b together signify a group of formula -(CH2)„b-, wherein nb signifies 2,3 or 4, mb respectively denotes 1, or 2, and Xb denotes 0 or NR1X, whereby Rxl possesses the definition given above, Yb denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Zb denotes CH2, CH-halogen, 0, S or NR«, wherein R6 possesses the definition given above, as well as their N-0xides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.
In formula I, halogen denotes fluorine, chlorine, bromine or iodine, preferably fluorine, bromine or iodine, especially fluorine or iodine, a (Ci_4)alkoxy group denotes methoxy, ethoxy, n-propoxy or isopropoxy, n-butoxy, i-butoxy, tert.-butoxy, especially methoxy, a (Cx_4)alkyl group denotes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert.-butyl, especially methyl or ethyl.
Compounds of formula I and their N-0xides are preferrably it 902409 - 8 100-7516 selected from: (1) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-l-cyclopent-l-enloxy)-2H-l-benzopyran-6-carboni trile (2) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-l-cyclohex-l-enyloxy)-2H-l-benzopyran-carbonitrile (3) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(4-iodo-3-oxol-cyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (4) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-l-cyclopent-l-enylamino)-2H-l-benzopyran-6-carbonitrile (5) (+)-(3R,4S)-trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3oxo-l-cyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (6) (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dime thyl-4-(3-oxo-lcyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (7) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[2-oxofuran-4(5H)-ylamino]-2H-benzopyran-6-carbonitrile (8) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[2-oxofuran^i 5H) -yloxy ]-2H-l-benzopyran-6-carboni trile (9) t rans-3,4-d ihydro-3-hydroxy-2,2-dimethyl-4-[N-methyl-N-(3-oxo-cyclopent-l-enyl)amino]-2H-l-benzopyran-6-carbonitrile (10) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(N-methyl-N-(2-oxyfuran-4(5H)-yl)aminoJ-2H-l-benzopyran-6-carbonitrile - 9 100-7516 (11) t rans-3,4-d ihydro-3-hydroxy-2,2-d imethy1-4-[N-me thy1-N-(methy l-2-oxo-pyrrol-4(5H)-yl)amino]-2H-l-benzopyran-6-carboni trile (12) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-[2-oxothiophen-4(5H)-yloxy]-2H-l-benzopyran-6-carbonitrile (13) trans-4-[N-formyl-[N-(3-oxo-cyclopent-l-enyl)amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-6-carbonitrile (14) trans-3,4-dihydro-3-hydroxy-4-[N-(2-hydroxymethyl-3-oxo-cyclopent-l-enyl)amino]-2,2-dimethyl-2H-l-benzopyran-6-carbonitrile (15) trans-3,4-dihydro-4-(2-formyl-3-oxo-cyclopent-l-enyl-amino) -3-hydroxy-2,2-dimethyl-2H-l-benzopyran-6-carboni trile (16) trans-4-[N-(2-fluoro-3-oxo-cyclopent-l-enyl)-amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-6-carbonitrile (17) trans-4-[N-(2-chloro-3-oxo-cyclopent-l-enyl)-amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-6-carbonitrile (18) trans-4-[N-(2-bromo-3-oxo-cyclopent-l-enyl)-amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-6-carbonitrile (19) 3-amino-[N-(trans-3,4-dihydro-2,2-dimethyl-3-hydroxy-6-nitro-2H(l)-benzopyran-4-yl)]-cyclopent-2-en-l-on (20) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[N-methyl-N-(2-oxo-furan-4(5H)-yl)-amino]-2H-l-benzopyran-6-carbonic acid-methylester it 902409 100-7516 (21) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[N-methyl-N-(2-oxo-furan-4(5H)-yl)amino]-2H-l-benzopyran-6-carbonic acid-dimethylamide (22) trans-2,2-diethyl-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (23) trans-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent-l-enloxy-spi ro(2H-l-benzopyran-2,1'-cyclohexan]-6-carboni trile (24) trans-3,4-dihydro-2,2-dimethyl-4-(3-oxo-cyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (25) 3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-pyrano[3,2-c]pyridin-4-yl)cyclopent-2-en-l-on (26) 3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-pyrano[3,2-cJpyridin-4-yl)cyclopent-2-en-l-on-N-oxide (27) trans-N-acetyl-2,2-diethyl-7-amino-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (28) 3-(trans-N-acetyl-6-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-l-benzopyran-4-oxy)-cyclopent-2-en-l-on The compounds of formula I, their N-Oxides their pharmacologically acceptable acid addition salts and quaternary ammonium salts are known from DE-OS 3815325.
The compounds of formula I used according to the invention appear both in racemic form and in optically active form. When in the 100-7516 compounds of formula I R5 has a definition other than hydrogen then the group X-C = Y- is in trans position to R5.
The compounds of formula I may be used in form of free beses or as salts. Acid addition salts are obtainable by reaction of compounds of formula I with e.g. hydrochloric acid, hydrobromic acid, malonic acid, maleic acid, fumaric acid, benzene-sulphonic acid, toluene-sulphonic acid, methane-sulphonic acid, malic acid, tartaric acid, camphor-sulphonic acid, formic acid, oxalic acid, phosphoric acid, sulphuric acid, trifluoroacetic acid and trifluoro-methane-sulphonic acid. Quaternary ammonium salts of the compounds according to the invention may be produced in known manner, for example by a reaction with methyl iodide. Of course, the acid addtion salts, the quaternary ammonium salts and the N-0xides of the compounds of formula I are all pharmacologically acceptable.
Particulary interesting ACE-inhibitors for the combination of the invention are: captopril (Merck) spirapril (Schering-Plough) CI-925 (Warner-Lambert) CI-906 (Warner-Lambert) pivalopril (Revlon) (Rev 3659) MC-838 (Chugai) Hoe 498 (Hoechst) S 9490-3 (Servier) fentiapril (Santen) zofenopril (Squibb) (SQ 26 991) MK-521 (Merck) alacepril (Dainippon) cilazapril (Roche) 100-7516 It 9UZ409 enalapril (Merck.) and enalaprilate (Merck.) lisinopril (Merck) RO 312 201 (Roche) CV 3317 (Takeda) EU 4867 (Morton Norwick) Sch 31-846 (Schering) CGS 13928 C (Cigy) CGS 13945 (Cigy) CGS 14824 (Cigy) CGS 14831 (Cigy) indolapril (Warner-Lambert) SQ 28555 (Squibb) especially, captopril, enalapril, pivalopril, CI-925, MC-838, S9490-3 and spirapril, particularly spirapril.
Spirapril being the generic name of a compound with the chemical denomination 7-(N-[l(S)-Ethoxycarbonyl-3-Phenylpropyl]-(S)Alanyl)-l,4-Dithia-7-Azaspirol[4,4]Nonane-8-(S)-Carboxylic Acid having the alternative chemical name [8S-[R*)],8R*]]-7-[2-[[l-(Ethoxycarbonyl)-3-phenyl-propyl]amino]-1-oxopropyl]-1,4-dithia-7-azaspirol[4.4]nonane-8-carboxylic acid. It is also identified by SCHERING as SCH-33844. This compound is described in Example 3 of the US-Patent No 4,470,972. In this US-Patent it is stated that the compound has antihypertensive activity. Pharmaceutical acceptable salt forms may be used. The hydrate may be used. In this US-Patent different salt forms are described that can be used instead of the free base e.g. the hydrochloride as described in Example 4 of this patent or the hemimaleate as described in Example 5 of this patent. The preferred form is the monohydrochloride monohydrate.
The new composition may be prepared by a process comprising formulating a potassium channel activator and component b) in a 100-7516 state of purity sufficient for pharmaceutical acceptability.
Conventional pharmaceutical excipient including carrier and diluents, may also be formulated therewith.
Both potassium channel activators and ACE-inhibitors are known to be useful in the treatment of hypertension.
Combinations containing both active principles would thus be expected to be also useful in the treatment of hypertension. Indeed investigations have shown that the specific combinations of the two active ingredients possess hitherto unknown properties making them remarkably advantageous and well-suited for the treatment of hypertension and of congestive heart failure.
Both components a) and b) may be in the free base or where appropiate in salt, e.g. in acid addition salt form.
The co-administration of a potassium channel activator as component a) and of a component b) exhibits potent anti-hypertensive activity and activity against congestive heart failure as indicated in pharmacological experiments.
The activity of the composition of the invention in the treatment of hypertension can be shown in conscious spontaneously hypertensive rats according to the method of Tschirki et al.(Arzneimittelforsch Drug Res.18 (1968)), 1285 and the treatment of congestive heart failure in a test described by Salzmann et al. in Journal of Cardiovascular Pharmacology 7 (1985) 588-596.
The compositions of the invention are therefore indicated for use in the treatment of hypertension and congestive heart failure.
The potassium channel activator may be administered at e.g. one 100-7516 third to 100 percent of the normal dose for treating e.g. hypertension or congestive heart failure. An indicated oral daily dosage of compounds of formula I is from about 0.1 mg to about 5 mg, particularly from about 0.25 to 5 mg, conveniently administered in divided doses 1 to 4 times a day in unit dosage form containing from about 0.06 mg to about 5 mg e.g. in sustained release form. The prefered compound is compound (6) described on page 8 of the instant application. An indicated dose is from about 0.25 to about 1 mg twice or once a day p.o. Component b) may be administered at e.g. one third to 100 percent of the normal dose for treating hypertension or congestive heart failure. Dosage forms considered include 2.5 mg, 5 mg and 15 mg especially 2.5 and 5.0 mg. It is advisable to use for 0.25 mg of compound a) 0.5 to 25 mg of compound b).
An indicated preferred weight ratio of a component a) to the component b) calculated on the free base moiety thereof, may be from about 1:5 to about 1:20, particularly from about 1:10 to about 1:15.
Thus for compound (6) as component a) and spirapril as component b) preferred ratio is from about 1:10 to about 1:15.
Conveniently, components a) and b) are administered in the form of a pharmaceutical composition in association with a pharmaceutical carrier or diluent. Such compositions may be formulated in conventional manner so as to be, for example, a solution such as an injectable solution or supension, or preferably a solid form such as a tablet or capsule. If desired one or both of the components may be in sustained release form.
If desired the active agents may be arranged in a pack to facilitate administration of a particular dosage regimen, e.g. in a parIE 902409 100-7516 ticular order in a blister pack.
A suitable composition may also consist of a pack containing separately a component a) and a component b) until required for concomitant administration, conveniently together with instructions for the concomitant administration of a predetermined amount of compodnent a) and a predetermined amount of one of the component b).
The following Examples are illustrative of compositions for use in the invention.
I fl· rs j· _ _ _ _ ic yuz40y - 16 100-7516 EXAMPLE 1: Hard gelatine capsules for oral administration Hard gelatine capsules containing the ingredients indicated below may be prepared by conventional techniques, and be administered once a day for the treatment of hypertension and congestive heart failure.
Ingredient Weight Compound (6) 0.25 mg Spirapril 2.5 mg Lactose 167.0 mg Sodium lauryl sulfate 5.75 mg Corn starch 130.0 mg Aerosil 200 1.5 mg Polyethylenglycol 6000 8.0 mg 315.0 mg EXAMPLE 2; Tablets for oral administration Sufficient amounts of the components are mixed in conventional manner and filled into gelatine capsules or compressed to tablets, which are administered once a day for the treatment of hypertension and congestive heart failure. lb 902409 - 17 - 100-7516 Ingredient Weight Compound (6) 0.25 mg Spirapril 2.5 mg Lactose 224.0 mg Sodium lauryl sulfate 2.25 mg Polyvinylpyrrolidone 8.4 mg Corn starch 15.0 mg Magnesium stearate 2.6 mg 255.0 mg EXAMPLE 3: Separate Co-administration Capsules of compound (6) may be made up with the following composition Compound (6) 0.5 mg Microcrystalline Cellulose (Avacel) 47 mg Cetyl Palmitate 10 mg Hydroxypropyl methylcellulose (Methocel E4M) 90 mg Silica colloidal 1 mg Magnesium stearate 2 mg 150.5 mg and Capsules of Spirapril may be made up with the following composition it 90^4υ - 18 - 100-7516 Spirapril 5 mg Lactose 349 mg Silica (colloidal) 10 mg Maleic acid (ground) 5 mg Stearic acid 16 mg 385 mg These may be arranged ln calendar packs. If desired combined capsules containing both active agents may be produced. iE 30Z4Uy - 19 100-7516
Claims (14)
1. A pharmaceutical composition comprising a) a potassium channel activator of formula wherein either A) V denotes R x -C, T denotes R 2 -C and V denotes H-C, wherein R x signifies hydrogen, halogen, ethynyl, hydroxy, cyano or the groups of formulae -NR 6 R 8 , -C0 2 R 6 or - C0NR 6 R 7 and R 2 signifies hydrogen, halogen, (C x _ 4 )alkoxy, hydroxy or the group of formula -NR e R 8 - whereby R« and R 7 independently of one another denote hydrogen or a (C x _ 4 )alkyl group and R 8 signifies hydrogen, a (C x _ 4 )alkyl group, a formyl, an acetyl or a trifluoroacetyl group - or one of R x and R 2 signifies nitro and the other of R x and R 2 is defined as above, or Β) V denotes N, T denotes R 2 -C wherein R 2 has the significance given above and V denotes HC, or C) V denotes R x '-C, T denotes H-C and V denotes N, wherein R x ' signifies hydrogen, a cyano or nitro group or D) V denotes N, T denotes H-C and V denotes N, R 3 and R 4 independently of one another, denote hydrogen or a IE 9UZ409 - 20 - 100-7516 (Ci_ 4 )alkyl group or R 3 and R 4 together signify a group -(CH 2 )n-, whereby n is 2, 3, 4 or 5, R 5 signifies hydrogen or 0R # , wherein R e is defined as above, R 9 and Rio respectively denote hydrogen or methyl or together signify an oxo- or a thio-group, m is 1,2 or 3, X signifies 0 or NRn, whereby R 1X signifies hydrogen, a (Ci_ 4 )alkyl-, formyl-, acetyl- or hydroxymethyl group, Y = CH, C-halogen, N, C-formyl or C-hydroxymethyl and Z = CH 2 , 0, S, CH-halogen or NR 6 , wherein R e is defined as above and their N-0xides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts. and b) an angiotensin converting enzyme (ACE-)inhibitor
2. A pharmaceutical composition according to claim 1 character ized in that the potassium channel activators are those of formula Ia. Ia 100-7516 wherein either A*) V* denotes R x a -C, T* denotes R2*-C and V· denotes H-C, wherein Rx* signifies hydrogen, cyano, halogen, -NReR8 ethynyl or a group -C02R« or -C0NReR7 and R2* signifies hydrogen, methoxy, hydroxy or a group of formula -NReR8, wherein Re, R7 and R8 have the significance given in claim 1 or one of Rx* and R2 b denotes nitro and the other of Rx· and R 2 * is defined as above, or Β·) V* denotes N, T* denotes R 2 *-C wherein R 2 * has the significance given above and V* denotes H-C, or C* ) V* denotes Ri*'-C, T* denotes H-C and W· denotes N, wherein R x *' signifies hydrogen, cyano or nitro or D*) V* denotes N, T* denotes H-C and W* denotes N R 3 * and R 4 * respectively signify hydrogen or (Ci_ 4 )alkyl or R 3 * and R 4 * together form a group of formula -(CH 2 )n*, wherein n* signifies 2,3 or 4 R 9 * and Rio* respectively signify hydrogen or methyl or together signify an oxo group, m* =« 1 or 2 X* denotes 0 or NRn, wherein Rn possesses the definition given in claim 1, Y* denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Z* denotes 0, NR 6 , wherein R 6 possesses the definition given in claim 1, CH 2 , CH-halogen or -S22 100-7516 and their N-oxides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.
3. A pharmaceutical composition according to claims 1 and 2 characterized in that the potassium channel activators are those of formula lb lb A b ) V b denotes R3 b -C, T b denotes Ra b -C, vherein Rx b signifies hydrogen, ethynyl, cyano or a group of formula -NReR 8 , -C0 2 R e or -C0NR e R 7 and R 2 b signifies hydrogen, hydroxy or a group of formula -NReR8 vherein R6, R7 and R8 have the significances given in claim 1, or one of Rx b and R2 b signi fies nitro and the other of Ri b and R 2 b is defined as above or B b ) V b denotes N, T b denotes R2 b -C, vherein R2 b has the significance given above, R 3 b and R< b respectively signify hydrogen or (C1_4)alkyl, or R3 b and R4 b together signify a group of formula -(CH 2 )„ b -, vherein n b signifies 2,3 or 4, m b denotes 1 or 2, and it 902499 - 23 100-7516 X b denotes 0 or NRn, whereby Rn possesses the definition given in claim 1, Y b denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Z b denotes CH 2 , CH-halogen, 0, S or NR 6 , wherein R 6 possesses the definition given in claim 1, and their N-oxides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.
4. A composition according to any of the claims 1 to 3 wherein component a) is selected from: (1) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4(3-oxo-l-cyclopent-l-enyloxy)-2H-l-benzopyran-6 -carbonitrile (2) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3 oxo-l-cyclohex-l-enyloxy)-2H-l-benzopyran-carbonitrile (3) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(4-iodo-3-oxo-l-cyclopent-l-enyloxy)-2H-lbenzopyran-6-carbonitrile (4) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-lcyclopent-l-enylamino)-2H-l-benzopyran-6-carbo nitrile (5) (+)-(3R,4S)-trans-3,4-dihydro-3-hydroxy-2,2dimethyl-4-(3-oxo-l-cyclopent-l-enyloxy)-2H- 24 100-7516 ih 802409 l-benzopyran-6-carboni trile (6) (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl4-(3-oxo-l-cyclopent-l-enyloxy)-2H-l-benzopyran -6-carbonitrile (7) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[2-oxofuran-4(5H)-ylamino]-2H-benzopyran-6-carbonitrile (8) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[2-oxofuran-4(5H)-yloxy]-2H-l-benzopyran-6-carbonitrile (9) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(3-oxo-cyclopent-l-enyl)amino]2H-l-benzopyran-6-carboni trile (10) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(2-oxyfuran-4(5H)-yl)amino]-2H-lbenzopyran-6-carboni trile (11) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(N-methyl-2-oxo-pyrrol-4(5H)-yl)amino]2H-l-benzopyran-6-carbonitrile (12) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-[2-oxothiophen-4(5H)-yloxy]-2H-l-benzopyran-6carbonitrile (13) trans-4-[N-formyl-[N-(3-oxo-cyclopent-l-enyl) amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-lbenzopyran-6-carboni trile (14)trans-3,4-dihydro-3-hydroxy-4-[N-(2-hydroxymethyl- 25 100-7516 IE 902403 3-oxo-cyclopent-l-enyl)amino]-2,2-dimethyl-2H-lbenzopyran-6-carboni trile (15) trans-3,4-dihydro-4-(2-formyl-3-oxo-cyclopent-lenyl-amino)-3-hydroxy-2,2-dimethyl-2H-lbenzopyran-6-carbonitrile (16) trans-4-[N-(2-fluoro-3-oxo-cyclopent-l-enyl)amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl -2H-l-benzopyran-6-carboni trile (17) trans-4-[N-(2-chloro-3-oxo-cyclopent-l-enyl)amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl -2H-l-benzopyran-6-carboni trile (18) trans-4-[N-(2-bromo-3-oxo-cyclopent-l-enyl)amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl -2H-l-benzopyran-6-carboni trile (19) 3-amino-[N-(trans-3,4-dihydro-2,2-dimethyl-3hydroxy-6-nitro-2H(l)-benzopyran-4-yl)] -cyclopent-2-en-l-on (20) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nme thyl-N-(2-oxo-furan-4(5H)-y1)-amino J-2H-1benzopyran-6-carbonic acid-methylester (21) t rans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(2-oxo-furan-4(5H)-yl)-amino]-2H-lbenzopyran-6-carbonic acid-dimethylamide (22) trans-2,2-diethyl-3,4-dihydro-3-hydroxy-4(3-oxo-cyclopent-l-enyloxy)-2H-l-benzopyran - 26 100-7516 -6-carboni trile (23) trans-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent1-enyloxy)-spi ro[2H-l-benzopyran-2,1’-cyclohexan]6-carbonitrile (24) trans-3,4-dihydro-2,2-dimethyl-4-(3-oxo-cyclopent1- enyloxy)-2H-l-benzopyran-6-carbonitrile (25) 3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2dimethyl-2H-pyrano[3,2-c]pyridin-4-yl)cyclopent-2-en-l-on (26) 3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2dimethyl-2H-pyrano(3,2-c]pyridin-4-yl)cyclopent-2-en-l-on-N-oxide (27) trans-N-acetyl-2,2-diethyl-7-amino-3,4-dihydro 3-hydroxy-4-(3-oxo-cyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (28) 3-(trans-N-acetyl-6-amino-3,4-dihydro-3-hydroxy2,2-dimethyl-2H-l-benzopyran-4-oxy)-cyclopent2- en-l-on
5. A composition according to any one of claims 1 to 4 wherein component a) is (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethy1-4-(3-oxo-l-cyclopent-l-enyloxyl-2H-l-benzopyran-6carbonitrile.
6. A composition according to any one of the claims 1 to 5 wherein component b) is 100-7516 7. -(Ν-[(1(S)-Εthoxycarbonyl-3-Phenylpropy1]-(S)-Alanyl)I, 4-Dithia-7-Azaspiro-[4,4]Nonane-8-(S)-Carboxylic Acid or pharmaceutically acceptable salts thereof.
7. A compostion according to any of the claims 1 to 6 for use in the treatment of hypertension and congestive heart failure.
8. A composition according to any of the claims 1 to 7 characterized in that the weight ration of component a) to component b) is from 1:5 to about 1:20.
9. A composition according to claim 8 wherein the weight ratio of component a) to component b) is from 1:10 to 1:15.
10. A process for the preparation of a composition according to any of the claims 1 to 9 characterized in that component a) and component b) are mixed optionally together with conventional adjuvants and diluents.
11.II. A pack or dispenser device containing a pharmaceutical composition according to any one of the claims 1 to 9 together with instruction for use in hypertension or congestive heart failure.
12. A method of treating hypertension or congestive heart failure which comprises co-administering component a) and component b) as defined in any one of the claim 1 to 10 to a subject in need of such treatment.
13. Use of a combination of components a) and b) as defined in any of the claims 1 to 10 in the manufacture of a pharmaceutical composition for the treatment of hypertension a congestive heart failure. - 28
14. A pharmaceutical composition substantially as hereinbefore described by way of Example.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898915315A GB8915315D0 (en) | 1989-07-04 | 1989-07-04 | Pharmaceutical compositions for use against hypertension and congestive heart failure |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE902409A1 true IE902409A1 (en) | 1991-06-19 |
Family
ID=10659511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE240990A IE902409A1 (en) | 1989-07-04 | 1990-07-03 | Pharmaceutical composition for use against hypertension and¹congestive heart failure |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPH0344321A (en) |
| BE (1) | BE1004478A4 (en) |
| CH (1) | CH679641A5 (en) |
| DE (1) | DE4020133A1 (en) |
| FR (1) | FR2649320A1 (en) |
| GB (2) | GB8915315D0 (en) |
| IE (1) | IE902409A1 (en) |
| IT (1) | IT1241456B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0519013A2 (en) | 2004-12-13 | 2009-11-03 | Lilly Co Eli | single compound or stereoisomers, mixtures of pharmaceutically acceptable stereoisomers, salts, tautomers or prodrugs thereof, pharmaceutical composition, and use of a compound |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2055709T3 (en) * | 1986-12-06 | 1994-09-01 | Beecham Group Plc | A PROCEDURE FOR PREPARING A PHARMACEUTICAL COMPOSITION. |
| DE3815325A1 (en) * | 1987-05-16 | 1988-11-24 | Sandoz Ag | Benzo[b]pyrans, pyranopyridines and pyranopyrimidines, processes for their preparation and their use in drugs (medicaments, pharmaceuticals) and cosmetics |
| FR2615191B1 (en) * | 1987-05-16 | 1991-01-11 | Sandoz Sa | NOVEL BENZO (B) PYRANS AND PYRANNOPYRIDINES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS |
-
1989
- 1989-07-04 GB GB898915315A patent/GB8915315D0/en active Pending
-
1990
- 1990-06-25 DE DE4020133A patent/DE4020133A1/en not_active Withdrawn
- 1990-06-27 FR FR9008201A patent/FR2649320A1/en not_active Withdrawn
- 1990-06-27 BE BE9000656A patent/BE1004478A4/en not_active IP Right Cessation
- 1990-06-29 CH CH2176/90A patent/CH679641A5/de not_active IP Right Cessation
- 1990-07-03 IE IE240990A patent/IE902409A1/en unknown
- 1990-07-03 GB GB9014705A patent/GB2235382A/en not_active Withdrawn
- 1990-07-03 JP JP2177203A patent/JPH0344321A/en active Pending
- 1990-07-03 IT IT48106A patent/IT1241456B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| FR2649320A1 (en) | 1991-01-11 |
| IT1241456B (en) | 1994-01-17 |
| DE4020133A1 (en) | 1991-01-17 |
| IT9048106A0 (en) | 1990-07-03 |
| CH679641A5 (en) | 1992-03-31 |
| GB2235382A (en) | 1991-03-06 |
| IT9048106A1 (en) | 1992-01-03 |
| GB9014705D0 (en) | 1990-08-22 |
| JPH0344321A (en) | 1991-02-26 |
| GB8915315D0 (en) | 1989-08-23 |
| BE1004478A4 (en) | 1992-12-01 |
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