GB2235382A

GB2235382A - Pharmaceutical composition for use against hypertension and congestive heart failure

Info

Publication number: GB2235382A
Application number: GB9014705A
Authority: GB
Inventors: Robert Paul Hof; Ulrich Quast
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1989-07-04
Filing date: 1990-07-03
Publication date: 1991-03-06
Also published as: JPH0344321A; CH679641A5; GB8915315D0; BE1004478A4; IE902409A1; IT9048106A1; IT1241456B; IT9048106A0; FR2649320A1; DE4020133A1; GB9014705D0

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

k -I- PHARNACEUTICAL CONPOSITION FOR USE AGAINST HYPERTENSION AND

CONGESTIVE BEART 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 wide range of such compounds are now known and have found wide therapeutic application, in particular in the treatment of cardiovascular distur- 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 coadministration of component a) and component b) possess surprisingly and unexpectedly advantageous pharmaceutical properties with an especially favourable or improved pharmacologicalltherapeutic 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.

1 100-7516 The potassium channel activator for use in the composition of invention as component a) is of the class of benzo[b]pyranes and pyranopyridines of formula I, (CH X X R9 RS C'00 A. 0.

R 3 0 wherein either I A) V denotes RI-C, T denotes R2-C and W denotes H-C, wherein R, signifies hydrogen, halogen, ethynyl, hydroxy, cyano or the groups of formulae - NR6R$-C02R6 or -CONR6R7 and R2 signifies hydrogen, halogen, (CI-4)alkoxy, hydroxy or the group of formula -NRfiRI whereby R6 and R7 independently of one another respectively denote hydrogen or a (Cl-Oalkyl group, and Rs signifies hydrogen, a (CI-4) alkylgroup, a formyl-, an acetyl- or a trifuoroacetyl group - or one of R, and R2 Signifies nitro and the other of R, and R2 is defined as above, or B) V denotes N, T denotes R2-C wherein R2 has the significance 1 given above and W denotes HC, or 100-7516 C) V denotes R,'-C, T denotes H-C and V denotes N, wherein R,, signifies hydrogen, a cyano or nitro group or D) V denotes Nt T denotes H-C and W denotes N, R3 and R4 independently of one another, denote hydrogen or a (Cl-4)alkyl group or R3 and R4 together signify a group -(CH2)n-, whereby n is 2, 3, 4 or 5, R5 signifies hydrogen or 0%, wherein % 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 NRI1, whereby R,, signifies hydrogen, a (Cl-4)alkyl-, formyl-, acetyl- or hydroxymethyl group, Y - CE, C-halogen, N, C-formyl or C-hydroxymethyl and Z, CH29 0, S, CH-halogen or NR6, wherein R6 is defined as above, as well as their N-Oxides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.

Of the compounds of formula I, preferred compounds possess formula Ia, (CH), Z a RjOA a Ir X Y 09 v R a T:

W R 4 3& wherein either 100-7516 14 A&) V& denotes R,&-C, T& denotes R2&-C and V& denotes R-Cv wherein Ria signifies hydrogen, cyano, halogen, -NR6R8 ethynyl or a group -CO2R6 or - CONR6R7 and R24 signifies hydrogen, methoxy, hydroxy or a group of formula -NR6R&, wherein R6,A7 and R8 have the significance given above, or one of R,& and R2 b denotes nitro and the other of R,& and R2& is defined as above, or B&) V& denotes N, T& denotes R24-C wherein R2& has the significance given above and V& denotes H-C, or C&) V& denotes R,&'-C, T& denotes H-C and V& denotes N, wherein R,&' signifies hydrogen, cyano or nitro or D&) V& denotes N, T& denotes H-C and W& denotes N R3& and R4& respectively signify hydrogen or (C,-4)alkyl or R3& and R4A together form a group of formula -(CH2)nA, 100-7516 wherein n& signifies 2,3 or 4 Rg& and Rjo& respectively signify hydrogen or methyl or together signify an oxo group, m& m 1 or 2 X& denotes 0 or NR11, wherein R,, possesses the definition given above, P denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and ZA denotes 0, NR6, wherein R6 possesses the definition given above, CH29 CH-halogen or S, as well as their N-Oxides, their pharmacologically acceptable acid addition salts and quaternary ammonium salts.

of the compounds of formula I, especially preferred compounds posses formula Ib, h 5() (CH)M v 1,b b r 0) A 4 R 3 1h Ab) Vb denotes R1h-C, Tb denotes R2b-Ct wherein R1h signifies hydrogen, ethynyl, cyano or a group of formula -NR6Rg, -CO2R6 or CONR6R7 and R.,h signifies hydrogen, hydroxy or a group of formula -NR6R8 wherein R6, R7 and % have the sig- 100-7516 nificances given above, or one of Rlb and R2b signifies nitro and the other of Rlb and R2b is defined as above, or Bb) Vb denotes Ny T b denotes R2 b-C, wherein R2b has the significance given above, R3b and R4b respectively signify hydrogen or (Cl-4)alkyl, or R3b and R4b together signify a group of formula -(CH2)n b_ 9 wherein nb signifies 2,3 or 4, mb respectively denotes 1, or 2, and Xb denotes 0 or NR11, whereby R,, possesses the definition given above, - Yb denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Zb denotes CH22 CH-halogen, 0, S or NR6, wherein R6 possesses the definition given above, as well as their N-Oxides, 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 (Cl-4)alkoxy group denotes methoxy, ethoxy, n-propoxy or isopropoxy, nbutoxy, i-butoxy, tert.-butoxy, especially methoxy, a (Cl-4)alkyl group denotes methyl, ethyl, npropyl, i-propyl, n-butyl, i-butyl, tert.-butyl, especially methyl or ethyl.

Compounds of formula I and their N-Oxides are preferrably selected from:

100-7516 (1) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4(3-oxo-l-cyclopent-lenloxy)-2H-1-benzopyran-6-carbonitrile (2) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-l-cyclohex-l-enyloxy)-2H-1-benzopyran-carbonitrile (3) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(4-iodo-3-oxo1-cyclopent-lenyloxy)-2H-l-benzopyran-6-carbonitrile (4) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-l-cyclopent-l-enylamino)-2H-1-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-dimethyl-4-(3-oxo-lcyclopent-lenyloxy)-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-[N-methyl-N-(3-oxo-cyclopent-l-enyl)aminol-2H-1-benzopyran-6-carbo- nitrile (10) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[N-methyl-N-(2-oxyfuran-4(5H)-yl)aminol-2H-l-benzopyran-6-carbonitrile 100-7516 (11) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[N-methyl-N-(methyl-2-oxo-pyrrol-4(5H)-yl)aminol-2H-l-benzopyran-6-carbonitrile (12) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-[2-oxothiophen-4(5H)-yloxy]-2H-1-benzopyran-6-carbonitrile (13) trans-4-[N-formyl-[N-(3-oxo-cyclopent-l-enyl)aminol-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (14) trans-3,4-dihydro-3-hydroxy-4-IN-(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)-3hydroxy-2,2-dimethyl-2H-l-benzopyran-6-carbonitrile (16) trans-4[N-(2-fluoro-3-oxo-cyclopentl-enyl)-amino]-3,4-dihydro-3-hydroxy-2,2-dimethyl-2E-l-benzopyran-6-carbonitrile (17) trans-4-[N-(2-chloro-3-oxo-cyclopent-l-enyl)-aminol-3,4-di hydro-3-hydroxy-2,2-dimethyl-25-1-benz6pyran-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(1)-benzopyran-4-yl)l-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 100-7516 (21) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[N-methyl-N-(2-oxo-furan4(5H)-yl)aminol-2H-1-benzopyran-6-carbonic acid-dimethylamide (22) trans-2,2-diethyl-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent-lenyloxy)-2H-l-benzopyran-6-carbonitrile (23) trans-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent-l-enloxy-spiro[2H-lbenzopyran-2,11-eyclohexanj-6-carbonitrile (24) trans-3,4-dihydro-2,2-dimethyl-4-(3-oxo-eyclopent-l-enyloxy)-2H-1benzopyran-6-carbonitrile (25) 3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-pyrano[3,2c]pyridin-4-yl)cyclopent-2-en-l-on (26) 3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-pyrano[3,2clpyridin-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-oxocyclopent-l-enyloxy)-2H-l-benzopyran-6-carbonitrile (28) 3-(trans-N-acetyl6-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-lbenzopyran-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. Yhen 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, methanesulphonic 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-Oxides 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) CI906 (Warner-Lambert) pivalopril (Revlon) (Rev 3659) MC-838 (Chugai) Hoe 498 (Hoechst) S 9490-3 (Servier) fentiapril (Santen) zofenopril (Squibb) (SO 26 991) MK-521 (Merck) alacepril (Dainippon) cilazapril (Roche) enalapril (Merck) and enalaprilate (Merck) lisinopril (Merck) RO 312 201 (Roche) CV 3317 (Takeda) EU 4867 (Morton NorwiclC) Sch 31-846 (Schering) CGS 13928 C (Cigy) CGS 13945 (Cigy) -CGS 14824 (Cigy) CGS 14831 (Cigy) indolapril (Warner-Lambert) SO 28555 (Squibb) 100-7516 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-[1(S)-Ethoxycarbonyl-3Phenylpropyl]-(S)Alanyl)-1,4-Dithia7-Azaspirol[4,4]Nonane-8-(S)Carboxylic Acid having the alternative chemical name [8S-[R)],8R11-7-[2[[1 -(Ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl1-1,4-dithia-7azaspirol[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 pharmaceuticalcarrier 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 par- 1 - 1J 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 compo nent b).

The following Examples are illustrative of compositions for use in the invention.

- 16 100-7516 EXAMPLE 1: Hard gelatine capsules for oral administration 0.

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 Compound (6) Spirapril Lactose Sodium lauryl sulfate Corn starch Aerosil 200 Polyethylenglycol 6000 Yeight 0. 25 mg 2.5 mg 167.0 mg 5.75 mg 130.0 1.5 8.0 315.0 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.

Ingredient Compound (6) Spirapril Lactose Sodium lauryl sulfate Polyvinylpyrrolidone Corn starch Magnesium stearate EXAMPLE 3: Separate Co-administration 100-7516 Weight 0. 25 mg 2.5 mg 224.0 mg 2.25 mg 8.4 mg 15.0 mg 2.6 mg 255.0 mg Capsules of compound (6) may be made up with the following composition Compound (6) 0.5 -mg Microcrystalline Cellulose (Avacel) 47 Cetyl Palmitate 10 Hydroxypropyl methylcellulose (Methocel E4M) Silica colloidal Magnesium stearate mg mg mg 1 mg 2 mg 150.5 mg and Capsules of Spirapril may be made up with the following composition Spirapril Lactose Silica (colloidal) Maleic acid (ground) Stearic acid 100-7516 mg 349 mg mg mg 16 mg 385 mg These may be arranged in calendar packs. If desired combined capsules containing both active agents may be produced.

1

Claims

WHAT WE CLAIM IS:

1. A pharmaceutical composition comprising a) a potassium channel activator of formula / z R 10 (CH) Y\ - 1 % _ 19 1.9 4_. 3 It 0 4 Q9 T 0 R3 wherein either 100-7516 1 A) V denotes R,-C, T denotes R2-C and V denotes H-C, wherein R, signifies hydrogen, halogen, ethynyl, hydroxy, cyano or the groups of formulae - NR6Re, -C02R6 or - CONR6R7 and R2 signifies hydrogen, halogen, (Cl- 4)alkoxy, hydroxy or the group of formula -NR6R8 - whereby R6 and R7 independently of one another denote hydrogen or a (Cl-Jalkyl group and R$ signifies hydrogen, a (Cl-4)alkyl group, a formyl, an acetyl or a trifluoroacetyl group - or one of R, and R2 signifies nitro and the other of R, and R2 is defined as above, or B) V denotes N, T denotes R2-C wherein R2 has the significance given above and V denotes HC, or C) V denotes R,'-C, T denotes H-C and V denotes N, wherein R,' signifies hydrogen, a cyano or nitro group or D) V denotes N, T denotes H-C and V denotes N, R3 and R4 independently of one another, denote hydrogen or a 1007516 (Cl-Jalkyl group or R3 and R4 together signify a group -(CH2)n-, whereby n is 2, 3, 4 or 5, R5 signifies hydrogen or OR$, wherein % is defined as above, R9 and R10 respectively denote hydrogen or methyl or together signify an oxo- or a thio-group, m is 1,

2 or 3, X signifies 0 or NRil, whereby R,, signifies hydrogen, a (C14)alkyl-, formyl-, acetyl- or hydroxymethyl group, Y - CH, C-halogen, N, C-formyl or C-hydroxymethyl and Z ' C527 OP S, CH-halogen or NR6, wherein R6 Is defined as above and their N-Oxides, their pharmac0' ' logically acceptable acid addition salts and quaternary ammonium salts.

and b) an angiotensin converting enzyme (ACE-)inhibitor 2. A pharmaceutical composition according to claim 1 characterized in that the potassium channel activators are those of formula Ia.

Z a RIO& (CH ly..'R 9 X ON R a 4 R 3& Ia wherein either 100-7516 A&) V& denotes R,&-C, T& denotes R24-C and W& denotes H-C, wherein R,& signifies hydrogen, cyano, halogen, -NR6R& ethynyl or a group -CO2R6 or - CONR6R7 and R2A signifies hydrogen, methoxy, hydroxy or a group of formula -NR6R8, wherein R6, R7 and Re have the significance given in claim 1, or one of R,& and R2b denotes nitro and the other of R,& and R24 is defined as above, or W) V& denotes N, T& denotes R24-C wherein R24 has the significance given above and W& denotes H-C, or C&) V& denotes R,&'-C, T& denotes H-C and V& denotes N, wherein R,&' signifies hydrogen, cyano or nitro or D&) V& denotes N, T4 denotes H-C and Va denotes N R3& and R4& respectively signify hydrogen or (Cl-4)alkyl or R3& and R4a together form a group of formula -(CH2)n4, wherein n& signifies 2,3 or 4 Rg& and R104 respectively signify hydrogen or methyl or together signify an oxo group, m& m 1 or 2 P denotes 0 or NR11, wherein R,, possesses the definition given in claim 1, Y& denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Za denotes 0, NR6, wherein R6 possesses the definition given in claim 1, CH2, CH-halogen or S- 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 Ib / Z h (CH)Mh so;2-1 T 0 -h 4 R! 3 Ib Ab) VII denotes Rlb-C, Tb denotes R2 b-CP wherein Rlb signifies hydrogen, ethynyl, cyano or a group of formula -NR6R$, -C02R6 or -CONR6R7 and R2 b signifies hydrogen, hydroxy or a group of formula -NR6R8 wherein R6, R7 and Rs have the significances given in claim 1, or one of Rlb and R2 b signifies nitro and the other of Rlb and R2 b is defined as above, o r Bh) Vb denotes N, Th denotes R2b-C, wherein R2b has the significance given above, R3b and R4b respectively signify hydrogen or (Cl-4)alkyl, or R3b and R4 b together signify a group of formula -(CH2),b_ wherein nb signifies 2,3 or 4, Mb denotes 1 or 2, and 100-7516 Xb denotes 0 or NR11, whereby R,, possesses the definition given in claim 1, Yb denotes CH, C-halogen, C-hydroxymethyl, C-formyl or N and Zb denotes CH2, CH-halogen, 0, S or NR6, wherein R6 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-lenyloxy)-2H-l-benzopyran-6 -carbonitrile (2) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3 oxo-l-cyclohex-lenyloxy)-28-1-benzopyran-carboni t rile (3) trans-3,4-dihydro-3-hydroxy-2t2-dimethyl-4-(4-iodo-3-oxo-l-cyclopentl-enyloxy)-29-1benzopyran-6-carbonitrile (4) trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-lcyclopent-lenylamino)-2H-1-benzopyran-6-carbo nitrile (5) (+)(3R,4S)-trans-3,4-dihydro-3-hydroxy-2,2dimethyl-4-(3-oxo-lcyclopent-l-enyloxy)-2H 1-benzopyran-6-carbonitrile (6) (-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl4-(3-oxo-l-eyclopent-lenyloxy)-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-3hydroxy-2,2-dimethyl-4-[Nmethyl-N-(3-oxo-eyclopentl-enyl)aminol2H-1-benzopyran-6-carbonitrile (10)trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(2-oxyfuran4(5H)-yl)aminol-2H-1benzopyran6-carbonitrile (11)trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(N-methyl-2-oxopyrrol-4(59)-yl)amino] 2H-1-benzopyran-6-carbonitrile (12)trans-3,4-dihydro3-hydroxy-2,2-dimethyl-[2-oxothiophen-4(5H)-yloxy]2H-l-benzopyran-6carbonitrile (13)trans-4-[N-formyl-[N-(3-oxo-cyclopent-l-enyl) aminol-3,4-dihydro-3hydroxy-2,2-dimethyl-2H-1benzopyran-6-carbonitrile (14)trans-3,4-dihydro-3-hydroxy-4-[N-(2-hydroxymethyl- 100-7516 3-oxo-cyclopent-l-enyl)amino]-2,2-dimethyl-2Hbenzopyran-6-carbonitrile (15)trans-3,4-dihydro-4-(2-formyl-3-oxo-cyclopent-1 enyl-amino)-3-hydroxy2,2-dimethyl-2H-1benzopyran-6-carbonitrile (16)trans-4-[N-(2-fluoro-3-oxo-cyclopent-l-enyl)amino]-3,4-dihydro-3hydroxy-2,2-dimethyl -2H-1-benzopyran-6-carbonitrile (17)trans-4-[N-(2-chloro-3-oxo-cyclopent-l-enyl) amino]-3,4-dihydro-3hydroxy-2,2-dimethyl -2H-1-benzopyran6-carbonitrile (18)trans-4-[N-(2-bromo-3-oxo-cyclopent-l-enyl)amino]-3,4-dihydro-3hydroxy-2,2-dimethyl -2H-1-benzopyran-6-carbonitrile (19)3-amino-[N-(trans-3,4-dihydro-2,2-dimethyl-3hydroxy-6-nitro-2H(1)benzopyran-4-yl)] -cyclopent-2-en-l-on (20)trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(2oxo-furan4(5H)-yl)-aminol-2H-1benzopyran-6-carbonic acid-methylester (21)trans-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-[Nmethyl-N-(2-oxo-furan4(5H)-yl)-amino]-2H-1benzopyran-6-carbonic acid-dimethylamide (22)trans-2,2-diethyl-3,4-dihydro-3-hydroxy-4(3-oxo-cyclopent-l-enyloxy)2H-l-benzopyran 100-7516 (23)trans-3,4-dihydro-3-hydroxy-4-(3-oxo-cyclopent1-enyloxy)-spiro[2H-1benzopyran-2,11-eyclohexan] 6-carbonitrile (24)trans-3,4-dihydro-2,2-dimethyl-4-(3-oxo-eyclopent1-enyloxy)-2H-lbenzopyran-6-carbonitrile (25)3-amino-N(trans-3,4-dihydro-3-hydroxy-2,2dimethyl-2H-pyrano[3,2clpyridin-4-yl)cyclopent-2-en-l-on (26)3-amino-N-(trans-3,4-dihydro-3-hydroxy-2,2dimethyl-2E-pyrano[3,2clpyridin-4-yl)cyclopent-2-en-l-on-N-oxide (27)trans-N-acetyl-2,2-diethyl-7-amino-3,4-dihydro 100-7516 3hydroxy-4-(3-oxo-eyclopent-l-enyloxy)-2H-1-benzopyran-6-carbonitrile (28)3-(trans-N-acetyl-6-amino-3,4-dihydro-3-hydroxy2,2-dimethyl-2H-lbenzopyran-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-dimethyl-4-(3-oxo-lcyclopentl-enyloxyl-2H-l-benzopyran-6carbonitrile.

6. A composition according to any one of the claims 1 to 5 wherein component b) is f 100-7516 7-(N-[(l(S)-Ethoxycarbonyl-3-Phenylpropyl]-(S)-Alanyl)1,4-Dithia-7Azaspiro-[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. 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.

Published 1991 at The Patent Office. State House, 66/71 High Holbo.m. LondonWClR4TP. Further copies may be obtained from Sales Branch. Unit 6. Nine Mile Point. Cwmielinfach. Cross Keys. Newport, NPI 7HZ. Printed by Multiplex techniques lid. St Mary Cray, Kent.