PH26364A - Combination of angiotensin converting enzyme inhibitors with potassium channel modulators and use thereof in pharmaceuticals - Google Patents

Description

ee ————————————————————————— ee

B | 0 fir

EH yt Sal vo SFE . n : “ Ce 26364

Description ur ’

Combination of angiotensin converting enzyme inhibitors with potasium channel modulators and use thereof in pharmaceuticals : : a The present invention relates to a combination of angiotensin converting enzyme inhibitors (ACE inhibitors) with potassium channel modulatore and use thereof in pharmaceuticals, i or in particular in hypotensive pharmaceuticals. , . ) KE 10 ACE inhibitors are compounds which prevent the - conversion of angiotensin I into the pressor active agiotensin 11. Such compounds are : described, for example in the following patent applications or patentg: USPS 4,350,633,U8-P8 4,344,949, Us-rs 4,294,832, Us-pPs 4,350,704, EP-A 50,800, EP-A 31,781, EP-A 81,020, EP-A 49,658, EP-A 49,609, EP-A 29,488, ' ..

EFP-A 46,953, EP-A 52,870, EF-A 72,022, © EP-A 84,164, EP-A 89,637, EF-A 90,341, EP-A 90,362,

E : 20 EFP-A 109,102, EF-A 109,020, EF-A 111,873, "EP-A - 2 - BE .

: § off 113,880. "

Their hypotensive action is well documented. fotassium channel modulators are those compounds which influence the outflow of potasium inns from cells, in particular smooth muscle cells, and thereby lead te a membrane hyperpolarization. Such compounds and their hypotensive action are set down in patent applications and publications, for example in

J. Med. Chem. 29 (1986) M4-2201 and European

Fatent Applications EP-0 76,07%, EF-A 107,423, . : EF-A 120,427 and EfF-A 120,428.

Both groups of substances intervene in various blood pressure regulation systems. : ’

Surprisingly here, on combined administration the effect of the one component of . the combination is increased by the other respective component. On combined - oe ee : administration, this leads Lo a lower tng of ‘the ..

A : { 2 dose of the respective components of the : combination, compared with individual : administration. Tr this way. the accurrence of - Xe .

——————————————————— — eR see side effects known for the two clases of substances can be lowered or avoided. ‘ Combinations of representatives of these classes . of active compound have not previously been a described. suitable ACE inhibitors are the following compounds of the formula 1 ar their physiologically tolerable salts: * * * . 3 _ - - - - -CH~ = 1 '“ »300c - CE - KN - C - CH - NE ih (cm) =k (1) , , I I coor? oo

R R 0 R “ : ». : w Te . ~ “- - ’ in which : n is 1 or 2. i

Se

R denotes hydrogen, a

To an optionally substituted . aliphatic - radical having 1-8 carbon atoms, i. *. an optionally auhatituted alicyclic radical having 3-9 carbon atoms, an optionally substituted aromatic x - 4 = 5 . 8 . 3

Ca

So ER CeO : TE 26364 radical having 6-12 carbon carbon atoms, , an optionally substituted araliphatic ’ radical having 7-14 carbon atoms, an optionally substituted alicyclic aliphatic radical having 7-14 carbon atoms, -

BN a radical OR® or SR®, in which

R2 represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally asubatituted . ; aromatic radical having 6-12 carbo atoma or an optionally substitisted . heteroaromatic radical baving 8-12 ring 18 atoms, - : rl denotes hydrogen, SL

Co an optionally substituted aliphatic radical having 1-64 carbon atoms. an : optionally substituted alicyelic radical having 3-9 carbon atoms, S.

BE an optionally substituted alicyelic- oo aliphatic radical having 4-13 carbon

LL atoms, - - 8 a .

i wr - anh? 26364 an optionally substituted aromatic radical havina 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-16 carbon atoms, : an optionally substituted 3 heteroaromatic radical baving 8-12 ring ’ atoms or the side chain, protected if necessary, of a naturally occurring d-amino acid,

RZ and R° are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1-6 carbon } : atoms, an optionally substituted alicyclic radical having 3-9 carbon atoms, oo 13 an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-16 carbon atoms-and- . rR? and rR together with the atoms carrying them o form a heterocyclic bi- or tricyclic ring system having 9% to 1% carbon . atoms. :

- yo

Yu

Suitable rina =ystems of this type are in particular those from the following groups? tetrahvdroisoquinoline (AR) decahydraoiasonquinnl ine (HY: octahvdroindole (CC) a octahydrocyclopentalbipyryole (DR): 2- azaspitnl A. decane (Fa Peaznapirold4.4Inonane (Fs apirof (hicye lof 2.2.) Theptane) 2,3" ~ pyrrolidine} (5): spiral (hicyclol 2.2.2 1nctane)~ - 2.3 pyrrolidine] (trys oR azatricyclof4.%.0.1% 7 decane (I) ' decahydrocyclobenptal bilpvr role (J): oc tahydrot asoindols (Kg actahydroeye lopentale pyr ole (Ls 2eTgla 4,0, 7a-heahyd cindale (Mz Pe ia azabicve lol mo Uo The ano (N) naxahvidrocyctopentalhiporrnle (A), which can all be optionally subetbitated, However, the unsubstituted avatems are preferrved.- ooo oes in the compounds which have a number of chiral atoms, nmsuitable racemates or Pnantiomers’ are all possible diastereomers, Or mit ures af : - 7 | *

BAD ORIGINAL 9 ee ————————

Gene J } Sd ! /

PT ad Fr dF ’ a difber Pp b ' T . HARRY Fd . aT . FE coon a : : ba oO .

Lo To different diastereomers. ;

The cyclic amino acid esters which are suitable have the n ’

Co —- ny — i. .

Lr .. i } . oe iy - oo Cee . - 8 - : .

To se ce

Ce Co ee fli - i i . i wh) following structural or : : w" $ . { . | i 2 23 3

COOR COOR® _ i oo = Og! . . . k

A | B - COOR 0 N \ coon’ : coor? oq b CX oo coor’

FE

Jo , { I . i ‘ OOR ;

N COOR | 2) coor’ , . | (

AV{[) ee

COOR N oor?

I

' J 1 | t .

J) coor? —coor? N RS

CONT | | :

M N °

Co oo a

RE | | = :

Uo

Co . | v . . . oo | ; r -9- \ : 3 ! . ot : . i

Tr rer or ETT re Wr eToys rg Fry TET ———

———— pr!

IY \ \ Particularly preferred ACE inhibitors are those

Lh ~of the formula 1 in which Ci fn is 1 or 2 ~

R denotes hydrogen, 3 alkyl having 1-8 carbon atoms, alkenyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl having 6-12 carbon atoms, which can be monosubstituted, disubstituted or trisubstituted . by (Cy~Ca)-alkyl, (€4-C4)- : alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (Cy=Cy)- . . ' alkylamino, di-(Cg=Ca)- alkylamino, (Cq~Cy)- } alkanoylamino, methylenedioxy, cyano and/or sul famoyl, oo : o alkoxy having 1-4 carbon atoms, - a aryloxy having 6-12 carbon atoms, 20 . which can be substituted Can ~ described above for aryl, N

Ll mono- or bicyclic heteroarylony .. having 5-7 or 8-10 ring atoms, of a which 1 or 2 ring atoms are sui tur or 23 o oxygen atoms and/or 1 to 4 ring atoms are nitrogen, a — i — | *

NEC a oq - which can be mubsti ited ss described above for aryl " . amino—(C,;~Ca)-alkyl, © (04-4) -alkanoylamino-(C,-C,)-alkyl; (C,-Cyx)~aroylamino—(Cy-Cyh)-alkyl, (Cy-C4)~atkoxycarbonylamino-(C;-Cq)= alkyl, (Co=Cyn)-aryl—(C -Cy)- alkoxycarbonylamino-(C,-Cz)-alkyl; (C4=Cyom)=aryl=(C,-Cq)—alkyl amino—(C,~ Co

Ca)-2lkyl, (Cy-Cqh)-alkylamino-(Cj—

Cy)-alkyl, i d1-(Cy-Cq)-alkylamino=(C,~Cy)-alkyl,

N guanidino-(C;-Cy)-alkyl, wo h imidazolyl, indolyl, Co 18 : (Cy~C4)-alkylthio, hi (€4-Cq)-alkyl thio (Cy-Cal=alkyl, = - (C4-Cyp)-aryl thio=(Cy=Ca)-alkyds in

C which can be substituted in the T aryl moiety as described above : tor aryl, A (C4=Cy 3) -aryl=(C ~C4)~alkylthio, iE which can be substituted in the aryl moiety as described above ee ———————————————————— eee ( ny oo oo | LY > 26364 ‘ for aryl, carbonyl-(Cy-Cyh)-alkyl, carboxyl, carbamoyl, carbamoyl-(C,;-Cy)-alkyl, ‘ a (Cy-Cy)-alkorycarbonyl~-(Cy-Cy)-alkyl, (Cu=Cyn)—aryloxny—(Cy-Ch)-alkyl, which can be substituted in the aryl moiety as described above . . for aryl ar (Co=Cia)—aryl-(C;-Ch)-alkony, " - | which can be substituted in the - aryl moiety as described above } for aryl, . ri denotes hydrogen, } alkyl having 1-6 carbon atoms, oo ~ alkenyl having 2-& carbon atoms, ~ alkynyl having 2-6 carbon atoms, © .. cycloalkyl having I-92 carbon atoms, cycloalkenyl having 5-9 carbon atoms, . (Cx=Cg)-cycloalkyl—(Cy-Cq)-alkyl, (Cg-Cg)-cycloalkenyl=(Cy-C,)-alkyl, aryl, which is optionally partly - hydrogenated, having 6-12 carbon

! Be Ce i GU

Cet atoms. which can be substituted as described above for R, - (Cp lypdmaryl=(y ig) alkyl or (C,-

CyzY-Aatoyl-(C; ar Cio)-alkyl Lo which can hoth be substituted

Vike the abovementioned aryl, . mona or bicyclic heteroaryl, which is optiemally partly bryan. . . . having 85-7 or 8-10 ring atoms, of which 1 or 2 ring atoms are sul fur or axyaen atoms and/or 1 to 4 ring atoms are nitroaen atoms, which can be substituted like the abovementioned aryl or Co 15 . the optionally protected side chain } of a naturally coccourring a amino

CL er Jape . - acid KI-CH(NHL) COOH, LE ..

Ro and Ry are identical or different and ‘denote hydrogen. hr alkyl! having 1-6 carbon atom=a, Ve alkenyl having 2-6 carbon atoms,

Lo di=(C ~04)~alkylamina=(C;-Cy)-alkyl, : (€4=Cg)-alkanoy lony=(Cy~Ca) -alRyl,

CE wo. u . : C .

: bY 26364 } E (Cy-Cyl-alkoxycarbonyloxy—(Cy~Gg)- alkyl, (Cy-Cyx)-aroylony—(C -Cyh)-alkyl, (Ce~Cypl)-arylonycarbonylony-(Cy~Cq) = 3 alkyl, . aryl having 6-12 carbon atome, (Cq=Cyp)-aryl—(Cy-Cyh)-alkyl, (Cx-Cg)-cycloalkyl or ' (Cx~Cgl-cycloalkyl-(Cy-Cy)-alkyl and on rR and RY have the abovementioned meaning.

Particularly preferred compounds of the formula

I are those in which tl nis 1 or 2, 19 R denotes (Cy-Cgli-alkyl, (Co-Cp)-alkenyl, (Cx-Cgl-cycloalkyl, amino-(C,~C,y)~ alkyl, (Ca=Cq)-acylamino—(C,-C4)- alkyl, (C;=Cyy)-aroylamino=(C]=C4)<" - . alkyl, (€4-Cq)-alkexycarbonyismins (Cy —Cyal-alkyl, (C4=Cyp)=aryl-(Cy=Cyl- alkoxycarbonylamino~(Cy~Ca)-alkyl, (CeCyn)-aryl which can be monosubstituted, disubstituted or : - trisubstituted by (C,~Cq)-alkyl, (Cy-

Cg)-alkoxy, hydroxyl. halogen, nitro, : amino, (11, ~C4)-alkylamino, di-1Cy- 3 ' C4)-alkylamino and/or methylenediony , or 3-indolyl, in particular methyl, . ethyl, cyclohexyl, tert.- tose ar bony 1main=(C Ca) -alkyly ben oy Loc arbony Lanino=(Cy-Cq)-alkyl 10 . ar phéhy1 which can ~~ ‘be monosubstituted or disubstituted by ’ oo phenyl, (Cy-Cp)—alkyl, (Cy or Cp) aL alkoxy, hydroxyl, fluorine, chigrine, bromine amino. (C,~Cq)-alkylamino, 18 di-(0C,~Cy)—alkylamino,nitra and/or i . methylenedioxy or, in the canal bt or methoxy, trisubstituted, Ce - rl denotes hydrogen or (Cy-Cg)-alkyl which: can oi optionally be substituted by -amiho; . ‘ 20 Ea (Cy-Cg)—acylamine or ” benzoylamino, (G-g)-alkenyl, . (E5- :

Cg)-cycloalkyls (Cq-Cg)-cycloalkenyl, (CoC) -cyelnalyl=(F;-Cq)-alkyly C4" - 18 — SL * : i at

Cin)-aryl or partly hydrogenated aryl, which in each case can be substituted by (Cy-C,)-alkyl, (Cy or : Co)-alkoxy or halogen, (Cy—Cyop)-aryl- a (Cy—Chl)—alkyl or (C5;-Cyx)-aroyl=(C,~

Co), which can both be substituted in the aryl radical as defined in the oo foregoing a mono— or bicyclic heterocyclic radical having 8 to? or ol . 12 8 to 10 ring atoms, of which 1 or 2 ring atoms are sulfur or oxygen atoms -

LL and/or 1 to 4 ring atoms are nitrogen atoms, or a =ide chain of a naturally occurring, optionally protected da - 13 amino aid, but in particular hydrogen, (C;-Cy)-alkyl, (Cy or Cx)= alkenyl, the optionally protected ~ side chain of lysine, benzyl, 4- methoxybenzyl, 4-atho¥ybenzyl, - . ~ phenethyl, A4-aminobutyl or benzoylmethyl, oo

RZ and R> denote identical or different radicals, hydrogen, (C) Cg )~alkyl, a

¥ Nn

Tou . GL aE i (Cp-Cg)—alkenyl or (Cy-Cyp)—aryl=(Ey=

Cy) -alkyl, but in particular hydrogen, (C~Cq)—alkyl or benzyl and r* and RY have the abovementioned meaning. 3 Aryl, here as in the following. is preferably to be wnderstond as meaning optionally substituted phenyl. biphenylyl or naphtyl. the same applies to radicals derived from aryl wuch as aryloxy or arylthio. Aroyl is to be taken ) 1A as meaning. in particular. benzolyl. Aliphatic radicals can be straight-chain or branched.

A mono-— oF bicvelic heterocyclic radical having to 7 or 8 to 19 ring atoms, of which 1 ar 2 ring atoms are sulfur or oxygen atoms and/or of which { to 4 ring atoms are nitrogen atoms is 13 to ‘be taken Aas meaning, for example, thisnyl, } benzolblthienyl, furyl., pyranyl, benzotiryl, pyrrolyl, imidazolyl, pyrazolyly “pyridyl, oyrimidinyl, pyridazinyl. indazolyl, o isoindolyl. indolyl, purinyl, quinoiizinyl, imoquinolinyl, phthalazinyl. haphthyridinyl, quinoxalinyl. quinazolyl, cinnolinyl, —- 17 = i .

CI oo | nbd - : \ pterridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be partially or completely hydrogenated.

Naturally occurring A —amino acids are, for 3 example, described in Houben-Weyl, Methoden der

Organischen Chemie (Methods of Organic

Chemistry), Vol. XV/1 and XVvrs2. vo — If rl represents a side chain of a protected naturally occurring d-amino acid, such as, for example, protected Ser, Thr, Asp, Aan, Blu, 61n, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp,

His or Hyp, groups which are customary in peptide chemistry as protective groups are preferred (compare Houben-Weyl, Vol. XV/1i and

XV/72). In the case in which R! denotes the protected lysine side chain, the known amino ] . protective groups, but in particular 2, Boe ar - (Cy=Cy)-alkanoyl, are preferred. Possible | ti- " protective groups for tyrosine are preferably (Ci-Cypr—-alkyl, in particular methyl or ethyl. NB o : - : .

£0 ide : Lad rl mE dagen A EEL ie fi a a Bl ; go a Et A RES EAT . Eo 8 By i Cod Th BEWERT CER os ie Uo Cen } STEYR YS KR PAR Sy 7 SE

Si hg Leen ag SR Ca LI be x gol LAA - . Ti - Fue BOLE IT PIT i & [og ep . 2g . RRR Ys CARCI CRE ©:

BIL ky gL & Sa Sh LH RISE gE 0S ACHE yr UTR eg RATE URN oe

Lori Tar {lene a AAR OR

BoE ee JEEP te Ag Bir es HY SE sos of ER EA PI IL CHE sod de ; Bs, ERNE a : : Je + * . ' 447% FATE TE ROR.

FEE hop CELT LL RR Rd hes

HS EE Pst CRE } ; Rs RE Ce he . Lele SYR yy . ot a JOR i RNA . SAT RE Gf

Co Ra CE GET LE : Ci SN k z VIR . LL NC “ i . . SL ; A Lal EL f Pagticular ly preferred compounds are 2h; -_ TR A, . Cg i J CRE ; A SEO HEART . Be . cd w : 1A, her TEPER g-ethoxy-car tian) = t-phpny propyl )-B-alany it A ¥ : ite a Re . AR SEAR aE . ve abe . } CAA HALT RE . <r (1838.98) -2-azahicyc 10{3.3.@loctane~3~ ANE i tage hg . a No Sey VIG ed

Je . - \ angie Tasty . 0 LEY “, cakboxylic ar id (ramipril), 1-rniids- SOUERTIR ! A. . PIR # Ag . :

Sn 3 athbxyearbonyl = phenyl propyl )-G~alanyl =k 7% . Cae ws i. 1. het ti cr EY

E ad TENG Cen wnt SE b . . - “ aah CAT ae TER : ie (28, 31 Jaf) —ce babhydr el 1d lndale-2-carboxyg, HB Cp TEE ir CAEN A . SoA

Lt Oy Bete gs maa te. belek ANT LAE i CE ie

SU ple achat (trandotapril) and 2-{ Nida SAL sr Ce qa - : WET LIS SET Ee Rand od Na I CEE

Co athoxvear bony - Lephrmylpropyl)=8-alanyl l= 43. ’ La

Cow Se YE SE

B = Veer Ch 5" 7 Lo ETRY 2! i ERT Ln wl BR

Co . 1, ZX. a-tetrahvdr oi sogy ino hie Sm Gmc ar boAYL G cle ea

Pool “i Ep wr EE

SEEN CE , bao Ln ’ iQ acid (quinapril). Es BE ey : . Te CEE * am ok ~ CL pi 4 . 8 , SE . i Fg? vg ine . , i . . “ . rN ge! , Coy

Se Thé: preparaticn of the ACE inhibitors offi he Ce . \ RE ayy . ET on

LE CELA vod - - } RR Cres u Ey 8

Ln faotmula 1 Ls described in the patent HE

Lo, aE nek Cond i . ab vated L— . Lh : i Cen ; ] . Ce : AN : no appl feations ro patent mentioned on page Aa : i

SY ry ei ‘ : hE a SESE : ) Te {gE oe : . , ThA oo , to Suitable potansiuwn channet modulat ore. ii Are . £, 5 7 ST . x ha ed ‘ wo 13 cofigbunds of the formula 11 pat . Ca eee : : La Cen Ap - wot So : . Sera at Bl Ca til, ; rly CE TR Cooly

SEN ARE EE Fria ; LE rong ieee A Re eng Sek i . Lae “AST Co = } ~ EE abn FREES ipo * Cr ett ! by wl EES HERA Loe : 3 Sigh BL =o HE “5 5. “ } 5 [RE Rea DRG RE a oe Cran yk Tl GUE Re alg

Lo RX Sirs CR : SRR oi : Arle

SRT ey One ! - . SE 5a) pp : Gan Se "

CL HR TERE cle HE don, Ce RARE : fe get es id

Wt a JAE cari Lad : Le, ob hoo fee Rae LE

Vo : 2 Lose Rss ind { ood lh ERT CRE : Coe : . Ce LT ed Cd . . Cl CAE

So ot Re

Ls Le Sia =

Boo pe ERIN 7 oon : id ds i : A . ES ds n ied ii * ce oof vo

Foo SB Lg . }

Ea - ly a Lo ile ws BY a Sn

Ua INR ror a CL rad

Lei fy CE, BAD Lge ond Fi oo CE & Co Ha - RA NOrAD o. i Co Son

SIE ak 3: ve Te = 5 Ey SETA: ; RFI ’ {aE : WET

Po Le CE Coe Td * \ ar AER ol a n wl RN

Cod A AER Cond!

Bap REAR SCIN EE A

— © _ — ee ———— ee ——— EL ——————————— . x : . i a ( =e on : sos he a, Dg

BYE, ~ : 73% 3G (11) . in which

Co rR represents CN, NOs. 50,,~(Cy~Cg) alkyl or 80,~Ar» where n is 1 or 2. Ar represents an aromatic Jor 9 heteroaromatic aystem which is unsubstituted ar substituted by 1 to - % identical or different radicals from the series comprising (ty -Cp)- . alkyl, (Cy -Cp)-alkoxy, halogen, tm 10 trifluoromethyl, CN, NOo co-(Cy Cp) - alkyl or 80, (Cy ~Cp) alkyl and Pp : . . | ’ represents 1 or 2.

L rR? represents hydrogen, hydroxyl, (Cy—Cp)- alkoxy. (C,-Cp)-alkyl, halogen OF 1% nr1OrYL, where cl® and RY are jdentical or different and represent hydrogen , (C,-Cp)-alkyl or (Cy4-Cp)~ : Co alkylcarbonyl, wherp the ; abovementioned meanings of RE and TR’ ’

Se can also be interchanged el r8 and Rr? are identical or aifterent and represent alkyl having 1-4 carbon atoms, Ra }

CY oL i oo on = " of

X represents a (CH,) chain which im - unsubstituted or substituted by at least 1 and at most 2m—1 (Cy=Cp)= alkyl groups, and can be interrupted a by a heteroatom Y with the meaning of 0, NR? or 8 and RZ denotes H or : (Cy-Cy)-alkyl and m represents 2, 3 or 14, where the configuration of Cs and C, is always opposite, ro i 186 an aromatic system Ar is preferably understood as meaning phenyl, naphtyl or biphenyl, a 3 or b-membered heteroaromatic system Ar = is preferably a radical of a 3 or b&-membered 0, N and/or 8 heterocyclic ring, in particular ’ furyl, thienyl, isothiarolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, . pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or thiazinyl. wr eet che - / - . } i» Lo

Halogen is understood as meaning F, C1, Br or

I, preferably F and Cl, .

a ———— EEE nbd 26364

The carbon atoms 3 and 4 of the 3, 4-dihydro- 2H-benzolbl-pyran system (subsequently also designated as "chroman system”) of the formula 11 are asymmetrically substituted. The 3 invention relates only to those compounds which : have opposite configurations at these centers.

This means that the lactam ring an a substitutent on C-4 and the OH group on C-3 are always orientated "trana" to one another. The } 10 abovementioned definition of X means that in addition the lactam ring contains at least one, ' ' but at most mm (m having the definition mentioned at the beginning), chiral carbon atoms. The invention thus relates both to compounds having centers both with the R= and the * S-configuration. The same applies inthe case in which RY, rR’, R? and R? contain centers of . asymmetry or produce a center of symmetry with themselves as substituents. The. compounds . 2a can.’ then exist as optical isomers,’ as o . diastereomers, as racemates or as a mixtire thereat. : . _ no BN a . [ER a i ol

Preferred compounds are those of the formula 1 in which 7 '

R®, R77. R® and RY have the abovementioned : meanings and X represents a (CH,) , chain which ‘ 3 is unsubstituted or substituted by a (Cy ~Cy)- alkyl group, and can be interrupted by a heteroatom Y which represents 0, 8 or NRIZ with r12 having the meaning of hydrogen or (Cop=Cyd)- - alkyl, and where m represents 2, 3 or 4. 18 Further preferred compounds of the formula II are those in which

R® to R” have the abovementioned meanings and. X represents a (CHA) chain which is . unsubstituted or substituted by a (Cy-Cxr-alkyl group where m represents 3 or 4, }

Very particularly preferred compounds herd: are - those of the formula II in which rR to R? have the abovementioned meanings and X represents a (CH) chain, where m represents X or 4, which

. RE [RAN vf

AW? is substituted by mn (Cy~Un)-alkyl group on the carbon atom which is adjacent to the nitrogen atom of the lactam ring.

Farticularly preferred compounds are those in a which Ro to RY have the ahovementioned meanings and X represents a (CH) chain having m = 3 or 4 whirh is unsubstituted or substituted by a ‘ (Cy4-Co)-alkyl group on the carbon atom which is el adjacent to the nitrogen atom of the lactam ring, in particular in such a way that the configuration of this carbon atom is the same as that of the A4-carbon atom of the ahr system, : . ‘ Very particularly preierred compounds are aise those of the formula [1 in which

RO represents ON or 80.,-UHy and r7 -represents - hydrogen, rS and rR? are identical or different and tepresent alkyl having 1 or 2 carbon atoms,

X represents a (CHL) chain having m = 3X or 4 which is unsubstituted or substituted by a (€;- - 2G | : : BAD ORIGINAL 9 rt

Cy)-alkyl group on the carbon atom which in i adjacent to the nitrogen atom of the lactam ring, in particular in such a way that the configuration of this carbon atom is the same 3 as that of the 4-carbon atom in the chroman system; similarly preferred compounds are - those compounds I1 in which RO represents 805-Ar, with

Ar having the meaning of phenyl which is unsubstituted or substituted by 1 to © 3 : substituents as mentioned above, : rR’ represents hydrogen or OCH. } RS and rR? are identical or different and represent (Cy-Un)-alkyl, A 19 X represents a (CHy), chain having m = x or 4 which is unsubstituted or substituted by a" (Cy-

Cpl-alkyl group on the carbon atom which ins adjacent to the nitrogen atom of the “lactam ring, in particular in such a way~ Ena the - configuration of this carbon atom is the same - as that of the 4-carbon atom in the chroman system. ° a

—_—————— ee qm 26364

Preferred compounds are also those in which RrR® to R7 have the abovementioned meanings and X represents a (CHa) 0 chain having M= 3X or 4 which is unsubstituted or substituted by a (Cy a Col—alkyl group on the carbon atom which is adjacent to the nitrogen atom of the lactam ring, in particular in such a way that the configuration of this carbon atom i= opposite to that of the 4-carbon atom of the chioman i io system. ~

Very particularly preferred compounds 11 are . also those in which h rR represents CN or 80,-CHx and R7 reprasents hydrogen, RE and rR? are identical or different 13 and represent alkyl having { or 2 carbon atoms,

X represents a (CHx) 0 chain having m = 3 or 4 which is unsubstituted or substituted by a. (Cy-

Col-alkyl group on the carbon atom_ which iw ] adjacent to the nitrogen atom of the lactam T ring, in particular in such a way that’ the } configuration of this carbon atom is opposite to that of the 4-carbon atom in the chioman

. A

We He? ee SR systems : similarly preferred compounds are those compounds II in which : ro represents S0,-Ar with Ar having the meaning a of phenyl which is unsubstituted or substituted by 1 to % substituents as mentioned above, rR’ representa hydrogen or QOCHs, :

R® and R7? are identical or different and represent (Cy-Co)-alkyl, . 10 X .represetns a (CH,) chain having m = 3 or 4 which is unsubstituted or substituted by la (C,-

Co)=alkyl group on the carbon atom which is adjacent tn the nitrogen atom of the lactam ring, in particular in such a way that | the 13 configuration of this carbon atom is opposite to that of the a-carbon atom in the ¢hroman aystem. zl

The following combinations are -— of- very - particular significances LR o ia ramipril + (£)-6-cyano-%,4-dihydro, ‘2,2 : dimethyl -trans—4—(2-oxo-1- Cr i - 27 - | - ‘ a ee —————— ee ——————————— mm a | Ug | J

Ag Ao” fo 4 .

Cyrrolidinyl)-2H-benzolblpyran-3<61 : (chromakalim), ramipril + b~cyano-3-hydrony—-2,2-dimethyl-4-(3- methyl -2- oro-1-pyrrolidinyl )ad,4- 3 dihydro~2H-benzolbl-pyran, - . ramipril + 2,2-dimethy 1 -I—hydrony=—6- - . phenylsul fonyl-4-(2~- ané=1- . i pyrrolidinyl)-3,4-dihydro—2H- rk i benzolbl-pyran, Lo

C- 1a trandolapril + chromakalim, Cl : trandolapril + 6-cyano-3—hydroxy=2,2- dimethyl-4- oo (8—= methyl-2-oxo-1-pyrrolidinyi)- § 3,4-dihydro-2H-benzolblpyran, - trandolapril + 2, 2-0 ime thy1-3-hydroky—6- 19 i. phenylsul fonyl-4-(2-oxo-1- -

Lo pyrrolidinyl)-3,4~dihydro-2H- Fr rk benzolblpyran, quinapril + chromakalim, Exe quinapril + b-cyana-3-hydroxy-2, 2-dimethyl<4- . es (S-methy1-2-oxo-1-pyrrol Ldinyl £3 4- o or dihydro-2H-benzolbl-pyran, oe auinapril + 2,2-dimethy1-3-hydrony-6- in Sheny aul fony 1-4-(2-ono-1-pyrrolidinyl) 28 - i ‘

bs | i» ih ~0” = - 3, 4-d1ihydro-2H-benzo-[blpyran, ramipril + (18,4) ~b-Cyano~3 ,4-dihydro-2,2- dimethyl-d-(Z~ oso-l-pyrrolidinyl)-

ZH-benzolblpyran-3—-ol,

A trandolapril + (38, AR) ~6-Cyano-3 , 4-d Lhydro=2, 2 dimethyl -4-(2-oxo-l-pyrrolidinyl)- 2H~benzolblpyran-3-ol, j quinapril + (38,4R)-&-cyano-3,4-dihydro~2,2- dime Lhy1=4-( 2-0no-1-pyrrolidiny})- 2H~benzolblpyran-3-ol, ramipril + (38,8R)~6-phenylsul fony 1-3, 4 di hvero-2, 2-dime thy 1~4~(2—oxo-1~ pyrrolidinyl)-2H-benzolbl-pyran=3—- ol, 13 trandolapril + (35,4R)~6-phenylsul fonyl-3,4-- dibydra~g,2- dimethyl-4- (2~ono-1- pyrtolidinyl)-H-benzolb pyr an-3-01 , quinapril + (AS .4R) -6-phenylsul fony1=3,4- 1hydro-2 2d ime thy 1-4 (2-oxo~1<" - pyrrolidinyl)-2H-benzol bl=pyran=3sol - and in each case the physiologically tolerable salts of the individual components mentioned, if these can he formed. - - 29 - | oe :

—— ee ————— ee

Ln :

Er phy . ¢ Vv 26364

Potassium channel modulators can be prepared by the process described in J. Med. Chem, 29 (19846) 2194-2201, EP-A 76,073, EP-A 107,423,

EP-A 120,427 and EF-A 120,428. oo oo 3 The invention also relates to very general products which containg , - a) an ACE inhibitor of the formula I or itm physicloaically tolerable salt and : b) a potassium channel modulator of the i © formula 11 or ite physiologically tolerable salt ' CL as a combination preparation for simultaneous, separate or sequential administration in. the treatment of high blood pressure. Lo

Table 1 shows the mean arterial blood pressure, - measured on the conscious spontaneously " hypertonic rat analogously to the mathod described in Arzneimittelforschung 34 (11); Pp. 1419 (1984). so ~- 2A - | *

ag . yore f ne

Table 1:

Mean arterial blood pressure in conscious spontaneously hypertonic rata after oral administration of a Broup 1: Placebo

Group 2: @.1 mg/kg of chromakalim 1

Group I1 @.3 mg/kg of chromakalim

Group 4: 1.0 mg/kg of chromakalim . Group 5: @.1 mg/kg of chromakalim + 1.0 mg/kg : . : ie of ramipril ‘

Group 6: 0.3 mg/kg of chromakalim + 1.0 mg/kg of ramipril

Co mii

ES Coe ” .. eT i oe . - 3X1 -

$4 i i ! [9 3 9 3 Vv” ow! 4 BE : { mean arterial pressure [mmHg] : . | t SEM (n = 6) : ot + Co Group : Co min| ; 1 2 | 3 4 5 6 . 0 | 164+ 8 136¢ 8 | 153+ 8 162+ 6 166% 6 154+ 3

Co 2 1158+ 4 167:10 | 139216 152+ 9 158+ 6 155: 7 3 ! 158+ 4 162+ ¢ 134:+16 124+10 151+ 5 143+ 8 ; 4 !

Table 1 continuation: a ! | mean arterial pressure [mmHg] , i - } - | | + SEM (n = 6) t | Group } 1 i i i : { ! [min]: 1 2 3 | 4 5 6 : 5S | 161: 8 165: 8 1ief2 107: 7 137: 4 120213 : 1632 8 151211 89s! 9 84: 5 116: 6 91+ 4 TL 164+ 8 141212 89s! 8 B4s 4 103: 6 85+ 3 - 20 | 161: 8 139213 84s) 7 79: 4 96: 7 82: 3 ol Chen an2s 163% 8 138213, Nf. 88217... 78: 3.0 942 9 79s 3 ill . cts eo] wh CTE i, ol a" TH ell Bites pte wo ADRESSE dle Sl

Te Cn nln r 30 "1604 8 142315 | 86: 5 4 Bi 3 194 8 A rx 33 3k RARE RAE i : oy aE Gi ps Sei:'s to 139:aa fri snud, 82t!3'l{ 106 51h ges CT r

DR Soop HEE he Seelive coon hd Yun om yo ey URGE 0 oy oo LoD SPREE AL BL i SRY Hi 40. shal 1139814 4 gol ahr 82k alt 106 Is 7.i1l ase 20% HIN Hs J 8 Shh 5 iN Cn BE eT TT ee Woot Ra i , Trg CRTRaER Se, fea SHV RE h eb RE 0 ‘ Lo ae lds in 1592471 142243 i Lys 924 ath 024 4. 10945 4100872 3" iM AL: . ike Hh Er gi 2 v I. He fT ; ' bE A co ‘ LAREN I [i 9 ras! fred Lye a Pio : Ch dg 50 [1582 oO leze11 |) 92:14 1) 84% 3 abd 191 4 <i ps £5 NU “L a" : . Pod bars et lu rT ee ok RIES if {hn eas) RUE BEAR HUE AEE A

Fi i Pils 4 " 158: 9 143:11 8 982 5! ‘ust! 3 110015 53: 4a TH pati gi ibe Bi : ; 2 i free i ie2s 8 121143211 * [ihc 99s adhere a, st islifieee {JE A gh © ih Ji 4 A

Son enh Moyo Ch CO pa ca abi eye CHEER hg Wp HOR a] Ce ;

CTs oases. taxa, rome 7 fans 4 120 gf Hoes 8 ie i me ye Pl

To i Ly '90 J 11612 51 142#11 1 111: ali i 904 ae st itd ! Hi i bs a 1 . 1H gre ral es To rol BE a 4 fq rth Wg ar ETRE Re eT fain : CH Pos T 157s 6 139:12° 113: 2p ros} s HPiiabs i 524" 31M i Ha Cp oo nea 120 Jas3s er 17138812 hiatos &yliiost alls 114, 8 i {91s > Int i cA aif

TRL | : aay C3000 peg TRY fol seen THER ft Rey cls 1135 le 148s 7.140812 5 1095( 6.3. 988 5 |. dls o 918-3 up = .. cre TS IER Af EE Phe TERS at RT eS Rn a fil

CNL EE TIso—isae a 141212 | 1112/5 100s 3, 1108 T1952 2 his i bon oo vit a ad Cli 1es asses 13812 | 'ad3s| 6% 103k 710 nad shi sh sity Ap ; BE Hn J ‘ : A wll , : Cf td Lt te igi kEg Lo. fly Np» . al Teip dab a

Co vo 180 41-1528 6 - 161212 © {111208] 81): 10121314), 10918 Lup ierait piers Bb I HS g ; : : . . fl oh a - Cal a I ho Chad J : id iL Side pag Teli wl - Cob | CHEE nn ed pn fan fi) Ji eh THEA Ly 1 shel con Ee : sro Fubar RR ITT i Co Cb ela A eee JE ST whe . Co The combinations are prepared by, either: intensively = i Ty lil

Lod Cy a Sn losin lpr Era CMe on he]

SET y -mixing the individual components as powder or by dissolv- coi b RAE

EN J vo Tre hE dial Blagg 0 TE : 10 ing the individual dompo ents in a suitable solvent: buch " ne wb . ' P . EE ! ] Ce ! gdh detalii b B ee Saha fd to as, for example, a Lowe . alcohol, Bnd then removing! the ait . i i Vo . . ; VE va (BR! Col aap i . } uk . i. CRA Sv x o vo aS bo oF solvent. ~~ 4 | ~~] a TE ho UE

Ce Coe ee Ei a maha ibe a ca Ak

Lo Co . y A a i : Doo, Bbsgid, Hb i di 41. gal l ] ‘ Pyle Cool en eat Yar dpemEE YY Sb ! CERT fd bl » ~ As) mentioned above, the combinations according’ tal the Cl roe fon hy erp ee cen ined sobs : invention can be used in pharmaceuticals, partichlarly Colas ed il . Copy gh ro ' } } . . . CE So Cb ena! PH / 15 for the treatment | of {high blood | pressure; ‘cardiac , Ap : ! ! . \ . yell, Ch \ > Cen coy gel x !. Co : Cobre Ll Credle vo . co i ji - . ] . ; | | - : eg: oo Cy lb | . 5 : f nA tent : Corer CE ON 4 of lo Co Co bho ee

Ce Co v - Lo Seg Cy he

Chee | | : | LE boon mim rod et mn Ea reer a . “i SE Ce ee . pe a . map yee a » - : oe Tr Co ote

Log edn | BE | ns ho ORIGINA Lh

Cp 1 Po NS : b BAD © pS

PoE he : CTE Ce ho EER CA ! { . ! RENEE EE - ' ro i . pel Top Lp Toa

. Lo

Be a : aa yey. CR i od

Li “A inauf ficiency and coronary heart disease i

The combinations according to the thvention can be administered orally or parenterally ih an appropriate pharmaceutical preparation. For a 3 torm for oral administration, the active ; compounds are mixed with the additives customary therefor such as excipients, . stabilizers or inert diluents and are brought by customary methods into suitable forme for administration, much an tablets, coated ' : tablets, hard gelatin capsules, aqueous, alcohol ic or oily suspensions or aquesus, alcohol ic or oily solutions. Bum arabic, magnesium carbonate, potassium phosphate, 13 lactose, glucose or starch, in particular maize . ’ starch, can for example, be used as trent

Ju Le carriers. In this connection, the preparation ) can result both as dry or moist granules, - } Suitable olly exipients or solvents are, for te example. vegetable and animal oils, such © i sunflower oil or cod liver oil. Ge - 37 - : EL . aro cin.)

BAD ORIGINAL ~)-

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts, if desired together with the substances customary for this such. as a solubilizers, emulsifiers or other auxiliaries, are brought into solution, suspension or emulsion. Possible solvents for the active combinations and the corresponding physiologically tolerable salts are, ' for example: water, physiological saline solutions, or alcohols, for example ethanol, propanediol , or glycerol and in addition also sugar : solutions such as glucose or mannitol solutions or amixture of the different solventsmentisned. 13 Possible salts of the compounds of the formula

I and 11 are, depending on the acidic or basic nature of these comnpounds, alkall ar alkaline earth metal salts or smsalte with physiologically tolerable amines or salts with tnorganic Tor i .. organic acids such as, for example, HC1, er,

H,80,, maleic acid, fumaric acid, tartaric. acid or citric acid. A { - 34 - 5 ) i . § So Co

He NW % bY¥ Lo . The following example serves to illustrate the present inventinn without it being intended to limit it thereto: + : ,

Example 1 a Freparation of an aral combination preparation from ramipril and chromakalim 1 : 1@0@ tablets which contain 2 mq of ramipril and

D.3 mg of chromakalim are prepared as follows: : ramipril 2 0 . . ta chromakalim n.3 g “7. maize starch 1am Q oT hE f gelatin 7.% g ou microcrystalline celiulase 2.9 a a i magnesium stearate 2.9 ag ..

So wri

The twn active compounds are mixed with. an Tr aqueous gelatin solution. The mixture ig dried i and ground tn form aranules. Microcrystalline cellulose and magnesium stearate are mixed - wih $y, . a Ea .

Cn } 2, J

Apres thr CEE - RE uf od

TET WT a : i yl . ig . UE ME YS 1 . > ‘ BN : ; i : with the granules. The granulea prepared in this way are pressed to give 1,000 tablets, } where each tablet contains 2 mg of ramipril and 2.3 mg of chromakalim. nel ; a ' .

A * ¢

Lal Ey > AY mee on A .. a RUAN

A fn - ’ EE :

EES

: aT . . - x6 - CT

Claims (1)

1. . elit Fr 4p SORE re . Sy SE oi JEON Hb TU ad — Co eo Coy 20364 rr Patent Claims: Te

   1. A pharmaceutical preparation containing an : effective amount of “ a) an ACE inhibitor of the formula I ® * * . , z00c - cm - ! - ¢ - en - NR - cH - (cay) ~ (1) : * ®° o x coor? TE Lo 3 in .which ng n is 1 or 2, CL ‘ . BH ] R denotes hydrogen, edn COE : alkyl having 1-8 carbon atoms, Ca : alkenyl having 2-4 carbon atoms, Cs i cycloalkyl having 3-9 carbon atoms, aryl having 6-12 carbon atoms, = . Co which can be monosubstituted, : me - oo disubstituted or trisubstituted .. by (Cy-Cq)-alkyl, (Cy~Cq)- 19 alkoxy, hydronyl, halogen, nitro, amino, aminomethyl, Se, - - 37 - i . . " J IR ee . Se nd Th - 26364 Cyr—-alkylaminag, di-(Gy=Cy)- alkylamino, (Cy=Ca)- alkanoylamino, methylenedioxy, . cyano and/or sul famoyl, . 3 alkoxy having 1-4 carbon atoms, oo arylousy having 6-12 carbon atoms, ’ which can be substituted as - deaecribed above for aryl, ] } mono- or hicyclic heteroaryloxy having io 5-7 ob 8-10 ring atoms, of which 1 or 2 ’ ring atoms are sulfur or oxygen atoms . and/or t to 4 ring atoms are nitrogen, which can be substituted as described above far aryl, amino (€ ~Cy)~alkyl, (€)-Ca)-alkanoylamino=(C,~Ca)=alkyl, (Cy-Cyx)-aroylamino- (0 —Cq)-alkyl, = = (64-04) =a koxyearbony 1 anino=(Cq-Ca)= _ } BE alkyl, Cm Tr i (Co=Cp)—aryl—(C ~C4)- CE alkoxycarhonylamino-(C -C4)-alkyl, i (C=C) aryl=(C~Chr-alkylamino— (Cy ~~

   Loe ea Ee Co 26364 Chl-alkyl, . . (Cy~Cg)-alkylamino=(C,~C4)-alkyl, - : / © di=(€;-C4)-alkylamino-(C,-C4)-alkyl, guanidino-(C ~Ch)-alkyl, ] imidazolyl, indolyl, \ (Cy-Cyxl-alkylthio, (Cy-Cq)-alkylthio-(C,~C4)-alkyl, Ce a (Ca=Cyp)-arylthio-(Ci~Ca)-alkyl, ‘ cele which can be substituted fe . : - 10 aryl molety as described, ibove - for aryl, , el . . ’ (€4=Cyp)-aryl-(Cy-Chl)-alkylthio, which can be substituted in the aryl moiety as described. above 13 for aryl, : carboxyl—(Cy-Cyh)-alkyl, oo carboxyl, carbamoyl, Ra carbamoyl-(C,-Cy)-alkyl, we = (€y-C4)-alkonycarbonyl-(CyCq) ~alkyl ji: Smid lde p

   20 . (Cy—Cyp)-arylony—(Cy-Cyh)~alkyl, aT . which can be substituted inthe aryl moiety as described above for aryl or a - 39 - wl .

   } . Ly yrtt 26364 , on (€Cg=Cyn)-aryl—(Cy-Cyh)-alkoxy, » - which can he substituted in the arvl moietv as described’ above for aryl, a5 rl denotes hydrogen, . alkyl having 1-4 carbon atoms, CL alkenvl havina 2-4 carbon atoms, p alkynyl having 2-& carbon atome, ! cycloalkyl having 3-9 carbon atoms, . - 10 cycloalkenyl having 3-9 carbon atoms, ’ . (Co-Colryclnalkyl-(C,~-Cyh)-alkyl, (Pg-Cg)-cycloalkenyl=(Cy-Ch)-alkyl, aryl, which is optionally partly hvdrogenated having 6-12 carbon atoms, which can be substituted as described . above for Rk, ne CCC) mary l= (C—O) ~alkyl or } - (Ca-Cy=)-aroyl-(Cy or Cs)-alkyl . - - which can both be substituted .

   20 . like the above-mentioned aryl, oo mono~ or bicyclic heteroaryl, which “iw optionally partly hydrogentated, having t 8-7 or 8-10 ring atoms, of which 1 oF 2 ] ) . a - BAD OR, 9 Y . hp?

   &e J Lo wr pd EO SL SO : cy - a ring atoms, are sul fur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen oo . atoms. : which can be substituted like 8 the above-metnioned aryl or - - the optionally protected eide chain ot a ~~ naturally occurring -amino acid RCH) - COOH, CO Co r2 and ®> are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, Ls 43-0, -Cq)-alkylanine- (€4-C4)= — alkyl, ) oY 13 (Gy ~Cg)-alkanay loxy=(Cy-Cg)= oo alkyl, Eh *. (6,-C 1 -alkonycarbony1oxy=(C1= oo Cq)-alkyly . (6G 3) -aroylony~(C3-Ca)-alkyls (6,=C 3) -ary 1onycarbony 1oxy=(Ey~ Ca)-alkyl, aryl having 6-12 carbon atoms,

   "g CN : : Wh i } Te Py - : : TRE Yb TE wig — | wr oo 2 EE i on | i ~ ¢ Rl i (Cgu=Cyp)=aryl-(Cy~C,p)-alkyly (Cx-Cg)-cycloalkyl or Ea (Cx~Cg)-cycloalkyl-(C,-C4)-alkyl and ‘ a rR? and RY together with the atoms carrying them form a heterocyclic bi- or tricyclic ring system having 5% to 15 carbon ‘atoms, or its physiologically tolerable malt Cn ” and C - 12 b) a potassium channel modulator of the formula II: or . x Ls N (11) r® 6 5 ve

   : ~. H vo . = | yy : 1 2 | RS “L 7 2 ~ } yt - rR’ 8 x? LH — da . in which Lo R® represent CN, NOg, 80,-C,-C,) on ~alkyl or 80.,-Ar, where n is 1 or 2, Ar 13 represents an aromatic system which is unsubstituted or substituted by 1 to 3 . & “ —- fA — : i :

   yi ( yl )t / 26364 identical or di fierent radicala from the eer ieee coupe ising of | bo) amt, (CC) . . EN albeovery halogen, byt finoromethyd, rh , ~ Ce Al ar a (or 1

   MOL. FO Ea athe oo “n f { Ly = atk and porepresents too 2, i’ represents beodroaoen, hydrosyl (iy (rd alkoxy, ( 1 SY ally by brer boreyeay or tie Pred ! where anel I are dent teal or ti f ferent and repracerdt rede aaerns, (1 tly) alkyl ar (Cy -- 1@ Co)-alkylearhon yl. where the abovementioned Le meanings: of fo arveh BB "ean ats be inter hanoed, a 7 CL - i. 4 . i KR and F di ident eal ov different and represent albyT bana bob a bon atoms, X pep people A CCH YL hia which 1 unsabstitoted op =vhatitaled hy at least 1 and at most wel (0 Co gealky Loar onps, and can be interrapted bie oa hederocatas with the meaning 1 12 nf ©, Hr” or 8 and R denotes H or (Cc ,-¢,)- alkyl and m represents 2, 3 or 4, where the . configuration of C, and Ca is always opposite. 1 Bb Ny INAL ld AD ORIG , mnt em

   Sin > ; Hy a Cyr ! or tts physiologically tolerable salt FE

   2. The preparation as claimed in claim 12 4n which in the ACE inhibitor of the formula I n . is 1 or 2, . \ - 8 R denotes (C,;~C,)-alkyl, (Cp-Cg)-alkenyl, (Cx~ Co)~cycloalkyl, amino-(Cy~C4)-alkyl, (Cp-Eg)- . acylamino(Cy-Cyr-alkyl, (€,-Cy 5) -aroylamino- (Cy-Cy)-alkyl, C,-C4)-alkoxycarbonylamino=(Cj~ . . Cal—alkyl, (Cgu=Cyn)—aryl which Can be . 10 monosubstituted, disubstituted © or trisubstituted hy (C -Chpl)-alkyl, no (Cy -Cq) alkoxy, hydroxyl, halogen, hE : nitro, amino, (Cy~Cyr-alkylamino, di~ ry (C4~C4)-alkylamino and/or. |e . . oo 18 methylenedioxy, or X-indolyl, in i - particular methyl, ethyl, cyclohexyl, = SF tert. -butoxycarbony lamina (C;-Cq)-alkyl, el : .. benzoylony-carhonylamino—(Cy~Cy)-alkyl . Zo or phenyl which can be monosubstituted 7: or disubstituted by phenyl, (Cy—Co)— . - 44 ~ | oo .

   , J { ' 2 oO € &boo4 alkyl, (0 or Ua) oA hoy hydroy lt, fluorine, chlorine, hr amine, amino, (Cy- Cy) —~alkylamino, di (1 Tg) ~aky lamina, nitra and/or methyl enod io OF, in the a case of methoty, Ur jenhatituted., 2 t denotes hydrogen oat Ly Lig Yen lbkyl which oan nptinnally he aubstituted by AMiie, (Cy “gy acy amino avr henzoy lanino, (Le ta) alkenyl, LQ ( Ug = Ge) mye Toallk yl, (Ce ~Cq) - eye loalkenyl, ( Ca Cy y- cycloalkyl Uy Fa allyl, (Cp Cogn? mar I or par Bly hy nagenated aryl. whitoh in pach caze can be aubstituted by (fy “Ly Y-alkyl, (Ly ow Lira) alkoxy or halogen, (gt 1 A) Ary 1 “Ca y-alliyl oy ce (eC 7 ga) array 10 17°C Vvoalkyl, which can hoth be substituted in 2A the aryl radical as defined in thie fovreqoint, a mee or hicye tic heterocyc lie radical having 5 to 7 or 8 tn 1 ring An Ng one PH

   PE ————— I ————— Ae } : Soba, ¢ co - wo pe Cog : . Go . o 6504 atoms, of which 1 or 2 ring atoms are sulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, or a side cthain 3 of a naturally occurring, . optionally protec ted ~amino acid, but in particular hydrogen, (Cy-Cx)-alkyl, (Go or Cx)-alkenyl, the optionally i IN 10 protected side chain of lysine, benzyl, 4-methonybenzyl, 4- ethoxybenzyl, phenethyl) 4 } aminobutyl or benzoylmethyl, RZ and R> denote identical or different radicals hydrogen, (Cy~Cp)- alkyl, (CoC )-alkenyl ar (C.- Cyp)-aryl-(Cy;-Cyhr-alkyl, but in particular hydrogen, (Cy~Cg)— oo alkyl or benzyl and - SS v rR? and RY have the meaning indicated in claim 1 or 2 -

   : . . - 46 - a.

   H 1 : 7-0 .)

   x. T hes peeparal ion as cai meet in claim 1 containing PF aes hevoy ear boy 1-7 phenylpropyl)-G-al ANY 1 1-18 78 [58 ) —2. azabicyo lol >, To lew bane Recarbhouy lie acid Oy i its physiologically tolerable salt.

   4. The reparation aa cl at med in claim 1 containing UTM 1-5 ethauycar horny 1-3 phenylpropyly=8-alanyl | -( 2a EARL Tas) - octahydrol 1H1indole- Aerarhosylic acid or ite 1 physiolonically tolerable salt .

   3. The preparation as claimed in rmlaim 1 containing APE Seething ye my bony 1-3. phenylpropyl)-S-alanv] 1-1, 2 ead tetrabydroi Sor ine pee eRe ge ay Dovey dae Aci or its physinlonically tolerable salt, »

   LH. The preparation as claimed in claim 1 containing a potassium channel sodulsa tor ofthe formula JT in which X represents a (erty chain which is 2A unsubetituted or snhetitoted hy a ( 1” —— a4. BAD ORIG = 2 ; bores

   . . go 4

   265. NEE - ' Co)-alkyl group, and can be interrupted by a heteroatom Y which represents 0. 5 or Nr12 with r12 having the meaning of hydrogen or (Ca—Chr—-alkyl, and where m represents’ 2, 3 I or 4, ot its physiologically tolerable } salt,

   7. The preparation as claimed in claim 1 containing a potassium channel modulator. of “_ the formula II in which X represents a (CH) chain which 1s unsubstituted or . . ) substituted by a (C;-Csy)-alkyl group where m represents I or 4, or its physiologically tolerable salt. . 8. The preparation as claimed in claim 1 18 containing a potassium channel modulator of the formula II in which X represents a nL (CH), chain, where m represents 3X or a, which is substituted by a (C;~Cp) -alkyl .. group on the carbon atom which is adjacent to the nitrogen atom of the lactam ring; or its physiologically tolerable salt. se - 48 - a . Co

   YL / 26364

   9. The preparal ion ae claimed in claim 1 containing a potassioam channel modatator of the formula 1 in which X represents a (CHL) chiatry bavineg mo = Lor 4 which ie HB uwnsnbatitaded or substituted by a (C4-Cn) - athyl groop on the carbon atom uhich is adiacent to the nitrogen atom of the lactam tring, in particn)ar an soho a way Thal, the configuralb ion of this carbon atom is t he ' [AME AS that of the 4 car bon atom of the chroman aye bem oy its physiological ly tolerable salt.

   10. The wmeparation as claimed in olaim 9, containing a potazsiam channel modoalataor of 1% the formela 11 0 uhich Fe represents G0L-Ar with Ar having the meaning of phenyl which . is unsubstituted or substituted by 1 to = substitutents as mentioned in claim 8, ®7 represents hydrogen or UH, 78 and KY are identical ar different and represent (Cy Ur) -alkyl, X represents a (CHL) oo chain having m = IX or “ Ye CN BAD ORIGINAL 9

   . IN Avr 26306 J Gx { : 4 which is unsubstituted or substituted by a / (C4-Cy)-alkyl group on the carbon atom which ia adjacent to the nitrogen atom of the i lactam ring, in particular in such a way that the configuration of this carbon atom : ) ie the same as that of the 4-carbon atom in ‘ the chroman system, or its physiologically tolerable salt. . oo 11. The preparation as claimed in claim 10, . 10 containing a potassium channel modulator of the formula II in which RO represents CN or 80,-CH and R’ represents hydrogen, RE and R? are identical oo or different and represent alkyl having 1 or 2 carbon atoms, . 18 X represents a (CH,). chain having m = 3 or 4 which is unsubstituted or subztituted by a (Cy4-Cop)- ~ alkyl group on the carbon atom which is adjacent to Co the nitrogen atom of the lactam- ring; -4n . \ particular Sh in such a way that the configuration of this carbon i atom is opposite to that of the 4-carbon dtom in { the chroman system, or ite physiologically ; : {

   { . . i . i

   Co . "

   : . - 9a - So ! . ! i tolerable salt.

   12. The preparation as claimed in claim ft, ir which in the ACE inhibitor of the formula I Rr anid F together with the adams carrying them form a 3 ving svebtom aolecled from The group consiating of tetrahydrol=soguanonl ines decahydrnicsoquinol ines octabydroindoles cotahvdrocyololpental bhlpyrroles 2 ~ > araspir oa-L AsO bdecane Jeazaspirol 4.4 Inonaneg . spiral (hicyclo-[2.7.Viheptane)-2, 53 pyr rol idinel 1 apirofl (hicyclnl 2.2.2) -aoctane) 2% ~pyrrolidinels 2 . a 54 azatricvelntd. 3.00107 I-decaney decahyrlvocyo loheptal bh lpyy roles ac tahydroisoindoles oc tahydiracyclopental oc lpyrroles deh la4,5, 7a hesahydeoindo es deacabhvicye lol A010 hexane 1% hexahydrocyclopental bipyerale, which can all he ’ optionally «ubsti bated, ' - Bp £ 3 ’ ~ b ~ ORIGINAL OF or