CA2129301A1 - Benzo-fused heterocyclic compounds with a 5-membered ring, process for their preparation, their use as medicaments, their use as diagnostic agents, and medicaments containing them - Google Patents

Abstract

HOECHST AKTIENGESELLSCHAFT - HOE 93/F 223 K Dr.VF/we Abstract Benzo-fused heterocyclic compounds having a 5-membered ring, processes for their preparation, their use as medicaments, their use as diagnostic agents and medica-ments containing them Benzo-fused heterocyclic compounds having a 5-membered ring, of the formula I

(I) where X is N or CR(6); Y is oxygen, S or NR(7); A and B
together are a bond or are both hydrogen, if, at the same time, X is CR(6) and Y is NR(7), one of the substituents R(1) to R(6) is a -CO-N=C(NR2)2 group;
the other respective substituents R(1) to R(6) are H, Hal or alkyl;
up to two of the other substituents R(1) to R(6) are CN, N02, N3, (C1-C4)-alkoxy, CF3; up to one of the other substituents is R(8)-CnH2n-Z- or phenyl;
R(7) is H, alk(en)yl or R(8)-CnH2n-, and pharmaceutically tolerated salts thereof, are described.
A process for the preparation of the compounds I which comprises reacting a compound of the formula II

Description

~1~9~

HORCHST A~TIENGESELLSCHAFT - ~OE 93/F 223 R Dr.VF/we DESCRIPTION -Benzo-fused heterocyclic compounds having a 5-~embered ring, processes for their preparation, their u~e ae m~dicaimento, their use as diagno~tic agent~ and medica-ments containing them The invention relate~ to benzo-fu~ed heterocyclic com-pounde having a 5-membered ring, of the ~ormula I

R( ) ~ i 4 ~ 3 1 (1) R(5) in which:
X 1EI N or CR(6), Y i~ oxygen, S or NR(7), A and B together are a bond or are both hydrogen, if, at the same time, X 18 CR(6) and Y i~ NR(7), ::~

OA~ O~ the ~ub~tituent~ R(l) to R(6) is a -CO-N-C(NH2)2 .
group, the other respective cub~tituents R(l) to R(6) are , hydrogen, F, Cl, Br, I or (Cl-C6)-alkyl, ao up to two of tho other ~ub~tituent~ R(l) to R(6) are CN, N02, N3, (Cl-C4)-alkoxy or CF3, up to one of the other ~ub~tituents is R ( 8) ~C"~2n~Z
n is zero to 10, wherein the alkylene chain -CnH2~ straight-chain or branched and wherein a carbon atom can be replaced by an 2 ~2~,;f' 1 r \ _ _ oxygen or S atom or by an N atom, R(8) i~ hydrogen, (C2-C6)-~lkenyl, (C3-Cl0)-cycloalkyl, which i~ uneub~tituted or substltuted by 1 to 4 methyl group~
or an OH group, or can co~ain an othylene group -CH-CH-, and wher~in a methylene group can bo replaced by an oxygen or S atom or by an N atom, phenyl, which le unsub~tltuted or .
~ubstituted by 1 to 3 ~ub~tltuont~ :
from the group cons~stl~g o~ F, Cl, Br, I, CF3, CH3-S(O)~-, . ;
8 1~ zero, 1 or 2, R(9)-Wy~~
R(9) is H, mothyl or ethyl, W i8 oxygen or NR(10), ~:
R(10) iB H or methyl, .~::
y 1~ zero or 1, CmF2m~
m 18 1 to 3, ~ ;
1- or 2-n~phthyl, pyridyl, gulnolyl or l~ogulnolyl, Z i8 -CO-, -CH2-, ~[CR(ll)(OH)]q~ . :::
g i8 1, 2 or 3, R(ll) i8 H or methyl, : :
oxygen, -NR(12)-, :
R(12) 1~ H or methyl, -S(O)~-, i8 zoro, 1 or 2, -SO2-NR(13)-, .: .
R(13) is H or (Cl-C~ lkyl, . ~, ,.
R(7) i~ hydrogen, (Cl-Cl0)-alkyl, (C2-Cl0)-alkenyl or R(8)-CnH2~-, .
,"'', ~;:

~ 1 ~ 9 3 ~ ~

and pharmaceutically tolerated salt~ thereof.

If substituent~ R(l) to R(5) cont~in one or more centers of asymmetry, the invention relate~ to both compounds of the S and of the R configuration. The compounds can exist as optlcal isomers, ~8 racemates or a~ mixture~ thereof.

The alkyl radicals defined can be e~ther straight-chain or branched.

Preferred compounds of the formula I are those in which:

X 18 CR(6) or N, 10 Y i~ NR(7), `~
A and B together are a bond or are both hydrogen, if, at the eame tlme, X 18 CR(61 and Y 1~ NR(7), and the radicals R(l) to R(7) have tho meanlng g~ven.

Particularly proferred compounds of the formula I are those ln whichs X i~ CR(6) or N, Y io NR(7), 0 A and B together are a bond or are both hydrogen, lf, at the ~ame tlme, X le CR(6) and Y i8 NR(7), one of the ~ubstltuent~ R(l) to R(6) i~ a -CO-N-C(NH2)2 group, and the other ro~pective substltuents R(l) to R(6) are hydrogen, F, Cl, Br, I or (Cl-C6)-alkyl, up to two of the other ~ubatltuent~ R(l) to R(6) aro CF3 or (Cl-C~)-al~oxy, 0 up to ono of the other substltuents R(l) to R(6) 18 CN, N02, N3 or R(8)~CnH2n~Z~~
n 1~ zero to 4, wherein the alkylene chain -CnH2n- can be straight-chain or branched and a carbon atom can be replaced by an - 2 ~
_~ 4 ~.

oxygen or S atom or by an N atom, R(8) is hydrogsn, (C3-C6)-alkenyl, (C5-C8)- -cycloalkyl, which is unsub~titutod or ~ub~tituted by 1 - 2 ~ethyl groups or an 0~ group, and wherein a ~ ;
methyleno group can be replaced by an oxygen or S atom or by an N atom, phenyl, which is unsubstituted or ~ubetlt~
utod by 1 to 3 sub~tltuent~ from the :~
group con~lstlng of F, Cl, Br, I, CF3, CH3-S(O)~
c i~ zero, 1 or 2, `;.
R(9)-Wy~ ~ ~:
R(9) i~ H, mothyl or ethyl, W 1~ oxygon or NR(10), .
R(10) i~ H or mothyl, y 18 zero or 1, ao CmF2m~
m i8 1 to 3, ;.
pyrldyl, qulnolyl or l~oqulnolyl, , ~: ,' Z 18 -CO-, - CH~-, oxyg~n, -NR(12)-, . ~:~
R(12) 1~ H or methyl, ~
-g(O),-, :
lc zoro, 1 or 2, -902-NR(13)-, R(13) 1~ ~ or (Cl-C4) -alkyl, , R(7) 1~ hydrogon, (Cl-C6)-al~yl, (C2-C~)-alkonyl or R(8)~CnH~n~

: Compound~ of tho formula I which aro prof~rred ln partl-cular aro thoso in whlch:
:~ X lc CR(6), : Y lc NR(7), ; 35 A und B togethor aro a bond or ~ 5 2 1 n! ~ 3 ~ ~
are both hydrogen, if, at the szme time, x i8 CR(6) and Y ~e NR(7), ~:
and R(1) i~ -CO-N=C(NH2)2 and the other re~pective aub~tituent~ R(2) to R(6) are hydrogen, F, Cl or Br, up to two of the sub~tituent~ R(2) to R(6) are CF3 or (Cl-C2) -alkoxy, up to one of the ~ub~tituent~ R(2) to R(6) i8 ~.
R ( 8 ) - C~2n ~ Z ~ ' n iB zero, 1 or 2, wherein the alkylene cha~n -CnH2n- 1B
~traight-chain or br~nched and wherein a carbon atom can be replacOEd by an oxygen or S atom or by an N atom, R(8) i~ hydrogen, phenyl, which i~ un~ub~tltuted or ~ub~tituted by 1 to 3 ~ub~titu-ents from the group con~i~ting of F, Cl, CF3, CH3-S(Ol,-, ~ i~ zero or 2, R(9)-Wy~~
R(9) 1~ H or methyl, W lc oxygen, y i~ zero or 1, pyridyl, quinolyl or i~oquinolyl, Z 1~ -CO-, -CH2-, -S(O),- or oxygen, c i~ zoro, 1 or 2, and R(7) is (Cl-C6)-alkyl, (c3-c4)-alkenyl or R(8)~CnH2n~-E~pecially proferrod compound~ are 5-chloro-1-methyl-2-indolylcarbonyl-guanidine hydro-chloride, :~
5-chloro-l-ethyl-2-indolylcarbonyl-guanidlne hydro-chloride, 3-chloro-1-methyl-2-indolylcarbonyl-guanidine hydro-chloride, 12~0~

3,5-dichloro-1-methyl-2-indolylcarbonyl-guanidine hydro-chloride, 5-fluoro-1-methyl-2-~ndolylcarbonyl-guanidine hydro-chloride, 3-chloro-5-fluoro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, 4,6-dichloro-1,3-dimethyl-2-indolylcarbonyl-guanidlne hydrochloride, 2-phenoxy-1-phonylindole-3-carboxylic acid guanidide methane~ulfonlc acid ~alt, 2-chloro-1-phenylindole-3-carboxylic acid guanid~de mothano~ulfonic ~cid ~alt, l-methyllndoline-2-carboxyllc acid guanidide hydro-chloride, lS 5-fluoro-1-mothyllndollne-2-carboxylic acid guanldide hydrochlorlde.

The compounde I are ~ub~tltuted acylguanidlnes.
The mo~t promlnent r~pre~entatlve~ of the acylguanidine~
is the pyrazine derivative amllorido, which 1~ usod ln therapy ac a calcium-~avlng diuretlc. Numerou~ other compounds o the amlloride type are deccrlbod ln the literatur-, cuch a~, for xample, dimethylamlloride or ~thyllcopropylamllorlde~
N H

C I ~c~N~ç~C~N~C~N H
,C~ ~C~

R'' Amilorldes R', R~ . ~
Dlmethylamilorides a~, R~ . CH3 Ethyli~opropylamilorides R' ~ C2H5, Rn e CH(CH3)2 Studies which indioate antiarrhythmic propertles of amllorlde moreover have beon discloced (Circulatlon 79;
1257 to 1263 (1989)). However, wide u~e as an --`` 2 1 2 9 ~ i, l ;
antiarrhythmic i~ impeded by the fact that thi~ effect i8 only slight and occurs acco~panied by an antihyperten~ive and isaluretic a~tion and the~e side effect~i are undesirable in the treatment of dl~turbance~ ln cardiac rhythm.

Indications of antiarrhythmic properties of amiloride have also been obtained from experimente on isolated animal heart~ ~Eur. Heart J. 9 (supplement 1): 167 (1988) (book of abstracts)). Thus, for example, it has been found on rat hearts that it was pos~ible to suppress an artificially lnduced ventricular fibrillation completely by amiloride. The abovementioned amiloride derivative ethyllsopropylamiloride wa~ even more potent than amilor-ide in this model.

Benzoylguanidino~ having antiarrhythmic properties are describod in Europoan Offenlegungsschrlft 416 499.

U.9. Patent 3 780 027 also describes acylguanidines, whiah differ fundamontally from the compounds I accordlng to the in~ontlon descrlbed here ln that they are trleub-etltuted bonzoylguanldlnos whlch aro derlved ln theirsubstitution pattern from commorclally available dl-uretics, euch as bumotanide and furo~emldo and havo an amlno group, whlch i~ important for the ~alidiuretic action eought, ln posltlon 2 or 3 rolative to tho carbonylguanldlno group. A potent ealldluretic activity is corrospondingly roportod for thoso compounds.

It was thoroforo aurprising that the compounds accordlng to tho lnvent~on have no undeair~ble and adverse eall-dluretlc proportle~ but vory good antiarrhythmlc propor-tle8, so they can be used for the treat~ent of health disorders,such as oxygen deficieney sy~ptoms. As 3 result of their pharmacologi-cal.properties, the co~pounds are outstandlngly suitable as anti-arrhythmic medicamonts having a cardioprotective compon-ent for prophylaxis of infarction and treatmont of infarction and for treatment of angina pectori~, where '~ 3 ~ ~ ~

they al~o preventively inhibit or greatly reducs the pathophyeiological proce~e~ in the development of i~chemically induced d~mage, in particular the initiation of i~chemically ~nduced cardiac arrhythmias. Becau30 of their protect$ve actions agAinst pathologioal hypoxic and i~chemic eltuations, the compounds of the formula I
according to the invention, ae a re~ult of inhibition of the cellular Na'/H' exchange mechanism, can be ueed a~
medicamente for the treatment of all acute or chronic damage cau~ed by i~chemia or di~eaee~ thereby induced primarily or secondarily. Thi~ applios to their u~e a~
medicament~ for ~urgical interventions, for example organ traneplante, where the compounde can be u~ed both for protection of the organs in the donor before and during removal, for protection of organe removed, for example during treatment with or storage thereof in physiological b~th flulde, and also during transfer to the recipient organiem. The compound~ are al~o valuable medicament~
which have a protective action while angioplastic ~urgi-cal interventione are carried out, for example on theheart and aleo on perlpheral veseels. In accordance with their protectlve action againet iechemically induced damage, the compounde are aleo ~uitable ae medlcaments for the treatment of ischemiae of tho nervoue eyetem, in particular tho CNS, where they are eultable, for example, for the treatment of apoploxy or cerebral edema. The compounde of tho formula I accordlng to the invontion moreover are aleo euitable for treatments of forme of ehock, euch ae, for example, allorgic, cardiogenic, 30 hypovolemic and bactorial ehock. ;~

The compounde of the formula I accordlng to the invention furthermore are dietingui4hed by a potent inhibitlng action on the proliferation~ of celle, for example flbroblaet cell proliferation and proliferatlon of emooth vascular muscle cells. The compounds of the formula I aro therefore po~sible valuable therapeutic~ for dieeaee~ in which cell proliferation is a primary or secondary cause, and they can therefore be ueed as ant~atherosclerotlce ~ ~ 2 ~
: - g -and ao agento againot delayed diabetic complications, cancer dieeasee, ~ibrotic dieeasee, euch ae pul~onary fibroeie, hepatic fibroeis or renal fibroeis, and organ hypertrophies and hyperpla~lae, in particular prootate hyperplaeia or prostate hypertrophy.

Tho compounds according to tho invention ase offect~ve inhibitors of the cellular oodium/proton antiport (Na'/H' exchanger), which, in numeroue dieeaeos (essential hypertension, atheroscleroeis, dlabetes and the like) is aleo increaeed in thoee celle whlch are readlly accee-eible for measurements, such as, for example, in erythro-cytee, platelets or leukocytee. The compounde according to the inventlon are therefore euitable ae out~tanding and e~mplo ocientific toolo, for ex~mple in their use ae diagnootico for determination and differentiat~on of csrtain forme of hyperteneion, but aleo of atherosclero-ele, dlabetee, prollferatlve dieeaees and the like. The compounde of the formula I furthormore are suitable for preventive therapy for preventlon of the origin of high blood preesure, for xample eseential hyporteneion.

The lnvention furthermoro relatee to a procese for the proparation of the compoundo I, which comprleee r-acting compounde of the formula II
~ 2) R(4) ~ A

in which one of the eubetituente R(l)' to R(5)' lo a -CO-L group and L ie a leaving group which can eaelly be replaced nucleophilically, and the other reepective oubetituento R(l)' to R(5)' have the meaning given, "
with guanidine to form the acylguanidine group ehown in ,' :, ` K; ~

formula I, -CO-N = C(NH2)2 and, if appropr~ate, converting the product into the pharmacologically tolerated salt.

The activated acid derivative~ of the formula II in which L is an alkoxy, preferably a methoxy group, a phenoxy group, a phenylth~o, methylthlo or 2-pyrldylthio group or a nltrogon-containing heterocycllc rlng, preferably 1-lmidazolyl, are advantageou~ly obtalned in a manner known per Be from the carboxylic ac~d chlorldo~ on which they are ba~od (formula II, L . Cl), whlch ln turn can be prepared, agaln in a manner known per ce, from the carboxyllc acld~ on whlch they are based (formula II, ~ OH), for example wlth thionyl chloride.
In additlon to the carboxylic acid chloride~ of the formula II (L . Cl), other activated acld derivative~ of the formula II can al~o bo prepar-d directly ln a manner known per BO from the heterocyclic oarboxyllc acid derlvativec on whlch they are baced (formula II, L . OH), ouch ae, for exampl-, the methyl ecter~ of the formula II, whore L . OCH3, by treatment with ga~eou~ HCl ln mothanol, the lmldazollde~ of the formula II by troatment with aarbonyldllmldazole (~ lmldazolyl, Staab, Angew.
Ch~m. Int. Ed. ~ngl. l, 351 to 367 (1962)), the mlxod anhydrldoc II with Cl-COOC2Hs or to~yl chloride ln the preconce of triethylamlne ln an inert ~olvent, and al~o the activatlons of carboxylic acid~ with dicyclohexyl-carbod~imlde (DCC). A number of ~ultable method~ for the preparatlon of aotivated carboxyllc acld derlvativee of the formula II are mentionod with reference to courco literature in ~. March, Advanced Organlc Chomi~try, Third Edition (John Wiley ~ Son~, 1985), pago 350.

The reactlon of an activated carboxylic acid derivative of the formula I with guanldine ic carrled out in a manner known per ~e ln a protic or aprotic polar but inert organic solvent. Methanol or tetrahydrofuran between 20C and the boiling point have proved ~ultable a~ solvents for the reactlon of the carboxylic acid methyl e~ter~ (II, L OMe) with guanidine. Mo~t of the reactions of compound~ II with guanid~ne have advantage-ou~ly been carr~ed out in aprotic $ner~ solvents, such a~
tetrahydrofuran, dimethoxyethane or dioxane. However, water can also be u~ed a~ the eol~ent for the reaction of II and guanidine.

If ~ i~ Cl, the reaction i~ advantageou~ly carried out w$th tho addition of an acid-trapping agent, for example in the $orm of oxceoo guanidine to bond the hydrogen halide acid.

Some of the heterocyclic carboxylic acid derivative~ on which the compound~ are baeed are known and are de~cr~bed ln the llterature. The heterocyclic carboxylic aoids II
(~ ~ OH) which are not known can bo prepared by method~
known from the literature.

Thu~, for oxamplo, the 2-benzimldazolecarboxylic acid~
~formula II with R(l) . -COOH, X ~ N and Y ~ -NR(7)~, which lead to proferred compounds according to the ln~ontion, are obtalned in a manner known per ~e by oxldation of the corre~pondlng 2-hydroxymethyl-benzlmida-zolos w~th pota~slum permanganate by a method analogous to that of Bi~trzycki and Przeworskl (~er. 45, 3483 ~19121)-The indole-2-carboxylic acide which lead to preferred carbonylguanldinss of the formula I are obtalned, for example, from the 2-nltrotolueno~ by the method of J.R. John~on et al. J. Am. Chem. Soc. 67, 423 (1945) l~ee al~o Noland and ~3aude, Org. Synth. Coll. Vol. 5, 567 (1973)], and by the Fl~cher indole ~ynthesis from pyru~lc acid and phenylhydrazone. Another preparation method for indole-2-carboxylic acid~ i~ the bromoform or iodoform roaction of 2-acetylindoles, whlch can be carried out by the method of Ra~ur et al., Synth. Commun. 22, 421 - 428 (1992). A preparat~on method $rom 2-ketoanll~ne~ i~

~ 12 ~ r.~ ~ 3 i. ~
de~cribed by Jonee et al. (J. Org. Chem 37, 3622 11972]).

Starting materials for the preparat$on of epecifically ~ubetituted indole-2-carboxylic acide can al80 be ~ndole-2-carboxylic acids th~mselvee, onto which eubst~tution reactione are easily carried out in a manner known from the literatuse. Numerous electrophilic eubetitution reactlone in the 3-position and also in tho remaining poeitione can be carried out particularly ~eloctively ln thle caee. Thus, for example, halogenatione procoed smoothly wlth a Hal~ transfer agent and with a complete converelon. Al~ylation and arylation reactlone llkewlee can be carriod out very eaeily on the nitrogen atom ln the l-poeition. ;

The indoline-2-carboxylic acide and eeters thereof can be obtained gonerally ln a mannor known from the literature from the lndole-2-carboxyllc aclde or eetere theroof on whlch thoy are baoed by reductlon or hydrogenatlon.
Treatment wlth metalllc magneelum in mothanol analogouely to the worklng proc-dure of Rwon Youn, Gyu Hwan ~on, Chwang Slek Pakt Tetrahedron Letters 27 (1986) 2409-2410 hae provod to bo partlcularly eultable.

Benzoylguanldin-o I are ln goneral weak baeoe and can bond acld to form oalts. Poeolblo acld addition ealto aro oalte of all tho pharmacologlcally tolerat-d acld~, for oxamplo halldoo, ln partlcular hydrochlorideo, lactateo, oulfateo, cltrat-~, tartratoo, acotatoe, phoophat-o, oulfonlc acid oaltc, cuch ao methyloulfonateo, p-toluon~-eulfonatoe and tho liko.

Madicamonto which comprieo a compound I can bo admlnlo-torod horo orally, parontorally, lntravenouoly or roct-ally or by inhalation, the preforred admlnlotratlon dependlng on the partlcular cllnlcal plcture of the diseaoe. The compoundo I can be used here by them olvoe or togother wlth galenlcal auxillariee, and in particular both in votorinary and in human medicine.

The expert 1~ familiar with the auxiliaries which are suitable for the dosired medicament formulat$on on the basis of his expert knowledge. In addition to ~olvente, gel-~orming agente, ~uppository bases, tablet auxiliaries and other active compound carriers, for examplo, anti-oxidant~, diapersing agenta, emulsifier~, defoamQrs, ~lavor correctant~, preservatives, solubilizing agents or dyostuffs can be used.

For an oral use form, the active compounds are mixed with tho additives suitable for this form, ~uch as carrier substances, stabllizers or inert diluents, and are brought by the customary methods into the suitable dosage forms, such as tablets, coated tablets, push-fit cap~ulos or agueous, alcoholic or oily solutions. Inert carriors which can be used aro, for oxample, gum arabic, magnesla, magnoslum carbonato, potasslum phosphate, lactoso, glucose or starch, in particular maizo ~tarch. The mixture can be formulatod either a8 dry or a~ moist granulos. Po~siblo oily carrier substancos or possible eolvonts aro, for oxamplo, vogota~le or animal oils, such a~ sunflowor oll or cod llvor oil.

For subcutanoous or lntravonous admlnlstratlon, lf do~lrod, tho activo compounde aro dis~olvod, susponded or emulsified wlth the substancea customary for thi~ pur-po0e, ~uch a~ solublllzlng agento, omulslflers or othorauxlliaries. Pos~iblo ~olvonts aro, for oxamplo: water, physiologlcal saline ~olutlon or alcohole, for oxample ethanol, propanol or glycerol, and ln addltlon al~o sugar solutlone, such as glucose eolutlon~ or mannltol 801u-tlon~, or al~o a mlxture of the variou~ ~olvent~mentlonod.

Suitablo pharmaceutical formulations for adminlstration in tho form of aorosols or spraya are, for example, solutions, suepensions or emulsions of tho act~ve com-pound of tho formula I in a pharmaceutically accoptable~olvont, such as, in particular othanol or water, or a 2~2~

mixture of such solvsnts. If requlred, the formulation can also additionally co~prise other pharmaceutical auxiliaries, ~uch as surfaotant~, emulsifier~ and atabil-izers, and a propellant ga~. Such a formulation u~ually compri~es the active compound in a concentratlon of about 0.1 to 10, in partlcular about 0.3 to 3% by weight.

The do~age of the active compound of the formula I to be administered and the freguency of administration depend on the action potency and durat$on of action of the compound~ used; and furthermore also on the naturo and severity of the di~ease to be treated and on the oex, age, weight and individual respon~e o$ the mammal to be treated.

On average, the daily doee of a compound of the formula I for a patlent welghing about 75 kg 18 at leaet 0.001 mg, proferably 0.01 mg to not more than 10 mg, proforably not mor- than 1 mg. For acute outbreaks of the disea~e, for example immediately after suffering cardiac lnfarctlon, even hlghor and above all more freguent do~ages may also bo noco~sary, for example up to 4 lndlvidual do~e~ per day. Up to 100 mg per day may bo noce~ary, o~pocla~ly wlth l.v. uee, for example on an lnfarctlon patlent in lntenslve care.

Examples ~eneral lnstructlons I for preparatlon of hoterocyclic acylguanidine~ (I) from heterocyclic carboxylic acids (II, ~ . OH) 0.01 M of tho carboxyllc actd derivatlve of the formula ~ OH) is dls~olvod or su~pended ln 60 ml of anhydrous tetrahydrofuran (THF), and 1.78 g (0.011 M) of carbonyldilmldazolo are then added. After the mixture ha~
been stirred at room temperaturo for 2 hour~, 2.95 g (0.05 M) of guanidine are introduced into the reactlon solution. After the mixture has been s~irred overnight, 3 Q l the T~F ie dietilled o~f under reduced ~reeDure (rotary e~aporator), water ie added~ the pH i~ brought to 6-7 with 2N HCl and the corre~ponding acylguanidine (formula I) is filtered off.

The heterocyclic acylguanidinee thus obtalned can be converted into the correaponding salte ~y trea~ment with aqueous or methanolic hydrochloric acid or other pharma-cologically tolerated ealte.

General lnstructione II for preparation of heterocyclic acylguanidineo (I) from the corresponding carboxylic acld eetere (formula II, ~ . alkoxy or phenoxy) -1 oquivalent of a corresponding carboxylic acld eeter of the formula II and 5.0 equivalents of guanidine are dissolved in isopropanol or euependod ln THF and the solutlon or ~uspenslon le boiled under a reflux condeneer unt~l the reaction 1B complete (monitoring by thln layer chromatographyi roaction time about 2 - 8 houre). Tho ~olvont le dletlll-d off under reducod prossure (rotary ovaporator), the resldue 18 taken up ln ethyl acetate and the mlxture 1~ washod 3 tlmes wlth eaturated sodium blcarbonat- ~olutlon.
Drylng of tho organlc pha~e over sodlum eulfate, removal of tho solvent by dlstlllatlon undor reduced proeeure and ahromatography of the roeldue over slllca gel uslng a ~uitablo moblle pha~o.
Converslon of the correspondlng hetorocycll¢ acylguani-dlne of the formula I obtalned lnto tho ¢orreepondlng hydrochloride is carriod out analogouely to lnetructions I.

The following compounds according to the inventlon were prepared ln accordance w~th the general lnstructions I
and II:

Example 1:
2-Benzofurylcarbonyl-guanidino hydrochloride, ~1~3~

Melting point 279 - 283C.

Example 2:
6-Chloro-2-b~nzofurylcarbonyl-guanidine hydrochlorlde, ~
Melting point 272 - 274C. : :

Example 3~
7-Methoxy-2-b~nzofurylcarbonyl-guanidino hydrochloride, Meltlng point 266C. -:
, " ~, ' Examplo 4:
7-Bromo-4-hydroxy-3-benzofurylcarbonyl-guanidine hydro-10 chloride, :
Melting point 239C. ~

Example 5: ~ :
7 Hydroxy-2-benzofurylcarbonyl-guanidino hydrochloride, .
Meltlng polnt 243 - 44C.

Exa~plo 6:

5-Dimethylamlnomethyl-2-benzofurylcarbonyl-guanidino dihydrochloride, Molting polnt ~ 250C.

Example 7 t 5,6-Dlchloro-2-bonzofurylcarbonyl-guanidlne hydro-chlorlde, Neltlng point ~ 250C.

Example 8:
7-Amino-2-benzothlazolylcarbonyl-guanidine dlhydro-chloride, Melting polnt ~ 250C.

Example 9:
2-Amino-6-bonzothiazolylcarbonyl-guanldino d~hydro-chlorldo, Meltlng po~nt ~ 250C.

21~3~

Example 10:

6-Chloro-3-methoxybenzo~b~thien-2-ylcarbonyl-guanidine hydrochlor~de, Melting point 202C.

Example 11:
Benzotrlazol-5-ylcarbonyl-guanidine hydrochloride, ~elting point 270C.

Example 12:
2-Benzothlazolylcarbonyl-guanidine hydrochlorlde, ~`
Melting point 273 - 275C.

Example 13:
Benzo~blthien-2-ylcarbonyl-guanidine hydrochloride, Melting point 296 - 298C.

Example 14:
2-Chloro-5-methylb-nzo[b~thion-2-ylcarbonyl -guanid ine hydrochloride, Nolting polnt 221 - 222C.

Examplo 15s 5-Nitrobenzo~b~thion-2-ylcarbonyl-guanidine hydro-chlorido, Moltlng point 2B5C.

Exumple 16:
5-Aminobenzo[blthion-2-ylcarbonyl-guanidine hydro-chloride, Melting point 250C (decompo~ition).

Examplo 17s lH-Benzimldazol-5-yl-carbonyl-guanidine hydrochloride, Melting point 265C.

Example 18:
1-(2-Chlorobenzyl)-lH-benzimidazol-5-yl-carbonyl-guani-dina hydrochloride, 3~
Melting point 265C.
: ' "':
Example 19:
l-(l-Hexyl)-lH-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Melting point 232 - 234C.

Example 20:
1-(2-Chlorobenzyl)-2-hydroxy-lH-benzlmidazol-5-yl-carbonyl-guanidine hydrochloride, Melting point 283C.

Example 21:
2-Methylthio-lH-benzimidazol-5-yl-carbonyl-guanidine hydrochloride, Meltlng point 211C.

Example 22:
1-(2-Chlorobenzyl)-2-methylthio-lH-benzimldazol-5-yl-¢arbonyl-guanldine hydrochloride, Meltlng point 220C.

Example 23s l-~l-Hexyl)-2-hydroxy-lH-bonzimidazol-5-yl-carbonyl-guanldlne hydrochloride,Meltlng polnt 227 - 229C.

Bxample 24:
6-~N-Methyl-N-(2-phenyl~thyl)~ulfamoyl]-lH-benzlmldazol-4-yl-carbonyl-guanldine hydrochlorlde, Melting point 205C.

Example 25s l-Methyl-2-methylthio-lH-benzimldazol-6-yl-carbonyl-guanidine hydrochloride, Melting polnt 246C.

Example 26:
6-Sulfamoyl-lH-benzimidazol-4-yl-carbonyl-guanldine 2 ~
- 19 - ~
hydrochloride, Melting point 223C.

Example 27 2-(2-Phenylethyl)-6-N-pyrrolidinosulfonyl-lH-benzimida-zol-4-yl-carbonyl-guanidine hydrochloride, Melting point 192~C (decompo~itlon~.
. . , Example 28:
6-Chloro-2-(2-phenylethyl)-lH-benzimidazol-4-yl-carbonyl-guanidine hydrochloride, Melting point 262 - 264C.

Example 29:
6-N-Pyrrolidinosulfonyl-lH-benzimidazol-4-yl-carbonyl-guanidine hydrochloride, Melting point 200 - 202C (decompo~ltion).

lS Example 30:
6-Methylsulfonyl-2-(2-phenyletffl l)-lH-benzimidazol-4-yl-carbonyl-guanidine hydrochloride, M-lting point 215C.

Example 31~
6-~N-Methyl-N-(2-phenylothyl)~ulfamoyl]-2-(2-phenyl-ethyl)-lH-benzimidazol-4-yl-carbonyl-guanidine hydro-chloride, Melting point 130C.

Examplo 32:
2-Benzylthio-6-methylsulfonyl-lH-benzimidazol-4 yl-carbonyl-guanidine hydrochloride, Molting polnt 215C.

Example 33:
5-Chloro-l-methyl-lH-benzimidazol-2-yl-carbonyl-guanldine hydrochloride, Melting point 228C.

- 20 - ~ 9 ~
Example 34:
5,6-D~hloro-l-methyl-lH-benzimidazol-2-yl-carbonyl-guanidine hydrochloride, Melting point 274C. (deco~position) Example 35~
3-Indolylcarbonyl-guanid$ne hydrochloride, Melting point 270C. (decompo~ition) ~ :

Example 36:
5-Indolylcarbonyl-guanidine hydrochloride, Melting polnt 258C. (docompo~ition) Example 37: ~:
l-Benzyl-3-indolylcarbonyl-guanidine hydrochlor$de, Melting point 256C. (decompo~ition) ~:

Examplo 38s 4-Indolylcarbonyl-guanidlne hydrochlorlde, Meltlng point 270C. (decomposition) Examplo 39s l-Mothyl-3-indolylcarbonyl-guanldlne hydrochloride, Meltlng polnt 250C. (decompo~itlon) Exumplo 40s 1-(2-N,N-Dlmethylaminoethyl)-3-indolylcarbonyl-guanldlne dlhydrochlorldo, Meltlng polnt 250C. (docompo~ltion) Example 41:
1-Methyl-2-lndolylcarbonyl-guanldine hydrochloride, Meltlng polnt 280C.

Example 42: ;
2-Indolylcarbonyl-guanldlne hydrochlor$de, Meltlng point 310 - 312C.
, ":

2 ~

Example 43:
5-Chloro-2-~ndolylcarbonyl-guanidine hydrochloride, Melting point 317 - 320C.

Example 44:
5-Methoxy-2-indolylcarbonyl-guanidine hydrochloride, Melting point 292C.

Examplo 45:
5-Chloro-l-methyl-2-lndolylcar~onyl-guan$d~ne hydro-chlorlde, Melting point 269C.

Example 46:
1-(3,4-Dichlorobenzyl)-2-indolylcarbonyl-guanidlne hydrochloride, Meltlng polnt 195C.

Examplo 47:
1-(2-N,N-Dlmethylamlnoethyl)-2-lndolylcarbonyl-guanldine dihydrochlorlde, Molting point 255C. (decomposition) Exumple 48s 1-Bonzyl-2-indolyl¢arbonyl-guanldine hydrochloride, Melting point 229C.

Ex~mple 49s l-Ethyl-2-indolylcarbonyl-guanidlne hydrochlorldo, Melting point 200 - 201C.

Example 50s l-Benzyl-5-chloro-2-indolylcarbonyl-guanidine hydro-chloride, Nelting point 198C.

Examplo 51:
5-Chloro-1-(2-N,N-dlmethylaminoethyl)-2-indolylcarbonyl-guanidine dihydrochloride, 2 1 . 3 ) ~ -~

Melting point 255C. (decompo~ition) Example 52:
5-Chloro-l-ethyl-2-indolylcarbonyl-guanidine ffl dro-chlor~de, Melting point 255~C.

Example 53:
5-Chloro-l-propyl-2-indolylcarbonyl-guanidine hydro-chloride, Melting point 255C.

Example 54:
5-Chloro-l-butyl-2-indolylcarbonyl-guanldine hydro-chlorido, Melting point 222C.

Exampls 55:
5-Hydroxy-l-methyl-2-indolylcarbonyl-guanidine hydro-chloride, Melting point 288C. .

Example 56:
3,5-Dichloro-1-(2-N,N-dimethylaminoethyl)-2-indolyl-carbonyl-guanidine dihydrochloride, Melting point 246C.

Examplo 57:
5-Mothoxy-l-methyl-2-indolylcarbonyl-guanidine hydro- :
chloride, Melting point 227C.

Example 58:
3-Chloro-l-methyl-2-indolylcarbonyl-guanidine hydro-chloride, Melting point 216C.

Example 59:
3-Chloro-2-indolylcarbonyl-guanidine hydrochloride, ~ . A ." . . . . .

- 23 ~ ' Melting point 222C.

Exampls 60:
3,5-Dichloro-1-(4-picolyl)-2-indolylcarbonyl-guanidine hydrochloride, Melting po~nt 220C.

Example 61:
5-Chloro-1-(4-picolylJ-2-indolylcarbonyl-guanidine hydrochloride, Melting point 287C.

Example 62:
5-Chloro-1,3-dimethyl-2-indolylcarbonyl-guanidlne hydro-chlorlde, Meltlng polnt 258C.

Ex~mplo 63s 5,7-Dlchloro-1,3-dimethyl-2-lndolylcarbonyl-guanidine hydrochloride, Molting polnt 307C.

Examplo 64s 4,6-Dichloro-1,3-dimothyl-2-indolylcarbonyl-guanldlne hydrochlorlde, Meltlng point 296C.

Fxamplo 65s 5-Chloro-l-methyl-3-phenyl-2-lndolylcarbonyl-guanldlns hydroahlorlde, Molting polnt 288C.

Example 66s 3-Bromo-l-methyl-2-indolylcarbonyl-guanldine hydro-chlorlde, Meltlng polnt 208 - 210C.

Example 67s 5-Fluoro-l-methyl-2-indolylcarbonyl-guanidine 2l2~ a:~
` - 24 -hydrochloride, Melting point 278C.

Example 68:
3,5-Dichloro-2-indolylcarbonyl-guanidine hydrochloride, :~
Melting point 208 - 210C.

Example 69:
3,5-Dichloro-l-methyl-2-indolylcarbonyl-guanidine hydro-chloride, Melting point 208 - 210C.

Example 70:
4,5,6-Trichloro-1,3-dimethyl-2-indolylcarbonyl-guanidine hydrochloride, Melting point 307C.

Example 71:
2-(4-Mothoxyphenyl)-benzimidazole-5-carboxyllc acid guanldlde methaneculfonlc acld calts Meltlng point 270C.

~xample 72s 2-(4-Trlfluoromethylphenyl)-benzlmldazole-5-carboxyllc acid guanldlde mothanosulfonic acid ~alt;
Meltlng polnt 275C.

Example 73s 2-Phonylbenzimldazolo-4-carboxyllc acid guanldlde Meltlng point 264C.

Example 74s 2-(4-Fluorophenyl)-l-methylbonzimidazole-5-carboxylic :~
acld guanidlde methaneculfonic acld ~alt;
Meltlng point 252C.

Example 75s :
2-(4-Methylphonyl)-benzimidazole-5-carboxylic acid guanidide mothane~ulfonic acid ~alt;

- 25 - 2~29~
Melting point 285C.

Example 76:
2-(4-Hydroxyphenyl)-benzimidazole-4-carboxylic acid guanidide methanesulfonlc acid ealt;
Melting po~nt 281C.

Example 77:
2-~4-(4-Chlorophenoxy)phenyl] benzimidazole-5-carboxylic acid guanidide methane~ulfonic acid ~alt;
Melting point 239C.

Example 78:
2-Benzylbenzimldazole-5-carboxylic acid guanldlde methanesulfonic acid ~alt;
Melting point 210C.

Example 79:
2-Undocylbenzimldazole-5-carboxylic acld guanldide methan~ulfonlc acld ~alt:
Melting polnt 252C.

Examplo 80:
2-Methylbenzimldazole-5-carboxylic acid guanidide methanesulfonic acid ~alt~
Melting point 279C.

Examplo 81s l-Mothyl-2-phenylbenzlmidazolo-5-carboxylic acld guanl-dlde methanesulfonic ac~d ~alt;
Docompo~itlon polnt: 230C.

Example 82:
l-Methyl-2-(2-t~ienyl)benzimidazole-5-carboxyli¢ ~cld guanidide methane~ulfonic acld ~alt;
Melting po~nt 211C.

Example 83:
2-Chloro-l-phenyllndole-3-carboxyl~c acld guanidide ~` - 26 - 2~2.93~
methaneeulfonic acid ealt;
Melting point 203 - 205~.

Example 84:
2-Phenoxy-l-phenylindole-3-carboxylic acid guanidide methaneeulfonic acld salt;
Melting point ao2 - 204C.

Example 85:
5-Chloro-l-ethylbenzimidazole-2-carboxylicacidguanidide hydrochloride;
Meltlng point: 244C.

Example 86:
3-Chloro-5-fluoro-1-methylindolyl-2-carboxylic acid guanldide hydrochlorlde;
Meltlng point: 234C.
. . .
Example 87:
5-Methoxy-l-phenyllndolyl-2-carboxyli¢ acid guanldide hydrochlorldo;
Meltlng polnt 266C.

Exampl- 88:
3-Ieopropyl-5-methoxylndolyl-2-carboxylic acid guanidlde hydrochloride;
Melting point: 210C.

Example 89:
5-Chloro-3-phenylthio-2-lndolylcarboxylic acid guanldide hydrochlorlde;
Melting polnt: 252C.

Example 90:
3,5-Dimethoxy-l-methyl-2-indolylcarboxyllcacldguanldide m~thaneeulfonlc acld ealt;
Meltlng polnt 212C.

~f~

Exiample 91:
3-I~opropoxy-5-methoxy-1-methyl-2-indolylearboxylie aeid guanidide methanesulfonie aeid ealt;
Melting point 248C.

Example 92:
5-Chloro-3-phonyleulfonyl-2-indolyl~arboxylic aoid guanidide methanesulfonic acid ~alt;
Meltlng polnt 240C.

Example 93:
5-Chloro-l-phenyl-2-indolyl¢arboxylic acid guanidide methaneoulfonie aeid salt;
Deeomposition point: 305C.

Example 94:
5-Chloro-3-l~opropyl-2-indolylcarboxyllc ac~d guanldide methane~ulfonic acld salt;
Doeompo~ition points 258 - 259C.

Example 95:
5-Chloro-3-methoxy-l-m0thyl-2-lndolylearboxylie acid guanidido mothaneoulfonic acid oalt;
Deoompo~ition points 234C.

Exampl- 96:
5-Chloro-3-i~opropyl-1-mothyl-2-indolylearboxylie aeid guanldlde mothanosulfonle aeid oaltt Doeompooltlon polnt: 164 - 166C.

Examplo 97:
5~Trlfluoromethyl-3-mothyl-2-lndolylearboxylie aeid guanidido hydroehlorido~
Deeompo~itlon point: 232 - 236C.

Example 98:
5-Trifluoromethyl-1,3-dlmethyl-2-indolylearboxylic acid guanidide hydrochloride;
Deeomposition point: 219 - 223C.

""", .,, , ,. , , , . .: :: ~ : . ", i . . :, - ~ : -- 28 - 212~t~
Example 99:
5-Benzoyl-1,3-dime~hyl-2-indolylcarboxylicacidguanidide hydrochloride;
Melting point 270 - 273C.

Example 100:
5-Cyclohexyl-1,3-dimethyl-2-indolylcarboxylic acid guanidide hydrochlorlde;
Meltlng polnt 191 - 194C.
: ~ ~
Example 101:
10 1,3,5-Trlmethyl-2-indolylcarboxylic acid guanidide .
hydrochloride:
Meltlng polnt 210 - 212C.

Example 102:
1,3,4,6-Tetramethyl-2-indolylcarboxylic acid guanldide 15 hydrochloride;
Docompo~ition point: 164 - 171C. ~

Example 103: ~:
5-Methyl~ulfonyl-2-indolylcarboxylic acid guanidide ~ :
hydrochlorido;
Molting point 298 - 305C.
, .
Example 104:
l-Methylindolino-2-carboxylic acid guanidide hydro-chloride:

a) Indoline-2-carboxyllc acld wa~ roacted wlth 2 equlva-lent~ of K2C03 and methyl iodlde ln dlmethylformamids to give methyl N-methyl-indolino-2-carboxylate.
Colorle~ oil MS (E8): 192 (M ~ 1) The e~ter from a) wae hsated under reflux with 5 equiva-lent~ of guanidine ln tetrahydrofuran. The ~olvent wa~
stripped off in vacuo, the ro~idue wa~ ta~en up in water and the mlxture was extracted three tlme~ with ethyl -- - 29 - ~ ~ 2. ~
acetate. The combined organlc phases were dried o~rer MgS04 and the re~ulting guanidide waEI isolated a~ the hydrochloride by addition of methanolic HCl.
Solid, melting point 162 - 170C.

5 Examplo 105:
l-Methyl-(S)-indoline-2-carboxylic acid guanidlde hydro-chlorlde Was propared in an analogous manner from (S)-indoline-2-carboxylic acld.
10 Solld, meltlng polnt 162C.

Example 106 5-Fluoro-l-methylindoline-2-carboxylic acid guanidide hydrochloride a) Methyl 5-fluoro-lndole-2-carboxylate was reactod with 15 magnesium ln m thanol in accordanco wlth lnstructlons known from tho literature ~In ~won Ysun, Gyu ~Iwan Yon, Chwang Slek Paks Tetrahedron Letters 27 (1986) 2409-24101 to giv- methyl 5-~luoro-lndollno-2-carboxylate.
Colorle~ oll, Ms (Eg)~ 196 (M ~ 1) b) The lndollne-2-carboxyllc acld ester from reactlon a) was N-mothylated wlth R2CO3 and methyl iodide in dimeth-ylformamide. After standard worklng up, methyl N-methyl-5-fluoro-indoline-2-carboxylate was isolated.
25 Colorlo~s oil, MS (ES)s 210 (M ~ 1) c) Tho product from reactlon b) wa~ heated under r-flux wlth 5 egul~ralent~ of guanidine in THF. The solvent was strlpped off ln ~racuo, the residue was talcon up ln water 30 and the mixture was extracted three tlmes wlth ethyl acetate. The comblned organlc phases were drled o~rer NgSO" and the resultlng guanidide was isolated as the hydrochloride by additlon of methanollc HCl.

~ 30 _ ~ ~2~3~
Reddi~h eolid, melting point 135 - 150C.

Ex~mple 107 5-Methoxy-l-methylindoline-2-carboxylia acid guanidide hydrochloride was prepared in an analogous manner.
Reddlsh eolid, melting point 169 - 174C.

This transformation of lndole-2-carboxylic acid deriva-tive~ into the corre~ponding indoline derivative~ in Examples 104 to 107 can also be applied to all the other indole-carboxylio acid~.

Example 108 l-Methylindole-2-carboxylic a¢id guanidide is obtained by treatment of a suspension of 1.5 g of 1-methylindole-2-carboxyli¢ acld guanldide hydrochlorlde in 30 ml of water with agueou~ sodlum bicarbonate solution.
Colorless crystals, melting point 95 - 100C.

Preparation methods for precureors A. 3-Iodoindole-2-carboxyllc acld derivativos are obtalned, for example, by dropwise addltlon of a ~olution of 0.02 mol of lodlne monochlorlde in glaclal acetlc acid to a solution or suspen~ion of 0.02 mol of lndole-2-carboxylic acid ester at room temperature and sub~oquent ~tirrlng at 40C for 30 minuto~. After the eolvent has been dlstllled off, the r~ldue is taken up in water and the cry~talline solld 18 fllterod off.

Ethyl 5-chloro-3-lodolndole-2-carboxylate: colorloss crystals, meltlng polnt 190-194C.

Ethyl 3-lodolndole-2-carboxylate: colorless crystals, melting point 127-131C.

5-~enzyloxy-3-iodo~ndole-2-carboxylate: colorles~
crystals, melting polnt 122 - 124C.

2 ~ 2 ~
.. ~, ,.

. . .
5-Fluoro-3-iodo~ndole-2-carboxylate: colorle~ orystals, melting point 154 - 158C.

B. 3-Bromoindole-2-carboxylic acid derivative~

are obtained, for exa~ple, by dropwi~e addition of a ~olution of 0.05 mol of bromine in glacial acetic acid to a solutlon or ~uspen~ion of 0.05 mol of indole-2-carboxyllc acid e~ter at room temperature and ~ub~eguent ~tlrring at 40C for a further 15 minute~. After the ~olvent ha~ been di~tllled off, the residue is taken up in water, the cryetalline sol~d 1B filtered off and the 3-bromolndole-2-carboxylic acid e~ter i~ pur~fied by rocry~tallization.

Example Bl:
Ethyl 3-bromo~ndole-2-carboxylate: colorle~ crystal~, meltlng ~olnt 143 - 144C.

Example B2s Ethyl 3-bromo-5-chloroindole-2-carboxylate: colorle~
cry~tal~, meltlng polnt 184 - 186C.

C. 3-Chloroindole-2-carboxyllc acid dorivative~

are obtalned, for example, by dropwice additlon of a colutlon of 0.05 mol of N-chloro~uccinlmide ln glaclal acetic acid to a ~olutlon or ~u~poncion of 0.05 mol of lndole-2-carboxyllc acid e~ter at room t^mperature, ~ub~eguent ~tirring at 40C for a further 15 minute~ and oub~eguent after-~tirring at room temperature. After the colvent ha~ been distilled off, the re~ldue i~ taken up in water and the p~ ie brought to 8 with ~aturated aquoou~ ~odium blcarbonate ~olutlon. The cry~talline ~olld i8 flltered off and the 3-chloro~ndole-2-carboxyllc acld e~ter 1~ purlfled by recry~talllzation.

Example Cl)s Ethyl 3,5-dichloroindole-2-carboxylate; colorle~

~ 32 _ 21293~
cry~tale, meltlng point 163 - 165C.

Example C2):
Ethyl 3-chloro-5-fluoroindole-2-carboxylate; colorles~
cryetals, melting point 138 - 141~.

Example C3):
Ethyl 3-bromo-5-chloroindole-2-carboxylate, cryotalllne ~olid, melting point 178 - 182C. ;~

D. 1-Alkylation~ of 2-indolecarbonyl derivative~

are carried out, for examplo, by a procedure in which a m~xture of 0.05 mol of the particular ~ndole-2-carboxylic acid o~tor, 0.06 mol of al~ylating agent and 0.015 mol of finely powdered, anhydrou~ potas~ium carbonate in 10 to 50 ml of acetone lc bolled under a reflux condenser for about 5 - 8 hour~ and the progre~ of the reaction i~
monitored by thin layer chromatography. The colvent i~
then di~tilled off, water i~ added to the residue and the mixturo 1~ extra¢ted wlth ethyl acetate.

Example Dl)s Ethyl 3-iodo-1-methylindole-2-carboxylate:
Alkylating agents methyl iodldes Propertiec: pale yellow oll.

Example D2)s Ethyl 5-chloro-3-lodo-1-methyllndolo-2-carboxylato:
Alkylatlng agents methyl lodides Propertl-~s colorles~ cry~talllne ~ub~tance, melting point 88 - 93C.

Exampl- D3)s Ethyl 3-iodo-1-(2-dimethylaminoethyl)$ndole-2-carboxylates Alkylating agents 2-dimethylaminoethyl chloride hydro-chloride;
Propertie~s pale yellow oil.

~2~

Example D4) Ethyl 3-iodo-1-(3,4-dichlorobonzyl)indole-2-carboxylate Alkylating agent 3,4-dishlorobenzyl chloride;
Propertiee pale yell~w o$1 Example D5) Ethyl 5-chloro-1-ethyl-3-iodoindole-2-carboxylate Alkylating agent ethyl bromlde Propertlee colorleee, cry~talline solid, meltlng point Example D6) Ethyl 5-chloro-3-iodo-1-propylindole-2-carboxylate Alkylating agent propyl iodide Propertiee colorleee, cryetalline ~olid, melting point Example D7) Ethyl l-butyl-5-chloro-3-lodoindole-2-carboxylate Alkylatlng agont butyl lodide Prop~rtle~ pale yellow oll Exampl- D8) Ethyl 5-chloro-3-lodo-1-leopropyllndole-2-carboxylat-Alkylatlng agont i~opropyl lodide Propertioe ¢olorloo-, cryetallln- eolid, meltlng polnt Exampl- D9) Ethyl 5-benzyloxy-3-iod¢-1-methyllndole-2-carboxylato Alkylating agent methyl ~odide Proportlee colorleee, cryetalline ~olld, lnexact meltlng point 90 - 105C

Examplo D10) Ethyl 5-fluoro-3-iodo-1-methyllndole-2-carboxylate Alkylatlng agent mothyl lodlde Propertlee colorlee~, cryetalline eolld, inexact meltlng point 76 - 79C

_ 34 _ ~12 2xample Dll):
Ethyl 3,i5-dichloro-1-methylindole-2-carboxylate:
Alkylating agent: methyl iodide :
Propertie~: colorle~B~ cry~talline solid, inexact melting point 54 - 56C.

Example D12):
Ethyl 3,5-dichloro-1-(2-dimethylaminoethyl)indole-2-carboxylato:
Alkylating agent: 2-dimethylaminoethyl chloride hydro-chloridePropertiee: oil.

Example D13):
Ethyl 3,5-dichloro-1-(4-picolyl)lndole-2-carboxylate:
Alkylating agent: 4-picolyl chloride hydrochloride Propertiee: melting point 100 - 103C.

Examplo D14):
Bthyl 5-chloro-3-iodo-1-(4-picolyl)indole-2-carboxylate:
Alkylatlng agent: 4-picolyl chlorlde hydrochlorlde Proportloes meltlng polnt 127 - 129C.

Example D15):
2-Acetyl-S-chloro-1,3-dlmethyllndole Alkylatlng agents mothyl iodlde Proportloes melting polnt 88C.

Examplo D16):
2-Acotyl-5-chloro-1-methyl-3-phenyllndole Alkylatlng agont: methyl iodide Propertlees melting polnt 89 - 91C.

Examplo D17)s 2-Acetyl-5,7-dichloro-1,3-dimethyllndole Alkylating agents methyl lodlde Propertiees melting point 105 - 108C.

_ 35 _ 212~.3~
Example D18):
2-Acetyl-4,6-dichloro-1,3-dimethylindole Alkylating agent: methyl iodide Propertiee: melting point 115 - 118C.

Example Dl9):
2-Acotyl-4,5,6-trichloro-1,3-dimethylindole Alkylating agent: methyl iodide Proportiee: melting point 129C.

Example D20)~
Ethyl 5-fluoro-3-chloro-1-methyllndole-2-carboxylate:
Alkylatlng agent: methyl iodide Propertlee: colorlees, cryetalline eolid, inexact meltlng point 65 - 69C.

Example D21):
Methyl 5-chloro-3-phenylsulfonyl-1-methyllndole-2-carboxylate by methylatlon of 5-chloro-3-phenyl~ulfonyl-indole-2-carboxyllc acld Alkylatlng agont: mothyl ~odlde Proportle~: colorloe~, ¢ryetalllne eolld, meltlng polnt 192 - 196C.

~xample D22):
Ethyl 3-bromo-5-chloro-1-methylindole-2-carboxylate by tho alkylating agont: methyl iodlde Propertioe: colorlose, cry~talllne eolld, moltlng poi~t 60 - 63C.

Examplo D23):
2-Acetyl-5-leopropyl-1,3-dimethylindole Alkylatlng agont: mothyl iodldo Proportles: colorlese, cryetalllno eolld, meltlng point 74 - 77C. ..

Example D23a):
2-Acetyl-5-benzoyl-1,3-dimethyllndole Alkylatlng agent: methyl iodlde ` ` 2 1 2 ~

Propertie~ colorle~s, cry~talline ~olid, melting point Example D24) ~
2-Acetyl-5-benzoyl-1,3,5-trimethylindole `
Alkylating agent methyl iodide Proportiee colorlese, cry~talline ~olid, meltlng point E Preparatlon o~ l-alkylcarboxylic acid derivatives by dehalogenating hydrogenation were preferably carried out with 3-iodo or 3-bromoindole-2-carboxylic acid derivative~
0 005 mol of tho 3-halogenoindole-2-carboxylic acid o~ter are hydrogenatod in mothanol wlth 300 mg of palladium-on-charcoal (10%), while ~haking at room temperature, untll the theoretlcal uptake of hydrogen ie reached, the eolvent ie dietilled off and water ie added to the re~idue Example El)s Ethyl 5-chloro-1-methylindol--2-carboxylate Propertiess colorleee, cryotalllne ~ubctance, meltlng point 68 - 72C

Examplo E2)s Ethyl 1-(2-dlmothylaminoethyl)indole-2-carboxylate Propertioes pale yellow oil Example E3) Ethyl 1-(3,4-dichlorobonzyl)indole-2-carboxylate Propertiee colorleee, cry~talline eolld; melting point Example E4)s Ethyl 5-chloro-l-ethylindole-2-¢arboxylate Propertlees colorlese, cryetalline eubetance, melting point 53 - 56C

3~3~

Example E5):
Ethyl l-i~opropyl-5-chloroindole-2-carboxylate Properties: colorleee, cryetalline eub~tance, melting point 151 - 155DC.

Example E6):
Ethyl 5-chloro-1-propylindole-2-carboxylate Propertiee: colorlees, cryetalline eubetance, meltlng polnt 49 - 54C.

Example E7):
Ethyl l-butyl-5-chloroindole-2-carboxylate Proportiee: oil.

Example E8):
Ethyl 5-bonzyloxy-1-methylindole-2-carboxylate Propertiee: colorleee, cryetalllne eubetance, melting point 120 - 127C.

Example E9):
Ethyl 5-fluoro-1-msthyllndole-2-carboxylate Propertioe: colorleee, cryetalllne eubetance, meltlng polnt 68 - 69C.

Example E10:
Ethyl S-chloro-1-(4-picolyl)lndole-2-carboxylate Propertlec: melting polnt 76 - 78C.
.:
F. Hydroly~le of lndole-2-carboxylic acld estere i8 carried out, for example, by heating the lndole-2-carboxyllc acid eet~r in a mlxture of water and methanol with about 3 mol of NaOH until the euspen~lon hae dleeolved. Worklng up, after rendering acid to pH 1 to 2 with 2N hydrochloric acid and extraction or cryetalllza-tlon.

~ - 38 A 2 1 ~ 3 Exanple Fl):
5-Chloro-1-methylindole-2-carboxylic acid Properties: decompo~ition at 235 - 239C.

Example F2):
1-(2-D~methylam~noethyl)~ndolo-2-carboxyl~c aci~;
Note: isolation by crystalli2ation from a l~ttle water a~
the inner salt at p~ 4 - 5.
Properties: colorle~, crystalllne eubstance, melting poinS 214 - 216C.

Example F3):
1-(3,4-Dichlorobenzyl)indole-2-carboxylic acid Properties: colorleso, crystalline solid; melting point 152 - 155C.

Example F4):
5-Chloro-1-ethylindole-2-carboxylic acid Properties: colorle~s, crystalline solid; melting point lg4 - 200C.

Examplo F5):
5-Chloro-1-propylindolo-2-carboxylic acld Proporti-~: colorle~s, crystalllne ~olids melting point 152 - 154C.

Example P6):
1-Butyl-5-chloroindole-2-carboxylic acid Proportio~: colorlec~, cry~talllne ~olids molting polnt 175C.

Example F7):
5-Benzyloxy-l-methylindolo-2-carboxylic ac$d Proporties: colorlese, crystalline solid5 melting point 218 - 222C.

Example F8):
5-Fluoro-l-methylindolo-2-carboxylic acid Propertie~: colorless, crystalline solid; melting poinS

~ _ 39 _ ~ 3 ~ ~
227C.

Example F9):
3,S-Dichloroindole-2-carboxylic acid Propertle~: colorles~, Gry~talline ~olid; melting point 235 240C.

Exampls F10):
3,5-Diehloro-l-methylindole-2-earboxylic acid Prop-rtieos colorlooo, cryotalllne oolid5 melting point 250 - 252C.

Example Fll):
3,5-Dichloro-1-(2-dimethylaminoethyl)indole-2-carboxylle aeid Propert~eo: colorleoo, cryotalline oolid; melting point a43 - 246C.

Examplo F12s 5-Methoxy-l-mothyllndolo-2-carboxyllc acid Proportlo~s colorlooo, cryotalllne eolld; moltlng point 211 - 214C.

Example F13s 3,5-Dichloro-1-(4-pleolyl)lndolo-2-earboxylle aeld Propertieos colorloso, cryotallln- ~ol~dt moltlng polnt 228 - 232C.

Examplo F14s 5-Chloro-1-(4-plcolyl)lndolo-2-carboxyllc acld Propertloo: moltlng polnt 288 - 290C.

Example F15s 3-Chloro-5-fluoro-1-methyllndole-2-earboxylic acld Propertiess eolorleoo, eryotalllne oolid; meltlng polnt 222 - 225C.

Example F16:
3-Ioopropyl-5-methoxylndole-2-carboxylic acld, - 40 - ~
crystalline solid; ~elting point 156 - 158DC. ..

Example F17:
5-Chloro-3-phenyl~ulfonyl-1-methylindole-2-carboxylic acid Properties: colorless, crystalline ~olid; melt$ng point 238 - 241C.

Ex~mple F18:
3-~odoindole-2-carboxylic acid Propertles: colorles~, cry~talline solid; msltlng point 177 - 179C.

Example Fl9:
3-Iodo-l-methylindolo-2-carboxyl~c acld Propertles: colorless, cry~talline ~olid; melting polnt 177 - 179C (decomposition) ~;
, .
~. Preparation of alkanodione monophenylhydrazones General synth-sls in~tructlons:
A ~olution of 0.127 mol of NaOH ln 20 ml of wator 1~
added to a eolution of 0.103 mol of ~-kotocarboxylic a¢ld est-r ln 25 ml of ethanol, while ~tlrrlng, and the mlxtur- 1B ~tirred at room tomperature for 30 minutes.
200 ml of water are then added and the mixture i~ stlrrod at room temperature for a furthor 4 hours and extracted wlth about 50 - 100 ml of diethyl ether.
An ice-cold diazonlum ~alt ~olution, whlch was prepared as follows, 18 poured into the aqueous pha~e thus prepared:
150 ml of 18% strength hydrochloric acid are added to 0.1 mol of the anlline component and the mixture 1 heatod, a thlc~ ~u~penslon of crystals usually forming.
After cooling, a solution of 0.1 mol of sodium nitrite i~
added dropwise, while stirring tho~ughly, under the surface of the liquid such that the tomperature is kept between 0 and 5C, and the mlxture 1B ~ubsequently stlrred for a further 10 mlnutes after the addltion. The '~ ~ '2 ~

re~ulting, uEually largely clear ~olution of the diazon-ium ealt i8 pourod in portion~ into the al~aline ~olut$on of the ~-ketocarboxylic acid ester. After addition of about 300 ml of water, the mixture ia brought to pH 5 by introduction of eodium acetate and the cry~talline preclp~tate i8 filtered, or oily precip~tate~ are extracted with ethyl acetate.

Example Gl) Aniline: 4-chloroaniline, ~-keto e~ter: ethyl 2-ethyl-acotoacetate End product: 2,3-pentanedione 3-N-(4-chlorophenyl)-hydrazone; malting polnt 153 - 157C.

Example G2) ;
Anlllne: 4-chloroanlline, ~-keto e~ter: ethyl 2-benzyl-acotoacotato End p~oduct: l-phonylbutano-2,3-dlone 3-N-(4-chloro-phenyl)hydrazonoJ melting polnt 98 - 104C

Examplo G3) Anlllnos 3,5-dlchloroanlllno, ~-koto o~ter: ethyl 2-othylacotoacetato End product: 2,3-pontanedlone 3-N-(3,5-dlchlorophsnyl)-hydrazono7 meltlng polnt 175C

Bxamplo ~4) Anllln-: 2,4-dlchloroanlllno, ~-koto oct-r: othyl 2-othylacotoacetato End product: 2,3-pentanedlono 3-N-(2,4-dlchlorophenyl)-hydrazone; moltlng polnt 48 - 53C

Examplo ~5) Anlllno: 2,3,4-trlchloroanlllne, ~-keto o~ter: ethyl 2-ethylacetoacetate End product: 2,3-pentanodlono 3-N-(2,3,4-~trichloro-phenyl)hydrazone; melting polnt 214 - 218C

~ i ~ ' ' ' ' , , " ' ' ' ' i ' ' . -' '~ . , .

~ ~9~

Example G6) Anil~ne 4-i~opropylaniline, ~-keto ester ethyl 2-ethylacetoacetate End product 2,3-pentanedione 3-N-(4-i~opropylphenyl)-hydrazone; melting point 214 - 218C

Example G7) Anlline 4-Aminobenzophenone, ~'-keto e~ter ethyl 2-ethylacetoacetate End product 2,3-pentanedione 3-N-(4-benzoylphenyl)-hydrazone; melting point 114 - 118C

Example G8) Aniline p-toluidine, ~-keto e~ter ethyl 2-etffl laceto-acetato End product 2,3-pentanedione 3-N-(4-methylphenyl)-hydrazonos melting point 136C (decompo~ition) Example G9) Anillno 3,5-dimethylaniline, ~-keto e~ter ethyl 2-othylacetoacetato End product 2,3-pentanedlone 3-N-(3,5-dimothylphenyl)-hydrazone) melting point 122C (decomposition) Exampl- G10) Anllin- 4-trifluoromothylaniline, ~-keto ~ter ethyl 2-othylacotoacotat-End product 2,3-pantanodion- 3-N-(4-trifluoromethyl-ph-nyl)hydrazono~ melting point 120C

Example G11) Aniline 3,5-bi~-trifluoromethyl-aniline, ~-~eto e~t-r othyl 2-ethylacetoacetate End product 2,3-pentanediono 3-N-(3,5-bi~-trlfluoro-methylphenyl)hydrazone Melting point extend~ from 110 to 160C

Example G12) Aniline 4-cyclohexylaniline, ~-keto e~ter ethyl 2-~; - 43 ~ 21293~

ethylacetoace~ats End product: 2,3-pentanedione 3-N-(4-cyclohexylphenyl)-hydrazone; melting point 107CC

H. Preparation of 2-acetylindole deri~ative~ by acld cycllzat~on of phenylhydrazonea (G.) (modified synthe~i~ of Ra~ur et al., Synthetlc Commun. (1992) 22: 421 - 428) Goneral ~ynthe~i~ lnstructionc:
0.02 mol of a phenylhydrazono (see G~ are dis~olved in 10 70 ml of trifluoroacetic acld, a few drops of trifluoro- `~
methanesulSonic ac~d are addod and the mixture ie boiled undor a reflux condenser for 5 - 10 hour~, the progress of the reactlon being monitored by thin layer chromato-graphy. The ~olvent is dietilled off, water i8 added to the usually dark re~lduo and the cry~talline preclpitate ie filtored off.

Example Hl:
2-Acotyl-5-chloro-3-m~thylindol-; meltlng polnt 172 176C.

Examplo H2 2 2-Acotyl-5-chloro-3-phonyllndole; meltlng point 124C.
:
Examplo H3s 2-Ac-tyl-4,6-dlchloro-3-methylindoleJ melting point 178C
~from a little othanol) Example H4:
2-Acotyl-5,7-dichloro-3-methylindole; meltlng polnt 165 -168C.

Example H5:
2-Acetyl-4,5,6-trichloro-3-mothylindole; long oxtended meltlng point 188 - 202C.

~ - 44 - 2~3~
Example H6:
2-Acetyl-5-isopropyl-3-methylindole: melting point 174 - 177C.

Example ~7:
2-Acetyl-5-benzoyl-3-methyl~ndole; melting point 158 -164C.

Example H8: .
2-Acetyl-3,5-dimothylindole wae methylated in the 1-poeition without ieolation ::

Example H9:
2-Acetyl-3,4,6-trimethylindole; melting point from 156C
: , Example HlO:
2-Acotyl-5-trifluoromet~yl-3-methylindolo: melti~g point from 246C
.
Examplo ~11:
2-Acetyl-5-cyclohexyl-3-methylindoleS meltlng polnt from Examplo ~12:
2-Acetyl-5-trifluoromethyl-3-methylindole~ melting polnt from 314C

I. Proparation of lndole-2-carboxylic acid deri~atlvee from 2-~cetylindole derivativoe Genoral eynthoele inetructione:
12.5 g (0.079 mol) of bromine aro 810wly added dropwleo to a eolution of 12.5 g (0.314 mol) of eodium hydroxide in 120 ml of water, while maintaining a reaction tQmpera-ture of betweon 0 and -5C, and lO0 ml of cooled dioxan~
~14C) are then added.
The eolution i8 now 810wly added dropwiee to a cooled eolution of 0.0242 mol of the 2-acetylindole euch that the reaction temperature ic ~ept between lO and 15C.

29~

The mixture $o ~tirred at 15 - 20C for a further 4 hours and a solution of 0.033 mol of eodium ~ul~lte ln 40 ml of water i~ then added. The reaction mixture i8 boiled under a reflux condonser for 30 mlnute~ and, after coollng to about 60C, about 30 - 40 ml of concentrated HCl are added. After cooling in an ice-bath, the cry~talc are filtsred off.

Example I/l):
5-Chloro-1,3-dimethylindole-2-carboxylic acid, melting point 244 - 247C.

Example I/2):
5,7-Dlchloro-1,3-dlmethylindole-2-carboxyllc acid, meltlng point 228 - 232C.

Example I/3):
4,6-Dlchloro-1,3-dimethyllndole-2-carboxylic acld, melting polnt 212C.

Example I/4):
5-Chloro-l-methyl-3-phenylindole-2-carboxyllc acld, meltlng polnt 218 - 220C.

Examplo I/5):
4,5,6-Trlchloro-1,3-dlmethyllndole-2-carboxyllc acld, meltlng polnt 232 - 237C (decompo~ltion) Example I/6)s 5-~enzoyl-1-methyl-1,3-dlmethyllndole-2-¢arboxyllc acld, meltlng polnt 238 - 240C.

Other precursors Other precursorc 1:
Ethyl 3-~opropyl-5-methoxylndole-2-carboxylate O.01 mol of 4-methoxyphonylhydrazine hydrochloride i~
reacted with ethyl 4-methyl-2-ketovalerate ln bolllng a ~
-~ - 46 -anhydrous ethanol (boiling time: 18 hour~), the ~olvent i~ then evaporated off, water ie thon added, the mixture is extra~ted with ethyl acetate, the organic pha~e i~
wa~hed with aqueous ~odium chloride solution and dried and the solvent i~ distilled off.
Recry~tallization from n-heptane. Colorless cry~tal~, meltlng point ~3 - 90C.

Othor precur~ore 2: (Ullmann arylatlon on the indole)~
A mixture of 0.015 mol of indole-2-carboxylic acid, 50 ml of anhydrous dimethylformamide, O.0165 mol of bromo-benzone, 0.5 g of Cu(II) oxide and 0.032 mol of KO~ 18 bolled under a reflux condenoor, while stlrrlng under an argon atmosphere, for 5 hour~. The dar~ ~uspension 18 poured into ice-water, the mixture i~ stlrred for lS 30 minutes and filtered through a clarifying layer or a layor of actlve charcoal and the filtrate is treated with active aharcoal again. Aftor filtratlon and acldlflcatlon to pH 1 - 2 wlth conc-ntrated HCl, the doolred acld 18 preclpitated, flltered of~, washed several tlme~ wlth water and drled.

Othor precur~or~ 2 a)s S-Mothoxy-l-phonylindolo-2-oarboxyllc aclds colorleo~ cry~tal~, meltlng point 194 -Pharmacological datas Inhlbition of tho Na~/H~ oxchangor of rabblt rythrocytos Whito New Zealand rabblts (Ivanovas) wore glven a etandard diet with 2~ of cholo~terol for ~ix week~ ln ordor to activate tho Na~/H~ oxchango and thu~ to bo ablo to determine tho Na~ influx into the orythrocytes via Na~/H+ exchange by flame photometry. The blood wae ta~en from tho oar artorle~ and rendered non-coagulable by 25 international units of potassium-heparin. A portion of oach sample was used for duplicate determination of the hematocrit by centrifugation. Aliquots of in each case 2~ 2~0~

100 ~1 were u~ed for mea~urement of the Na' otarti~g content of the orythrocyte~

To determine the amiloride-~en~itive ~odium in~lux, 100 ~l of each blood ~ample were incubatad at pH 7.4 and 37C in S ml portion~ of a hypero~molar ~alt/sucro~e medium (mmol/l: 140 NaCl, 3 ~Cl, 150 ~ucroeo, O.1 ouabaln, 20 tris-hydroxymiethylamilnomethane). The erythrocyte~ were thon wa~hed three tlme~ with ice-cold MgCl2/ ouabain eolutlon (mmol/l: 112 MgCl2, 0.1 ouabain) and hemolyzed in 2.0 ml of di~tillod water. The intracellular ~odium contont was dotermined by flame photometry. ~ ~ ;

The net Na~ influx wa~ ¢alculated from the diffsrence between the ~odium ~tarting value~ and the sodium contont of the erythrocyte~ after incubatlon. The sodium influx whlch can be inhibltod by amilorlde wa~ obtained from the dlfference between the ~odium content of the erythrocyte~
after incubation with and without am~lorlde 3 x 10-4 mol/l. Thi~ procedure wa~ al~o followod wlth the compound~ ~ccording to the lnv~ntion.

R~ult~

Inhibition of the Na~/H~ exchangers ~xample IC50 mol/l 52 4 x 10-8 53 5 x 10 B
54 2 x 10-7 j 61 3 X 10-7 , 69 _5 x 10-8 104 2 x 10-7 :
106 = S ~ Lo ~

Claims (19)

1. A benzo-fused heterocyclic compound having 5-membered ring, of the formula 1 (I) in which:
X is N or CR(6), Y is oxygen, S or NR(7), A and B together are a bond or are both hydrogen, if, at the same time, X is CR(6) and Y is NR(7), one of the substituents R(1) to R(6) is a -CO-N.C(NH2)2 group, the other respective substituents R(1) to R(6) are hydrogen, F, Cl, Br, I or (C1-C6)-alkyl, up to two of the other substituents R(1) to R(6) are CN, NO2, N3, (C1-C4)-alkoxy or CF3, up to one of the other substituents is R(8)-CnH2n-Z-, n is zero to 10, wherein the alkylene chain -CnH2n- is straight-chain or branched and wherein a carbon atom can be replaced by an oxygen or S atom or by an N atom, R(8) is hydrogen, (C2-C6)-alkenyl, (C3-C10)-cycloalkyl, which is unsubstituted or substituted by 1 to 4 methyl groups or an OH group, or can contain an ethylene group -CH=CH-, and wherein a methylene group can be replaced by an oxygen or S atom or by an N atom, phenyl, which is unsubstituted or substituted by 1 to 3 substituents from the group consisting of F, Cl, Br, I, CF3, CH3-S(O)s-, s is zero, 1 or 2, R(9)-Wy-, R(9) is H, methyl or ethyl, W is oxygen or NR(10), R(10) is H or methyl, y is zero or 1, CmF2m+1' m is 1 to 3, 1- or 2-naphthyl, pyridyl, guinolyl or isoquinolyl, Z is -CO-, -CH2-, [CR(11)(OH)]q-q is 1, 2 or 3, R(11) is H or methyl, oxygen, -NR(12)-, R(12) is H or methyl, -S(O)s-, s is zero, 1 or 2, -SO2-NR(13)-, R(13) is H or (C1-C4)-alkyl, R(7) is hydrogen, (C1-C10)-alkyl, (C2-C10)-alk-enyl or R(8)-CnH2n-, or a pharmaceutically tolerated salt thereof.

2. A compound of the formula I as claimed in claim 1, in which:
X is CR(6) or N, Y is NR(7), A and B together are a bond or are both hydrogen, if, at the same time, X is CR(6) and Y is NR(7), and the radicals R(1) to R(7) have the meaning given.

3. A compound of the formula I as claimed in claim 1, in which:
X is CR(6) or N, Y is NR(7), A and B together are a bond or are both hydrogen, if, at the same time, X is CR(6) and Y is NR(7), one of the substituents R(1) to R(6) is a -CO-N=C(NH2)2 group, and the other respective sub-stituents R(1) to R(6) are hydrogen, F, Cl, Br, I or (C1-C6)-alkyl, up to two of the other substituents R(1) to R(6) are CF3 or (C1-C4)-alkoxy, up to one of the other substituents R(1) to R(6) is CN, N02, N3 or R(8)-CnH2n-Z-, n is zero to 4, wherein the alkylene chain -CnH2n- can be straight-chain or branch-d and a carbon atom can be replaced by an oxygen or S atom or by an N atom, R(8) is hydrogen, (C3-C6)-alkenyl, (C5-C8)-cycloalkyl, which is unsubstituted or substituted by 1 - 2 methyl groups or an OH group, and wherein a methylene group can be replaced by an oxygen or S atom or by an N atom, phenyl, which is unsubstituted or substituted by 1 to 3 substituents from the group consisting of F, Cl, Br, I, CF3, CH3-S(O)s-s is zero, 1 or 2, R(9)-Wy-R(9) is H, methyl or ethyl, W is oxygen or NR(10), R(10) is H or methyl y is zero or 1, CmF2m+1, m is 1 to 3, pyridyl, quinolyl or isoquinolyl, Z is -CO-, - CH2-, oxygen, -NR(12)-, R(12) is H or methyl, -S(O)s-, s is zero, 1 or 2, -SO2-NR(13)-, R(13) is H or (C1-C4)-alkyl, R(7) is hydrogen, (C1-C6)-alkyl, (C2-C4)-alkenyl or R(8)-CnH2n-,

4. A compound of the formula I as claimed in claim 1, in which:
X is CR(6), Y is NR(7), A and B together are a bond or are both hydrogen, if, at the same time, X is CR(6) and Y is NR(7), and R(1) is -CO-N=C(NH2)2 and the other respective substituents R(2) to R(6) are hydrogen, F, Cl or Br, up to two of the substituents R(2) to R(6) are CF3 or (C1-C2)-alkoxy, up to one of the substituents R(2) to R(6) is R(8)-CnH2n-Z-, n is zero, 1 or 2, wherein the alkylene chain -CnH2n- is straight-chain or branched and wherein a carbon atom can be replaced by an oxygen or S atom or by an N atom, R(8) is hydrogen, phenyl, which is unsubstituted or substituted by 1 to 3 substitu-ents from the group consisting of F, Cl, CF3, CH3-S(O)s-, s is zero or 2, R(9)-Wy-, R(9) is H or methyl, W is oxygen, y is zero or 1, pyridyl, quinolyl or isoquinolyl, Z is -CO-, -CH2-, -S(O)s,- or oxygen, s is zero, 1 or 2, and R(7) is (C1-C6)-alkyl, (C3-C4)-alkenyl or R(8)-CnH2n-.

5. A compound of the formula I as claimed in claim 1, from the group consisting of 5-chloro-1-methyl-2-indolylcarbonyl-guanidine hydro-chloride, 5-chloro-1-ethyl-2-indolylcarbonyl-guanidine hydro-chloride, 3-chloro-1-methyl-2-indolylcarbonyl-guanidine hydro-chloride, 3,5-dichloro-1-methyl-2-indolylcarbonyl-guanidine hydrochloride, 5-fluoro-1-methyl-2-indolylcarbonyl-guanidine hydro-chloride, 3-chloro-5-fluoro-1-methyl-2-indolylcarbonyl-guani-dine hydrochloride, 4,6-dichloro-1,3-dimethyl-2-indolylcarbonyl-guani-dine hydrochloride, 2-phenoxy-1-phenylindole-3-carboxylic acid guanidide methanesulfonic acid salt, 2-chloro-1-phenylindole-3-carboxylic acid guanidide methanesulfonic acid salt, 1-methylindoline-2-carboxylic acid guanidide hydro-chloride, 5-fluoro-1-methylindoline-2-carboxylic acid guani-dide hydrochloride.

6. A process for the preparation of a compound of the formula I ae claimed in claim 1, which comprises reacting a compound of the formula II

(II) in which ono of the eubetltuente R(1)' to R(5)' is a -CO-L group and L is a leaving group which can easily be replaced nucleophilically, and the other respoctive substituents R(1)' to R(5)' have the meaning given, with guanidine to form the acylguanidine group shown in formula I, -CO-N = C(NH2)2 and, if appropriate, converting the product into the pharmaceutically tolerated salt.

7. The use of a compound as claimed in claim 1 for the preparation of a medicament for the treatment of arrhythmias.

8. A method for the treatment of arrhythmias, which comprises adding the customary additives to an active amount of a compound I as claimed in claim 1 and administering the mixture in a suitable dosage form.

9. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of cardiac infarction.

10. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of angina pectoris.

11. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic states of the heart.

12. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic states of the peripheral and central nervous system and of apoplexy.

13. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment or prophylaxis of ischemic states of peripheral organs and extremities.

14. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment of schock states.

15. The use of a compound I as claimed in claim 1 for the preparation of a medicament for use in surgical operations and organ transplants.

16. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the preservation and storage of transplants for surgical measures.

17. The use of a compound I as claimed in claim 1 for the preparation of a medicament for the treatment of diseases in which cell proliferation is a primary or secondary cause, and therefore its use as an anti-atherosclerotic or as an agent against delayed diabetic complications, cancer diseases, fibrotic diseases, such as pulmonary fibrosis, hepatic fib-rosis or renal fibrosis, and prostate hyperplasia.

18. The use of a compound I as claimed in claim 1 for the preparation of a scientific tool for the inhibi-tion of the Na+/H+ exchanger and for the diagnosis of hypertension and proliferative diseases.

19. A medicine comprising an effective amount of a compound I as claimed in claim 1.