AU637767B2

AU637767B2 - Annelated tetrahydropyridine acetic acid derivatives, the preparation and use thereof

Info

Publication number: AU637767B2
Application number: AU39925/89A
Authority: AU
Inventors: Dietrich Arndts; Walter Losel; Otto Roos; Gerd Schnorrenberg; Georg Speck; Ilse Streller; Werner Traunecker
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1988-08-16
Filing date: 1989-08-16
Publication date: 1993-06-10
Anticipated expiration: 2009-08-16
Also published as: FI893832A0; DK399789D0; NO893270L; EP0358957A1; HUT51277A; AU3992589A; ZA896205B; PH27356A; YU160189A; DD297640A5; DD295379A5; PL161521B1; DD285595A5; PT91451A; IL91301A0; KR900003129A; NO893270D0; JPH02160767A; FI893832A; HU208434B

Description

AUSTRALIA

PATENTS ACT 1952 637 1 -M 1 -4 b t iF06 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: he Lodged: Comnplete Specification Lodged: Accepted: ~Lapsed: Published: Priority: 0 C *Related Art: Ja S C c o go 1TO BE CMEPLIED BY APPLICANT Name of Applicant: Address of Applicant: Actual Inventors: Address for Service: BOEHRINGER INGELHEIM INTERNATIONAL GMBH of D-6507 Ingelheimn am Rhein, Federal Republic of Gennany WALTER LOSEL, CYOTTO ROOS, GERD SCHNORRENBERG, DIETRICH ARNDTS, GEORG SPECK, ILSE STRELLER and WERNER TRAUNECKER CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Carplete Specification for the invention entitled: ANNELATED TETRARYDROPYRIDINE ACEI'IC ACID DERIVATIVES, THE PREPARATION AND USE THEREOF The following statement is a full description of this invention, including the best method of performing it known to us:- I I la 24N54486/000 "Annelated tetrahydropyridine acetic acid derivatives, the preparation and use thereof" This invention relates to new annelated tetrahydropyridine acetic acid derivatives, to processes and new intermediates for preparing them, and to pharmaceutical preparations which contain these new compounds or structurally similar known compounds and the use of the new compounds or structurally similar known compounds for cardioprotection.

According to one aspect of the invention, we have 10 found a new and surprising use for compounds of general formula (I) A 4 S"

R

6

(I)

R

0 wherein A represents a benzo, thieno or indolo group; R represents a hydrogen atom or a halogen (F,C1,Br,I) atom, or a (C_-4)alkyl, hydroxy,

(C

1 _4)alkoxy, amino, methylthio, methanesulphonyloxy or methanesulphonamido group, or 25 two adjacent R substituents together represent -O-CH or -O-CH2-CH2-O-; m represents 1, 2 or 3 if A is a benzo or indolo group and 1 or 2 if A is a thieno group; R represents a hydrogen atom or a (C 1 _4)alkyl group; 2

R

5 represents a hydrogen atom, or a (Cl_ 10 )alkyl, phenyl, phenyl(C15)alkyl, (C 1 -4)alkoxy or -NHCOX group (wherein X is (C 1 5 )alkyl); R represents a hydroxy, (C1- 4 )alkoxy or -NR R group, wherein R 7 and R independently of each other represent

S.

1 15 2

S••

0

S.

o•

S•

a hydrogen atom, or a branched or unbranched alkenyl group with 3 to 6 carbon atoms, or a branched or unbranched alkynyl group with 3 to 6 carbon atoms, or a branched or unbranched alkyl group with 1 to 12 carbon atoms, in which the alkyl chain may be substituted by one or more of the following substituents: hydroxy, (C1- 4 )alkoxy, di(C 1 4 )alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl, phenyl or phenyl which is mono- or polysubstituted by hydroxy, methoxy or fluorine; or R represents a hydrogen atom and R represents a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group; or R 7 and R together with the nitrogen atom to which 3 they .arebound represent either a pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl ring, in which the piperazinyl ring may optionally be N-substituted by a methyl, unsubstituted phenyl, mono- or di(C1- 4 )alkoxyphenyl, pyrimidinyl or phenyl(C1- 4 )alkyl group; 0e *000

S

C. S

S.

S

7 R9 with R 4 may also represents a group herein R 9 ,representc a hydrogen at---mor a C- 3 lkyi. group; or the pharmaceutically acceptable salts thereof with an inorganic or organic acid in cardioprotection.

0 o o• According to a further aspect of this invention, we provide pharmaceutical preparations comprising a compound of general formula as hereinbefore defined or a pharmaceutically acceptable salt thereof with inorganic or organic acids in admixture with a pharmaceutically acceptable carrier, diluent or excipient, with the exception of: compounds of formula (Ig) o*S e o0o50 CH 0 (Ig) CO R wherein mull Am d Ik M I 4

R

4 is a hydrogen atom,

R

5 is a hydrogen atom and

R

6 is a NH(CH 2 3 0H, NH(CH 2 2 H or NH(CH 2 3 0CH 3 group; or compounds of formula I wherein o 0@ 15 OS S 00 0 A is an indolo group; R represents a hydrogen or halogen atom, or a

(C

1 4 )alkyl or (Cl-4)alkoxy group; m is 1,

R

4 represents a hydrogen atom or a (C1_4)alkyl group;

R

5 is a hydrogen atom;

R

6 represents a (C 1 4 )alkoxy or an NHR 8 group, wherein R represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms (which may be substituted by phenyl); or we provide pharmaceutical preparations as described above comprising a compound of general formula (Ih), 0 0 0@ o a (Ih) 00 wherein R 6 is an ethoxy or -NHCH 2 CH(CH 2 group.

According to a further aspect of the invention, we provide compounds of general formula (I) 5 m or the pharmaceutically acceptable salts thereof with an inorganic or organic acid, wherein A, R, m, R 4

R

and R are as hereinbefore defined with the exception of compounds of formula (Ic)

S.

S

bSSS 4S OS 0

S

(Ic) wherein R represents a hydrogen atom, or a hydroxy or methoxy group, sees 0 S we 5*

S

m is 1, 2 or 3,

R

4 and R 5 are hydrogen atoms and

R

6 is a hydroxy or ethoxy group; or compounds of formula (Ic) wherein m is 2 and 30 R represents methoxy groups in positions 6 and 7, and

R

4 is a hydrogen atom, R 5 is an ethyl group and R 6 is a methoxy group, or

R

4 is a methyl group, R 5 is a hydrogen atom and R 6 is a hydroxy or ethoxy group, or

R

4 is a hydrogen atom, R 5 is a methyl group and R 6 is a -6 ethoxy group; or (ii) compounds of formula (Id), (Id) se. 0 15 0 wherein R is a hydrogen atom or a methoxy group, R is a methyl group, *5 is a hydrogen atom or a phenyl. group and R is an ethoxy group; or (iii) compounds of formula (Ie),

H

C-N R~ ~B I I (le) 055.

4 S SO S 5* 4. 0 o 55 4* 0* S 0* 30 wherein R represents a hydrogen atom, or a (C 1 4 )al~kyl, hydroxy or (C 1 )alkoxy group, or two adjacent R 8 substituents together represent -O-CH 2 R represents a hydrogen atom, or an alkenyl or alkyl group which may be substituted by hydroxy, methoxy, dimethylamine or phenyl; (iv) compounds of formula (If), 7 (If) R4 i.

Lu

O

wherein R represents a hydrogen or halogen atom, or a (C1- 4 )alkyl or (C1- 4 )alkoxy group, R represents a hydrogen atom or a (C 1 _4)alkyl group; 6 8 R represents a (C 1 4 )alkoxy or an -NHR group, in which R represents a hydrogen atom or a (C1_4)alkyl group, whilst the alkyl may be substituted by phenyl.

Any formulae represented for compounds of'general formula I should be take to include all isomeric forms whether stereoisomeric and/or tautomeric forms thereof.

'r S 6 U 6 U 6 0 ego.

9 Some of the compounds covered by the general definition of formula I wherein A is a benzo or indolo group are known and some of these have already been described as tranquillisers, such as those reported 25 in: Eur. J. Med. Chem.- Chim. Ther, 14(1), 77-89 Heterocycles, 179-82 Syntheses 474-7 J. Med. Pharm. Chem. 3, 505-17 (1961) 30 EP 2 18 57 US 3 021 331 US 3 081 306 It is, however, new and quite surprising that such compounds included within the overall generality of compounds of formula I should have been found to have 8 a cardioprotective activity.

The compounds of general formula I may generally be prepared by methods known per se.

According to a further aspect of the invention, we provide a pro-ess for preparing a compound of formula as hereinbefore defined, wherein a compound of formula (II), A ss r -R a) conversion of a compound of general formula (II) *whe Ry g S....group -CH(R wherein R4 is a hydrogen atom to obtain the corresponding compound of formula wherein R4 is 15group

C

wherein A, R, m, R R and R are as hereinbefore codef ined is reduced to provide a compound of formula followed if necessary or desired, by one or more of the following reactions: he rresnin a) conversion of a compound of general formula (I) wherein R is a hydroxy or (C 1 )alkoxy group, into the corresponding amide wherein R is the group NR R (in which R 7 and R 8 are as hereinbefore defined except when R 7 together with R 4 represents a group b) N-alkylation of a compound of general formula (I) wherein R is a hydrogen atom to obtain the corresponding compound of formula wherein R 4 is a (C 1 4 )alkyl group; c) conversion of a compound of formula wherein R is a hydroxy group into the corresponding ester (R 6

(C

1 4 )alkoxy); 9 0S S. 0

S

S.

565e 15 5@50 S S *5 S. 55

S

*SSS

S S S@ S

S.

5

SS

5

*S

d) hydrolysis of a compound of formula wherein R 6 is a (C 1 4 )alkoxy or NR7R 8 group (in which R 7 and

R

8 are as defined above except when R 7 together with

R

4 represents a group -CH(R 9 into the corresponding free acid; e) isolation of any individual diastereoisomers; f) isolation of the compound in free form or in the form of its acid addition salt; g) conversion of a compound of general formula (I) wherein R 4 is hydrogen and R 6 represents the group

-NHR

8 into a compound of formula in which R 4 together with R 7 represents a group -CH(R 3 by reaction with an aldehyde of general formula R 9

CHO,

(in which R 9 is as hereinbefore defined); h) reduction of a compound of formula in which R 4 together with R 7 represents a group -CH(R 9 as prepared in above to give a compound of formula in which R 7 represents hydrogen and R 4 represents a group -CH 2

R

9 *S S Preferably, this process is applied to compounds of formula (II) wherein R is a hydrogen atom.

(Rn) Red.

(R)

m (IIa) (Ia) In order to prepare a compound of formula wherein 10

R

4 is a (C1_4)alkyl group, either of the following alternative methods may be used: i) a compound of formula (la) is N-alkylated; ii) a compound of formula (IIa) is converted into a quarternary ammonium salt thereof by reacting with (Cl_ 4 )alkyliodide) and subsequently reduced to yield the compound of formula wherein R 4 is a (C1- 4 )alkyl group.

C

S.

0@ 0 55

S

15 Complex metal hydrides (such as sodium boranate, sodium cyanoborohydride, optionally in conjunction with a noble metal catalyst) or catalytically activated hydrogen are suitable for the reduction of the compounds of formula (II) or (IIa).

S

C

The reduction is preferably carried out in a solvent such as methanol or ethanol at ambient temperature or optionally at elevated temperature up to the reflux 20 temperature of the reaction mixture.

In reaction above, the starting compound (optionally after previously protection of the basic nitrogen ring and/or activation of the carboxy or ester group) may be reacted with a corresponding amine NHR7R 8

(III).

Examples of reactive carboxylic acid derivatives include: acid halide, acid azides or mixed acid anhydrides with an aromatic or aliphatic carboxylic acid, alkylcarbonic acid or dialkylphosphoric acid, etc.), as well as acid amides (for example with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole, etc.) or active esters (such as cyanomethyl, methoxymethyl, vinyl, propargyl or p-nitrophenyl esters, etc.) or esters with 11 dimethylhydroxylamine, 1-hydroxysuccinimide, dicyclohexylurea, etc.; the active imidazolides are preferred.

Amide formation is generally affected in an inert solvent such as dioxan, acetonitrile, dimethylformamide or a mixture of one or more of these solvents, optionally in the presence of an organic or inorganic base as acid acceptor.

However, it is also possible to carry out the reaction without a solvent, using an excess of the amine.

The reaction temperature can vary within wide 15 limits depending on the starting materials used and may be between about 0°C and the boiling S* temperature of the reaction mixture.

With regard to reaction above, all the known alkylating agents are suitable for the N-alkylation provided that they have sufficient reactivity, e.g.

S. active alkylesters such as dialkylsulphate, alkyl toluenesulphonate or alkyl fluorosulphonate or alkylhalides such as alkylbromides or alkyliodides.

The reaction may be carried out at temperatures up to the boiling point of the reaction mixture. Here, the term 'alkyl' represents (C l_)alkyl. The aminoalkyl- Soo 1-4 ation may also be carried out according to Leuckart- Wallach (Ber. dtsch. Chem. Ges. 18, (1985), 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; 4 (1950) No. 378). In general, the substance is treated with an approximately 30% aldehyde solution, preferably formalin solution in the presence of formic acid at reflux temperature. The time taken ranges from 3 to 18 hours. This reaction is particularly suitable for compounds wherein R is not NH 2 or

NHR

8 12 In reaction above, the separation of the diastereoisomers occurs spontaneously to some extent by crystallisation or may be effected by applying the conventional methods of racemate separation, e.g.

column chromatography.

In reaction above, the free base of general formula may be converted into the acid addition salts thereof in a manner known per se.

U

6*

C*

0 S*

C

C.

SC

Inorganic acids suitable for salt formation include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric or nitric acids. Suitable organic acids include acetic, propionic, butyric, methanesulphonic, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, cinnamic or ascorbic acid.

In reaction above, the reaction is conveniently 20 carried out with a 30% aldehyde solution at elevated temperature. Preferably, the reaction is carried out with formaline solution in the presence of formic acid at reflux temperature.

In reaction above, the reduction may be carried out with NaBH 4 in glacial acetic acid, possibly with the addition of a solvent (as described by C. Djerassi, H.J. Monteiro, A. Walser, L.H. Durham J.

Am. Chem. Soc. 88, (1966) 1792). For this purpose, a compound of general formula (V)

R

8 -13 wherein R, m, A, R 5

R

8 and R 9 are as hereinbefore defined is dissolved in glacial acetic acid and an excess of sodium boranate is added in batches with cooling and stirring.

The duration of the reaction is determined to a very great extent by the length of the group R 5 and may range from 1 to 15 hours at ambient temperature. The reaction times increase in the following sequence:

R

5 H CH 3 C2H 5 C4H C5H11 Reaction times are either not or only insignificantly influenced by the R 0e *6 15 6* 6

S

The reaction temperature is largely uncritical and may be between 5°C and the boiling temperature of the reaction mixture. For safety reasons, the reaction can be carried out whilst cooling with ice at a temperature ranging between 5°C and ambient temperature.

The solvents may be, apart from glacial acetic acid, which is simultaneously present as a reactant, mixtures of glacial acetic acid and a suitable inert solvent, such as THF, dioxan, ethanol, etc. It is preferred to carry out the reaction in glacial acetic acid.

*S

25 0 005 A preferred embodiment of the reduction is for the starting compounds to be dissolved in glacial acetic acid. With stirring and cooling to 5*C the finely powdered NaBH 4 (4 10 fold excess) is added in batches. After the reaction has ended, water is carefully added, the mixture made alkaline with dilute NaOH and extracted with CH2C1 2 The organic phase is washed with water, dried over Na2SO 4 and concentrated by evaporation. The residue is crystallised, optionally after purification on a silica gel column 14 (eluant: CH 2 Cl 2 /MeOH 100:1.0).

The compounds of formula (II) may be prepared using methods known per se, for example by the method described in German Patent Application P 37 18 570.5.

In the presence of a condensing agent, a malonic acid diamide of general formula (IV)

S

15

H

CH

2 -CH2-NHCO -C CO R 6 m

R

(IV)

wherein R, m, R 5 and R 6 are as hereinbefore defined and Ar represents a phenyl, 2- or 3-indolyl or 2- or 3-thienyl group, may be cyclised to yield the corresponding compounds (II) and

(R)

m

(R)

m A, m, R, R and R are as hereinbefore defined, whilst

R

4 is a hydrogen atom or a (C1-4)a.lkvyl group.

g The actual procedure adopted will be discussed further hereinafter. If the reaction is carried out, for example, with a mixture of phosphorus pentoxide and (C1- 4 )alkylsulphonic acid, the compounds II and II' wherein R 4 is (Cl_ 4 )alkyl will be obtained in addition to the corresponding compounds II and II' wherein R is hydrogen.

Suitable condensing agents for this process include strong Lewis acids such as phosphorus oxychloride, 15 phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride and also inorganic acids such as polyphosphoric, sulphuric, fluorosulphonic and hydrofluoric acid, or mixtures of condensing agents, such as a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C1_4)alkylsulphonic acid, e.g. containing approximately 10% by weight of P 2 0 5 .0 If a compound IV is cyclised in the presence of the mixture of phosphorus pentoxide and (C1_4)alkylsulphonic acid, there will be obtained, in addition to the corresponding compounds II and II' wherein R 4 is a L5 hydrogen atom, the analogous compounds II and II' wherein R 4 is a )alkyl group, as hcs already been mentioned. Preferably, this alternative process is carried out with methanesulphonic acid.

6 6 6 66° 6 Cyclisation may be carried out in the presence or absence of a solvent. Any inert solvent is suitable S. S provided that it has sufficient solubility for the .6 reactants and a sufficiently high boiling point, e.g.

benzene, alkylbenzenes toluene, xylene), chloro- 25 benzenes, chloroform, acetonitrile and decalins. In a preferred variant of the process, the condensing agent, e.g. phosphorus oxychloride or a mixture of (C1_4)alkylsulphonic acid and phosphorus pentoxide, is used without any added solvent.

Preferably, cyclisation is carried out with phosphorus oxychloride or, in difficult cases, with a mixture of phosphorus pentoxide and (C1_4)alkylsulphonic acid (preferably methanesulphonic acid). The reaction may be carried out within a wide temperature range, preferably with heating to 50*C up to approximately the boiling point of the reaction mixture.

16 The reaction time required will be between 2 and hours, depending on the starting compound IV.

The tautomers of general formulae II and II' wherein

R

4 is a hydrogen atom may be separated by known methods, e.g. by column chromatography.

Compounds of general formula can be prepared as described in reaction above.

The compounds of general formula II and II' in which A 4 5 6 is an indolo group, R, m, R R and R are as hereinbefore defined for the compounds of general formula I, are new compounds, with the exception of those wherein i.

*6 a .9 r m is 1, R represents a hydrogen or a halogen atom, or (C1_4)alkyl, or (C 14)alkoxy group, RR represents a hydrogen atom or a (C 1 4 )alkyl group, R represents a hydrogen atom,

R

6 represents a (C 1 _4)alkoxy or an -NHR group, wherein R represents a hydrogen atom or a (C 1 _4)alkyl group, whilst the alkyl may be substituted by phenyl.

S L 5 .5 9

S

S.

2 *m 0S The compounds of general formula described possess, as mentioned hereinbefore, potentially valuable therapeutic properties both in their form of the bases and their physiologically acceptable salts.

In particular, these substances have been found to have a significant cardioprotective activity. This activity was determined as described below.

As is well known, the myocardiac Ca 2 content is a measurement of hypoxic heart damage or the heart damage caused by toxic doses of catecholamine (Higgins et al., Mol. Cell. Cardial. 10, 427-438, 1984; 17 Nakanishi et al., Am. J. Physiol. 242 437-449, 1982; Fleckenstein, A. Vortrfge der Erlanger Physiol.

Tagung 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenalin-induced myocardial calcium uptake is a measurement of the cardioprotective efficacy of calcium antagonists (Fleckenstein, loc.cit.), Calmodulin inhibitors (Higgins) and other drugs, e.g. Beta-adrenolytics (Arndts, Arzneimittelforschung 25, 1279-1284, 1975).

The cardioprotective activity was determined on conscious rats after subcutaneous or oral *o administration of the active substance using the method described by Arndts (loc.cit) and the potency of the test substances was given as the H50 value.

i* This value corresponds to the dosage which brings about a 50% inhibition in the myocardial radio-calcium uptake caused by the administration of 30 mg/kg of isoprenaline The compounds tested were found to be up to five times more effective than the known commercial product Propranolol.

25 In vitro tests on the smooth muscle (strips of aorta) have shown that the compounds according to the invention are calcium antagonists with a new mechanism of activity.

8 Calcium antagonists inhibit the flow of calcium ions through the membrane into the cell. This inhibition affects the voltage-dependent (slow) calcium channel in the cell membrane. The determination of flows of calcium ions through the membrane in strips of tissue under potassium depolarisation using the method described by van Breemen clearly indicates calcium antagonists (van Breeman et al., Chest. 78, 157, p 18 165; 1980; van Breemen et al., Am. J. Cardiol. 49, 507-510, 1982; Casteels et al. Pfllgers Arch. 392, 139-145, 1981; Deth and van Breeman, J. Membrane Biol.

363-380, 1977).

Investiqation in isolated rat hearts o* 0 0 0 0 *e

S

If an isolated heart which has been kept for some time under ischaemic conditions is perfused normally again, heart function is not immediately normalised. Indeed, there is a transitional.period characterised by contractions and arrhythmia. This arrhythmic phase is caused by changes in the function and structure of the myocardial cells with intracellular calcium over- 15 loading (Hess and Manson, J. Mol. Cell. Cardiol. 16, 969, 1984). Compounds with a cardioprotective activity such as verapamil and diltiazem reduce the calcium overloading and improve the contractile behaviour when perfusion is resumed (Watts et al., Am.

20 J. Physiol. 238, H 909, 1980; Meno et al., Am. J.

Physiol. 247, H 380, 1984). The cardioprotective activity was tested on isolated rat hearts under ischaemic conditions with subsequent re-perfusion.

0 0 00 Method I: Isolated hearts are exposed to a marked oxygen deficiency as a result of a substantial reduction in the coronary flow (more than As a result of disturbances in cardiac metabolism, cardiac activity rapidly comes to a standstill and after the reduction in coronary flow has ended the cardiac activity is reestablished only with some delay and irregularity and regular activity is observed only after 10 to minutes. Cardioprotective compounds added to the perfusion medium during the period of flow reduction reduce the period of irregular heart activity.

19 Compound Conc. [p/ml] Reduction in arrhythmia phase from 10-15 min to

A

B

C

Alinidin 13.2-26.6 6.6-13.3 6.6 13.3-33.3 6.2-10 4.0-4.8 2.3 3.25-4.15 2.6 min 3.75 min Propranolol 6.6 6.6

S

S. S S OS Method II: If the coronary flow of isolated hearts is reduced by 75%, the heart initially reacts with a decrease in the amplitude of contractions, and the heart does not stop for about an hour. Cardioprotective substances added to perfusion medium during the period of the reduction in flow prevent the decline in the amplitude of contractions. 20 oe Compound Concentrations required 55 S S 55 pg/ml, 1.0 pg/ml, 8.3 pg/ml.

5

S

OS..

Seosi.

S

Comparison: Alinidin Compounds A to F: 20 CH 3- 0 q// Ai 9 CN -C H2 H CH -0 3HN CH 3H C-HC0 C c 1I49 -O N -l 2- 2 l

S.

5 0 @5 S 0 S 55 5 0 50 0

OS**

S S S. S. 0 5

S

CHi 0 c Cil C H 111- CH-CO-NHI-CH 2-CH-CH2

*SS@

S S 05 S

S.

S S 55

OS

S 5

S.

C 6 1 5 (Cli 2

S.

5 S

S

@55555

S

:H-CONH-Ci 2-CH 2-P/ N 22

N-H

H-CONH-C H 4 9

CH

3 0 c 6 H 5 (CH 2 2

HCI

CH CH

N

7

I/C

2 NCH3 n-C 4H 11 21 .0.0 :-'006 e

U

On the basis of these findings, the compounds of general formula and their physiologically acceptable salts with acids may be used as active constituents for drugs for treating coronary heart disease.

According to a further aspect of the invention we provide pharmaceutical compositions which comprise compounds of general formula as defined above or pharmaceuitcally acceptable salts thereof with inorganic or organic acids in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

The pharmaceutical compositions may be provided in a form suitable either for oral or parenteral use. The main preparations used are tablets, coated tablets, ampoules and syrups. The single dose of these preparations is generally between 1.0 and 200 mg, preferably between 20 and 50 mg per 75 kg of body weight. Generally, depending on the gravity of the 20 case, 1 to 3 single doses should be administered daily.

U. US S S 55*

U

US*

55*

S.

The Examples described hereinafter are intended to illustrate processes and compositions of the invention, without being construed as limiting.

S

22 Example 1 2-(1,2,3,4-Tetrahydro-6-methylmercapto-l-isoquinolinyl)- N-(1-pentyl)-hexanamide 2.5 g of 2-(3,4-Dihydro-6-methylmercapto-l-isoquinolinyl)-N-(l-pentyl)-hexanamide are mixed with 0.5 g of NaBH 4 in 100 ml of methanol in batches and the resulting mixture is stirred for 3 hours at ambient temperature. After the reaction has ended, any excess NaBH 4 is destroyed, the solvent is removed in vacuo and the residue is distributed between CH 2 C1 2 and water. After the organic phase has been dried over anhydrous sodium sulphate, the mixture is concentrated by evaporation and the residue is crystallised from 15 ethyl acetate/petroleum ether.

M.p. Example 2 Ethyl 2-(1,2,3,4-tetrahydro-6-methylmercapto-l- 20 isoquinolinyl)-hexanoate hydrochloride.

g of ethyl 2-(3,4-dihydro-6-methylmercapto-lisoquinolinyl)-haxanoate are combined with 5.2 g of solid NaBH 4 added in batches, in 200 ml of boiling ethanol and the mixture is stirred at boiling temperature. After the reaction mixture has been worked up the hydrochloride is formed and crystallised from ethanol/ether.

M.p. 123*C Example 3 Ethyl 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-l-isoquinolinyl)-hexanoate hydrochloride 60 g of ethyl 2-(3,4-dihydro-6,7-dimethoxy-l-isoquinolinyl)-hexanoate are catalytically hydrogenated in 600 ml of ethanol, with the addition of 17 g of 23 concentrated HC1, in the presence of 6 g of PtO 2 at and hydrogen at 5 bar. After the catalyst has been removed, the reaction solution is evaporated down and the product is crystallised by the addition of ether.

M.p. 141-145°C Example 4 Ethyl 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl- 1-isoquinolinyl)-hexanoate hydrochloride A mixture of 12 g of ethyl 2-(1,2,3,4-tetrahydro-6,7dimethoxy-l-isoquinolinyl)-hexanoate, 33 g of formalin and 16 g of formic acid is heated to 15 boiling for 1 hour. After the reaction mixture has been concentrated by evaporation, it is made alkaline with half-saturated soda solution, then extracted with CH2C12, the organic phase is washed with water, dried over Na 2

S

4 and evaporated down in vacuo. The 20 reaction product is purified on Al 03 activity stage III (eluant CC1 4 and converted into the hydrochloride.

M.p. 156-157°C (ethanol/ether) Example 2-(l,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-lisoquinolinyl)-hexanoic acid hydrochloride 15.5 g of ethyl 2-(l,2,3,4-tetrahydro-6,7-dimethoxy-lisoquinolinyl)-hexanoate are heated to boiling in 100 ml of conc. hydrochloric acid for 1.5 hours.

After the reaction has ended, the mixture is substantially concentrated by evaporation in vacuo and a diastereoisomer is crystallised by the addition of acetone 180-183°C) whilst the second diastereoisomer remains in the mother liquor.

S 24 Example 6 2-(1,2,3,4-Tetrahydro-6-methylmercapto-l-isoquinolinyl)- N-(1-pentyl)-hexanamide 3 g of ethyl 2-(1,2,3,4-tetrahydro-6-methylmercapto-lisoquinolinyl)-hexanoate are heated to boiling in ml of n-pentylamine for about 14 hours. After the reaction has ended (monitored by TLC), any excess amine is removed in vacuo, the residue is taken up in CH2C12, extracted several times with water, the organic phase is dried over anhydrous Na 2

SO

4 concentrated by evaporation and the residue is purified on silica gel (eluant CH 2 C12/MeOH 100:3).

M.p. 95 0

C

S

S..

5* S S 55 5 *5 50

S

5.5

S

OS S

S.

S

S.

5*

S

5

S

S..

Example 7 2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-methyl-l-isoquinolinyl)-hexan-N-[2-(2,4-dimethoxyphenyl)-ethyl]-amide 20 2.58 g of 2-(l,2,3,4-tetrahydro-6,7-dimethoxy-2-Nmethyl-1-isoquinolinyl)-hexanoic acid are stirred in ml of anhydrous DMF with 3.2 g of N,N'-carbonyldiimidazole for 4 hours at ambient temperature. Then 3 ml of 3,4-dimethoxyphenylethylamine are added and after standing for 15 hours at ambient temperature the mixture is worked up. This reaction takes place without any structural change. If an isomer is used as the starting material, the corresponding isomer of the final compound is obtained.

Diastereoisomer 1: m.p. 94-96"C (ethyl acetate/ligroin) Diastereoisomer 2: m.p. 75-78*C (ethyl acetate/ligroin) Example 8 2-(1,2,3,4-Tetrahydro-6,7-dimethoxy-l-isoquinolinyl)hexan-N-(2-phenylethyl)-amide-hydrochloride 25 Og

C

COg 0@ S C gg g.e.

C C S. e.g :1.5 go S. g CC 00 S C g 20

S.

0 g

C.

go C g go a) 2-[1,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-(9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl I-hexanoic acid.

At 0 0 C, over a period of 30 min, a solution of 9.1 g of 9-f luorenylmethyloxycarbonylchloride in ml of dioxan is added dropwise to a mixture of 10.8 g of 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-lisoquinolinyl)-hexanoic acid, 70 ml of 10% aqueous soda solution and 35 ml of dioxan. After the mixture has been stirred for 1 hour at 0 0 C it is left to stand for 15 hours at ambient temperature, then poured onto 1000 ml of ice water and extracted 3 times, eacht ime with 100 ml of ether. The aqueous phase is adjusted to pH 2, the solid white precipitate is suction filtered and after being dissolved in CHC 3 /MeOH it is crystallised by the addition of petroleum ether.

M.p. 169-1720C.

b) 2-[l,2,3,4-Tetrahydro-6,7-dimethoxy-2-N-(9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl.]-hexan-N- (2-phenylethyl) -amide 2.65 g of 2-[1,2,3,4-tetrahydro-6,7-diw.ethoxy-2-N- (9-f luorenyl-methyloxycarbonyl) -1-isoquinolinyl] -hexanoi acid are reacted in 15 ml of anhydrous DMF with 1 g of N,N'-carbonyidiimidazole. After 1 hour, an equivalent quantity of 2-phenylethylamine is added; after a further 15 hours at ambient temperature the mixture is worked up, purified over silica gel (eluant CHC 2 /MeOH 100:2) and crystallised from ethyl acetate/petroleum ether.

M.p. 168-1100C.

C gg g C g g ogg ggg 0 C c) 1.5 g of 2-[l,2,3,4-Tetrahydro-6,7-dimethoxy-2-N- (9-fluorenylmethyloxycarbonyl) -1-isoquinolinyl]3-hexan- N-(2-phenylethyl)-amide are stirred in 30 ml of a 26 S 5

*S

S. 5

S

See mixture of trifluoroacetic acid and anisole for 15 hours at ambient temperature. After the removal of the solvent, the residue is distributed between CH 2 Cl 2 and a 10% sodium carbonate solution, the organic phase is washed with water, dried over Na 2

SO

4 concentrated by evaporation, the hydrochloride is formed and crystallised from ethanol/ether.

M.p. 154-156*C.

Example 9 Ethyl 2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-lisoquinolinyl)-butyrate hydrochloride a) Ethyl 2-(3,4-dihydro-6,7-dimethoxy-l-isoquinolinyl)-butyrate methyliodide 0.35 g of 2-(3,4-dihydro-6,7-dimethoxy-l-isoquinolinyl)-butyrate and 1 ml of methyliodide are heated to 60°C in 10 ml of an ethanol/nitromethane mixture for 1.5 hours. After the reaction has ended (monitored by TLC) the mixture is evaporated down in vacuo and the residue is crystallised from ethanol/petroleum ether.

M.p. 183-185'C.

b) 0.5 g of ethyl 2-(3,4-dihydro-6,7-dimethoxy-lisoquinolinyl)-butyrate methyliodide are stirred for 3 hours in 5 ml of ethanol at ambient.

temperature with 0.1 g of NaBH 4 After the reaction has ended (monitored by TLC) the mixture is worked up in the usual way and the hydrochloride is formed.

M.p. 164-166*C Example 2-(H-1,2,3,4-Tetrahydropyrido[3,4-b]indol-1-yl)-N-(2-morph 20 S. 5 e

C

a ago 0 27 g *i 'f 15 4 a, a) 2-(1H-3,4-Dihydropyrido[3,4-b]indol-1-yl)-N- (2-morpholinoethyl)-acetamide g of 2-(3-indolyl)ethylaminocarbonylacetic acid- N-(2-morpholinoethyl)-amide and 45 ml of POC1 3 are heated to 40-45*C for 5 hours in 250 ml of an acetonitrile/benzene mixture After the removal of the solvent and any excess POC1 3 the residue is distributed between ice water and chloroform, purified over Al203 (eluant:

CH

2 C1 2 /MeOH=100:3) and crystallised from ethyl acetate/ether with the addition of ligroin 55-75*C.

b) The product thus obtained in part is reduced analogously to Example 1, the product is isolated and converted into the hydrochloride (title compound).

M.p. 262-265°C In accordance with the processes described above or the above Examples, the compounds listed in the following Tables may analogously be prepared.

a a.

a.

sa a a k a a,.

a S a d S *a U a a.

a c Sep C a 6 .d 5 3 Table 1: No. R I R 4 Salt form OCH 3

OCH

3 OCH 3 OCH 3 OCH 3 OC

H

3 OCH 3

IH

OH

OCH 3 OCH 3 OCH 3 OCH 3 OCH 3 HH(CH

H

2 4 CH MIH3 111CH 2

CH

NH-CH 2COCH HHCH 2CII=f2 2 CH 2 N NC H 3) 2I N c C 2

H

5 2 130-134 111-114 221-225 137-140 209 -213 224-226 116-118 182-184 92- 98 76- 78 125-128 110-112 HC1 B S HC1 HC 1 HC 1 Bs 8s HqC1I B S

BS

B S 8 H 0CH 3 OCH 3 0CH 3

OCH

0 C H 3 OCH 3 CH 3

CHM

3 11H 0Cfl 3 OCH 3 CH 3 12 HI OCHJ3 OCHJ CH 3 13 HI OCH 3 0CM 3 Hi N1 0 C 2 H 5 CH 3 C160- 163 HCI

S

0

S

0

S

0 S SO@

S

0 6 5 0 0 *560S@S 0 S S *5 OS 0 0 5 r 0 00 00 No. R R R 4 5 R

R

Salt form OC

H

3 0CH 3

OCH

3 0CH 3 0CH 3 0CU 3 OCh3 OCH3

OCH

3

OCH

3

OCH

3

OCH

3

CH

3

CU

3

CU

3

CU

3

CH

3

CU

3

CH

3 C H 3

CH

3 MIJCH C If 3 2 1 i c H 2 CH( C1H 3 2 Nt

CH

2 CH c1 3 2

N((CH

2 2

CH

3 2 N(

(CH

2 3

CH

3 )3 2 N( (CH2 )3 ci 3 2

NH(CH

2 4 CH 3 21 H OCH 3

OCH

3 22 U 0CU 3 0CU 3 23 U OCU 3

OCU

3 24 H OCi3 OCH3 H 0CH 3 OCH3 26 H

OCH

3 OCiU 3

?H-CU

2 0 HI(-C 2 0 NJH-(CH 2 2

OCH

3 IH-i CHU 2 2 _3 198-202 183-185 97-101 22 5-229 66- 74 201-203 202-205 187-192 206-211 113-117 194-197 198-201 HC1 HC1 HC1 HC1 HC1 HC1 HC1 HC1 NC1

BS

HC 1 HC1

CU

3

CH

3 cli 3 201-206 HC1

S.

0S S *5 S S

S

.SS S No. R' R 2 R R R 6 S0 S S so *0 too 00 00 0 Salt form 27 H OCH 3 OCH 3 28 H 0CH 3 0 CH3 29 H OCH 3 OCH 3 0CH 3 0CH 3 0CH 3 0CH 3 0CM 3 0CH 3 0CH 3 0CH 3 0CH 3 0CH 3 0C it 0CH 3 0CM 3 0CH 3 OCH 3 OCH 3

H

Hf

H

If C H 3 CH 3 C

H

3

CMH

3

CMH

3

CMH

3 CH 3 CH 3 CH 3 CH 3 CH 3 ~C H 3 C H 3 NH- CHM 2 2 ocf 3 IIM-(CM 2 2i- CH 2) 2 NHCH(CH 3 CH 2 Cif 2 Cif 2

CH(CII

3 2 11H(CIf 2 3 N( CMif 3 )2 N H (C H 2 2 KL* 1 1H CH 2 2 CH NH-(CH 2 2 0CH 3 U H- C H 2 C H (C 11 3 2

UHC

2 2 OC"3 INCH 2 CH( CM 3 2

IIH(CII

2 4 C11 168-172 115-121 99-100 2 18-221 194- 195 81- 94 201 -206 188-191 169-172 192- 195 135-188 184-187 173 -17 6 2 06-208 205-206 HC1 HC1 HC 1 MC 1 MC 1 HC1 HC1 HC 1 HC 1 HC1 MCi MCi MC1 HC1 38 H OCH 3 0CH 3 CH 3 39 41 0CM 3 0CM 3 OCH 3 OCH 3 0CM 3 0 C H CM 3

H

CH 3 CM2H c2 H5 No.

4j2 43 44 46 47 48 49 51 52 53 54

R

H

H'

H

R

2 OCH 3 0CH 3

OCH

3

OCH

3

OCH

3

OCH

3 OCH 3 o Cif 3

OCH

3 OCH3

OCH

3 OCH3

OCH

3

OCH

3

R

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3 0CH 3

OCH

3

OCH

3 OCH 3 OCH3

OCHJ

R 4

H

H c H c C fi 3 c C H3 c

R

5

C

2

H

5 O H

CH

25g

C

2

H

5

C

2

H

5

C

2

H

2 5 :2 5 c 2 H5 '2 c 2

H

:Hs 2 H5 2 H 2H5 0 0 10 0 SS 0 0 I, S S C

R

6 go: oo to 0. 0. 00 01 0 0 to :0 *t S S D *0 OS S S S 0 5 *5 5.

NH(C11 2 2 OCi N(

(CH

2 2 C1 3 2

HN(CH

2 3 C11 3 2 HH-CH _R 2 0 HHCH(CH3

YCH

2

CH

2 c 2 iCi( 011H3 2 NH-(cii f2 HH-CCH2~ 2 Oci3 NH-(Ci NOHC H 2 U11 c it 2 3 H If 3 Oc 211 5 N( (CH 2

CH

3 2 ?4CCH) 3

CH

3 2 NH H 03 3 OH Mp 194-195 187-190 189-191 202-206 167-201 189-198 212-214 197-201 165-179 138-165(d) 129-146(d) 201-206 18 4 -185 184 -185 Salt form HC1 HC1

HCI

NC

HC

HC1 HC1 HC1 HO1 HC1 HC1 HCl

HCI

HC1 56 H OCH 3 OCH 3 C H c25 14 S- 14 7 HCI

S.

S S S S S S S S 0* S S S *S S S *5 *55 S S *SS S S S S S S S S S S 55 5O 55 S S S S *5 S* *SS S No. R R R 3 R R Salt form 57 H OCR OCR CRH 58 H OCR OCR CRH 59 H OCR OCH 3 CRH C 2R C2 CR2H HR(C 2 2 OCR 3 61 62 63 64 66 67 69 71 72 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3

OCRJ

OCR 3 OCR 3 OCR 3

OCII

3 OCR 3 OCR 3 OCRJ3 OCR 3 OCRJ3 OCRJ3 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3 OCR 3 CH 3

H

11

H

(CR

2 H 3

CH

3

(CRH

2 3

CH

3

(CRH

2 3

CRH

3

(CRH

2 3

CRH

3

CRH

2 3

CRH

3

(CRH

2 3

CHI

(C H 2 3 CH H 3 (CR 2 3 CR3

(CHR

2 3

CR

3

(CHA

2 3 C 3 0OC 2 H NH CRH 3 2HCH2 3 NRCH 2

CHC

HHCH 2 CH= CR 3 2

NHCH

2 CRH CR) 2 HR (0RH 2 4

CHR

?JHCH( CR 3 C 2 CH 2 CH 2 CRIf CR1 3 2 NH O 2 C H( 0 H)IC H 3 HR(C 2 2 OCR Oc 2 H3 168-169 157 -159 182-183 164-166 214-215 203-204 183-184 168-178 186 19 1-192 197-199 183-186 190-193 130- 135 167-169 HO 1 HC1 HCl Hcl

HOI

HNl

OS

Rcl Hcl HO 1 RC1I HC 1

NCI

HCl

HN

141-145

S

S S C C S S S 0 S Se C S S C C S 0 0 5 S CS SO *S S C C S S S. *SS No. R- R 2 R 3 R4 R5 R 6 M P Salt form o cI 13 0CH 3 OCH 3 0CH 3 H 0CM 3 0CM 3 76 H OCH 3 OCH 3 77 H OCH 3 0CM 3 78 H 0CH 3 0CH 3 (CM 2 3 CH 3 (CH 2 3

CHM

3 (CM 2 )3 CH 3 (CM 2 )3 CH 3

(CH

2 3 CH 3 C H 2 3 3 C .H 3 (CH 2)

CM

(H2 3 CH3 (CH 2)3

CHM

(CH 2 3 CH 3 (CH 2 3 CH 3 (CM 3CHM NII H 2 30 COi 3 HI(1 2

HM(CH

2 I 32I Nil-( CH 0 2d C 13 Hii'( CH 2 )2 /P 0CM3 HM-(CM H 3 C NH-(ClCM 2 ni(c 11 2 2 11c It 3 )2 9HM(Cl 2 3 1(CH 3 ~2 H C C 2 H 5 2 H Cit 2 3(C" 3 )2 178-179 1 4 2- 144 154-156 79 H 0CM 3 OCH 13 OCH 3 0CH 3 OCH 3 0CM 3 OCH 3 0CM 3 0CM 3 0CM 3 17 2-174 168-172 176-178 .204 -206 224 -225 121-123 188-191 149- 151 146-151 MCi Bs

MCI

MCi HC 1 MCi Mli

MCI

84 H CH3 OH3 H H 0CH 3 OCH 3 H N3 H 11- CH -C c I I 167- 170 MHO 9*

R

we.

s* a 9 S S C I S 5 5 @5 55 5 S S C *5 S@ 1 2 3 No. R R R Salt form 86 H OCH 3 OCH3 (CH 2 3 C 3 7 H OCH 3 0CHJ 0CH 3

OCH

3 OCH 3

OCH

3 0CH 3 0CH3 91 H

OCH

3 OCH 3

OCH

3

SCH

SCH3 OCH 3

OCH

3

H

0CH 3 (CH 2 CH 3

(CH

2 3

CH

3 (CH 2 3 CH3

(CH

2 3

CH

3 (CH 2 CH 3 (CH2 3

CH

3

(CH

2 3 CH3

(CH

2 3

CH

3

(CH

2 3 CH3

(CH

2 3

CH

3

(CH

2 3

CH

3

(CH

2 3

CM

3

(CH

2 3

CH

3 (c 11 2 3 CH 3 OCH 3 i

NHCH(CH

3

)C

2 11 5 H C H 3 2 NH(CH 2 3 0 H 0 HH(0M1 2 2

CH(CII

3 2 0C 2

H

NL(CH

2 4

C

3

H((CH

2 2

CH

3 2 IM(CII(0H 002

IH(

2 2 N if I OCH3 182-184 110-118 183-200 192-194 168-170 186-188 175-185 122-123 94- 95 179-180 94- 96 75- 78 156-157 161-163 138-140 HC1 HC1

HC

HC1 HC1

HC

BS

MCi B S

BS

HC1

BS

MO]i 96 H OCH 3

OCH

3 C1 3 97 H

OCH

3 OCMJ 98 H

OCH

3 OCH 3

CM

3

C

3 99 H OCH 0CM3 CH3 100 H OCM 3 C3 CH 3 3 4.: R R

S.

R

0 S 0 4 S S 5 S S a No. RI R2 101 H 0CH 3 102 H

OCH

3 103 H

OCH

3 104 H1 0C4 3 5 *e S S S .5 0* *e 0 S S *5 *S MD Salt form 105 106 107 108 109

OCH

3

OCH

3 OCH 3

OCH

3 OCH 3

OCH

3

OCH

3 OCH3

OCH

3

OCH

3

OCH

3

OCH

3 OCH3 OC

H

3

CH

3

CH

3

CH

3

H

(CH

2 3

CH

3 (C

H

2 3

CH

3

(CH

2 CH 3

(CH

2 4

CH

3 (CH )4

CH

(CH

2 4

CH

3 (CH) C 13'

(CH

2 4 C1H 3 C H2 4 CH 13 (CH 2)4

CH

(CH2)4 CH 3 (C 2 )4 CH3 (CH )4 CH3 (CH )4CH3 (CH CH3 (CH 2)4

CH

3 N( (CH 2 5

CH

3 0H

HH(CH

2 4

CH

3

NH(CH

2 2 CC( C11 3 2 HHC( CH 3 )3

IIH-CH

2 C IIC II2

IIH-CH

2 2 H-

CH

2 2 3)2

HI(CH

2 2-KZ NIICII 22 1 ci Nil- MI 2Z 2 -0 1 156-158 169-170 180- 183 134-137 112-114 172 88- 90 114-116 121-122 182-185 138-140 152 157 108 116-118 125

HCJ

HCI

HC1I

BS

HCI

9S

BS

110 H OCH3 OCH3 i11 H 112 H 113 H 114 H

QCH

3 OCH 3

OCH

3

OCH

3

OCH

3 0CH 3

OCH

3

OCH

3

BS

HC1

BS

Bs

BS

115 H OCH 3 OCH3 116 H OCH3 0CH 3 0*

S

SO

S

4 5 R R

S

S S S S 5 45 S S S 55 S 0 5 55 90 *e 00S .900 *09 090 00 No. R 1 RR salt form 117 H OCH 0 CH 3 (CH 2 )4 CH 3 NH- CH 2 2 CU2 3 114- 116 118 119 120 121 122 123 124 .125 126 127 0 C 3 OCH 3 OCH 3 OCH 3 OCH 3 OC

H

3 OCH 3 OC

H

3 OCH 3 OCH 3

H

OC

H

3 C 6Hf c6 H5 CU6H c6 H5 C 6 H 5

CUH

c6 C c6 H5 C 6H5 c6 H5

CUH

UHf CU 2 4 CH 3 N (C C 2 CH 2 CH) C U 2 C 6 I15 OH3 141 f2 2 of NH-(CU 2 NH-CU 2

HU

25 UU(C 3) OCH 3 NHCI

U

3

NHN-CU

3 153-160 UCi 156-160 HC1 188-192 UCi 150-152 *BS 140- 143 BS 138 (decomp) HC1 151 BS 136 B S 153-154 BS 153 BS 159-160 BS from 128 C (decomp) 162-163 BS 128 U 129

OCH

3 if

OCH

130 OCH 3 OCH U C c6 H5 UF-CU 2

C

6 f 5

I..

0* S S

S

S S S S S *0 S S OS S S S .5 S 556 S S S S S S S S S S S.

55 *0 S S 55 6 5* 5S *e St 555 2o.3RR 4 R R 6p Salt form

OCH

131 OCH 3 OCR 3

OCH

C 6H5 132 H OCH 3 OCR 3 133 H OCR 3 OCRIt 3 Hf 134 135 H 136 H o C 11 3 o c H13 o C If 3 OCH 3

C

6 If 5 C 6 H5 C 6 H 5 OCR 3 OCR 3

H(CR

2 2 q OCR 3 OCH 3

H]

N c 2 5 2 14( C11 2 OCif 3 HH( C 2 H 1 tH.0 H 0 OC 3 2 2-d C 3 tHCIf2 2 0 OC H

OCR

3 uC 2CRf 5

NH(CR

2 )3 3 CH 3 u if( CRf 2 2011f 58- 59 137 H OCH 3 OCR 3 138 H OCR 3 OCRi 3 180- 182 168-171 125- 127 172- 175 2 10o-2 13 132- 134 166-169 115-1 18 163 168 152-154 117-119 123- 124 HC1 HC1 B S

NCI

139

H

OCR 3

OCR

3 CR 3 OCR 3 OCR 3 OCR 3 OCR 3 OCRf 3

OCR

OCR 3 0 C H1

OCR

OCR 3 Cl H 3

H

C 6

H

5 (CH 2 2 C 6

RH

5 (CH 2 )2

C

6

H

5 (C C 2 2 4..

S

45 S C

S

04. sf C P 0 a a 10 S Ow c 0 a I 55 C S* No. R 1 R 2 R R R Salt form 145 H OCH 3 OCH 3 146 H OCH 3 OCH3 14 OH3 OH3 147 H OCH 3 OCH3 o C H 3 OC

H

3 OCH 3 OCH 3 o C H 3 OCH 3 C 6 H 5 (CH 2 2 C6 H 5(CH22 c6 15 (H2 2

C

6 H 5 CH 2 2 C 6 H 5 (CH 2 2

C

6 H 5 (CH 2 2 C 6 H 5 (CH 2 ~2 C 6 H 5 (CH 2 2 C 6 H 5 (CH 2 2 C 6 H 5 (H2 .2 NHCH(CH 3 (CH 2 3 CH (CH) 2 HH(CH 2 2 Eil

NH(CH

2 2 /0" IH( CH H 0 HH( CH2 2 )c C 6 1 5 NIIC

C

6 H 5 Ill-CH 7 H HF NH(CH 2 2 -d OCH3 14H(CH CH 3 144- 146 135-136 139-140 208-213 119-121 129-132 162- 164 14 1-144 156-159 129 124-126

BS

Bs 8S HC 1

BS

152 H OCH 3 OCH 3 1~53 H OCH 3 OCH3 154 H OCH 3 OCHI 155 H OCH 3 OCII a.

d *8

S

SO

SOS 0 S S a 0 0* U S S St a S d .5 p 555 S S S S L b S S 55 56 S I Sb ~S c~ e. St t 1 2 3 4 5 R R R R R Salt form No.

156 H OCH 3 OCH 3 CH 3 157 H 0CH 3 OCR 3 C H3 c 6 15 (CH 2 2 C H (CH 2 IIH(CH 0 2 2, NI( CH 2 CR 3 105- 106 106-108 158 H OCH 3 OCH 3 159 160 161 162 163 164 OCH 3 OCH 3 oH c13 OC 3 OCH 3

OC

OCSJ3 QCH 3 OCH 3 OCH 3 OCH 3 C

H

3 OCH 3 OCH 3 OCH 3 0CH 3 OCH 3 o cu 3 OCH 3 OCR 3 OCH 3 OCH 3 165 H OCH 3 c 2 H5 NII(CH 2) CiI WHH C 2 4 cH 3 ?JHCH 2 CH(CH 3 HH-CH CH=Clf 2 2 NJ H (C H 2- C C 3

IIII(CH

2 )2 WHCH 2 2 OCH 3 O c 2 H 5 O Cf NH(CH

-OCHR

OCI I

OA

NH(CRA

2 2 2 14-217 162 122-123 174 137 1 87 89- 90 71- 182-184 9 t -96 SC 1 SC 1 SC 1 HC1 SC 1

HCI

HCi j OC H OCR 167 H OCH 3

OCH

168 H OCI 1 3 0C 1 3 CH 3 169 ii OCHI OCH 3 CH 3 OCH 3 (CR 2 3 )CH 3

(CHR

2 3 CH 3 75-70 40 Table 2: R 4 R M P Salt form 0* S. 6 S *5 0* SS S

*SS*

S S. OS

S

S S *5 *5 0

S.

6 6*

SS

0 S 5..

S

1 70 171 172 173 174 175 CH 3 C 6

H

5 Ii 6 H 5 H C 6

H

5 H

C

6 H 5 (CH 2 2 H c 6 H 5 (CH 2 2 NH (CHt)-j NH(CH 0 2 2 N 0 N(C 2H52 N 0 171- 172 101-105 128 (decanp) 210-215 191-193 145 (decanp) Table 3: R 6 R 5 R 0 C 6H5 c6 H5 C 6H5

NHQ)

NH QCH -C H- NH-(CH N 0 175 (decomp) 195 (clecomp) (decomp) 41 Table 4: H 5/ R 0

S

S. S

S..

S.

S 55 5 5 SS S S. SO S 0 0 Salt form H C 6H5

H

NH(CH

2 2 N 0 NH -CH 2 CH( C H 3 )2 OC2 H5 197-200 0555 S S S. S 55 S S 55

S.

S S 55 180 181 182 262-265 165-168 128-130 05 S S 555.

555555 S S 42 Table H 3CO H 3CO MP (OC) Salt form

SS

0 0S 0 0* *000 0 000 0* 00 S SS Se 0 0 S 0 183 184 185 186 187 189 190 191 192 193 CH 3-CH 2-CH 2- CH 3- C =CH-CH 2 CH 3O-CH 2-CH 2- CH3 C 2 2 4 CH (CH 3' 2 3 (CH 3 2N-(CH 2)3 (CH 3) 2 CH-CH 2 (CH 3 2CH- CH 3O-(CH 2) 3- CHi 3-CH 2-CH 2-

H

CH3 95-9 6 9 6-100 87-91 Oil 87-90 74-7 5 170-190 (decomposed) 84-90 144- 14 5 71-7S 119-124

BS

HC 1

BS

9S

BS

0005 0 5 05 0 0 0@ 00 0 5

*S

00 0 0 194 1 QJCH 2 -C 2 195 C -(CH 2) 4- 196 Q -CH 2 -CH 2 197 (CH 3 2 CH-CH 2 198

OL

CH3 3 CR2H C2 H5 C 11 9 6-102 93- 8 6-89 110-112 123-125 BS 43 Table 6

CH

3 co I N CH 3 CO Nr. R i Salt form 199 -CRH CH 2 *li H f I :200 -CR H 226-228 C 3 *201 -CH CR=CH H 183-186 C 2 2 202 -CR 2-CR 2-OCR H 198-203 C C203 -H 2 CH 2 N(CH 3 2 H 173-176 HCl 204 -CR 2-CR 2-CR 2-CH -CR8911 C CIH2-C 2-C 2 2( 32 H- 168-179 HC1 208 CRCR -CH- 189-194 HCl 0* 2 2 2 3 so 0 206 -CR -CR -C 0-1 c 000,20 -H2-C 2- 2 (CH 3 2 H 1682-172 RC1 207 -CR 2- C- CH2C 3H 218-228 HC1 208 -CR CHCR 3 CH 3 8-9 HC1 323 m: 210 C 2 2 -R(CR 3 CH 3 182-184 RC1 211 -CR 2-CRCR -OCR CH 2069-208 RC1 212 2 2H 3 7-7 C ::212 C 2

C

2 CH 3 CH 3 1375 HCl 213 -CH CR..HOC CH 181-184 HCI 2 2- 3 217 -CR CR CR4R)C CH 3 168-270 HC1 44 Nr. Mp. (OC) Salt form

OCH

3 220 -CH 2CH -C 3 221 -CRi CH 2CH CR Cif

S

S SO

.~SS

S S @5 *5* S S *5 S. S*

S

0* S S 5* *5 S 0

SS

S

222 CH 2

CH

2

-K'

223 F 224 CR CHR OCR 225 -CH(CH 3 )CH 2 CH 2 CH 2 CH(CH 3 2 226 227 -CH CH 2 -3 C nC H nCH nCH nCH n-C H 4 9 n-C H n-C 5H 1 159-164 HC1 124-133 HC2.

192-202 HC 1 157-162 HC1 171-175 RCL 151-159 HC1 178-184 HCI 192-193 HC 1

V

228 229 230 231 -CH 2CH(CR )2 -CR CH=CH2 -CH 2-CR -N(CH )2 -CH CR OCR 164-167 76-78 (A) 181 47-62 (A) RC 1

HCI

HC 1 HC 1 232 -H2C 111-118 1~ 233 234 235 236 237 238 239 240

-CHR

2 C(C 3 2 -CR CR CR CR CR -CHR CR

CR

-CR CR H(C- -CH 2-0 9 5-9 6(A) 68-7 3 (A) 5 4-57 (A) 90-92(A) 197 -19 8 150-152 13 4-13 8 107- 10 9 HC I HC 1 HC 1 RC 1

HCI

RC 1 B S B S 45 Mp. (OC) Salt form 241 242 243 244 -CH -CR 2N 2 -CH CH 2 2 (H) -OCH 3 -OCR 3 n-C H9 155 127-128 HC1 B S HC 1

S.

S S

C

C. S C C

SC

e.g.

C S

C

.5.5 C C CC *C 0

C

(A:Amorphous isomer mixture Compound No. Isomer mixture S S SC C

SC

5 C

CS

C.

C

C.

229 231 233 234 235 236 50:50 70:3 0 40 9 0:3.0 60:4 0 7 0 C CC

S

CCC.

C C 46 Pharmaceutical Preparations a) Coated tablets 1 tablet core contains: Active substance of general formula I Lactose Corn starch Gelatine Magnesium stearate 30.0 mg 100.0 mg 75.0 mg 3.0 mg 2.0 mg 210.0 mg

S

4e S S

S*

S S SS S *0S* S S

S

S S 5

SS

S S Method The mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatine solution through a screen with a 1 mm mesh size, then dried at 40 0 C and passed through a screen again. The granulate thus obtained is mixed with magnesium stearate and compressed. The resulting cores are coated in the usual way with a coating applied by means of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated 25 tablets are polished with beeswax.

5 S 000 b) Tablets Active substance of general formula I Lactose Corn starch Soluble starch Magnesium stearate 30.0 mg 100.0 mg 70.0 mg 7.0 mg 3.0 mg 210.0 mg 47 Method The active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granulate is dried and intimately mixed with lactose and corn starch. The mixture is then compressed to form tablets weighing 210 mg.

c) Capsules

S.

56 0 1

S.

S

Active substance according to formula 1 Lactose Corn starch Talc 20.0 mg 230.0 mg 40.0 mg 10.0 mg 300.0 mg Method 0555

S

@4 S 5S

S

S@

6 The active substance, lactose and corn starch are first mixed in a mixer and then in a grinding machine.

The mixture is returned to the mixer, thoroughly mixed with the talc and mechanically packed into hard gelatine capsules.

Se S. S 4.

*56505

Claims

54486000.43 Claims 1. A method of treating cardiac conditions in a human or animal subject which comprises administering to the said subject an effective amount of a compound of general formula I I wherein A represents a benzo, thieno or indolo group; R represents a hydrogen atom, a (C 1 _4)alkyl group, a halogen Cl, Br, I) atom, a hydroxy, (C 1 4 )alkoxy, amino, methylthio, methanesulphonyloxy or methanesulphonamido group, or two adjacent R substituents together represent -O-CH 2 or S-O-CH 2 -CH 2 25 m represents 1, 2 or 3 if A is a benzo or indolo group and 1 or 2 if A is a thieno group; R 4 represents a hydrogen atom or a (C 14 )alkyl group; 30 R 5 represents a hydrogen atom, or a (C 1 0 )alkyl, phenyl, phenyl(C1- 5 )alkyl, (C 14 )alkoxy or -NHCOX oo ,group (wherein X is (C 1 s)alkyl); R 6 represents a hydroxy, (C 1 4 )alkoxy or a -NRR group, wherein R 7 and R 8 independently of each other represent 49 a hydrogen atom, a branched or unbranched alkenyl group with 3 to 6 carbon atoms, or a branched or unbranched alkynyl group with 3 to 6 carbon atoms, or a branched or unbranched alkyl group with 1 to 12 carbon atoms, in which the alkyl chain may be substituted by one or more of the following substituents: hydroxy, (C 1 i4)alkoxy, di (C 14 alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl, phenyl or phenyl which is mono- or poly- substituted by hydroxy, methoxy or fluorine; or R 7 represents a hydrogen atom and R 8 represents a phlnyl, fluorophenyl, pyridyl or N-benzylpiperidyl 25 group; or R 7 and R 8 together with the nitrogen atom to which they are bound represent either a pyrrolidinyl, 30 piperidinyl, morpholinyl, or piperazinyl ring, in which the piperazinyl ring may optionally be N-substituted by a methyl, unsubstituted phenyl, mono- or di(C. 4 )alkoxy- 35 phenyl, pyrimidinyl or phenyl(C 1 4 )alkyl group; or a pharmaceutically acceptable salt thereof with an I 50 inorganic or organic acid.
2. A pharmaceutical preparation comprising i) a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof with inorganic or organic acids, with the exception of: a) compounds of formula I, wherein A is a benzo group, R is a methoxy group (in positions 6 and 7), m is 2, R 4 is a hydrogen atom, R 5 is a hydrogen atom and R 6 is a NH(CH 2 3 0H, NH(CH 2 2 0H or NH(CH 2 3 0CH 3 group; b) compounds of formula I wherein A is an indolo group; R represents a hydrogen atom, a (CI 4 )alkyl group, a halogen atom or a (C,4)alkoxy group; m is 1, 25 R 4 represents a hydrogen atom or a (C- 4 )alkyl group; R 5 is a hydrogen atom; R 6 represents a (C 14 )alkoxy or an NHR 8 group, wherein R 8 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms (which may be 30 substituted by phenyl); c) compounds of formula I, wherein A is a benzo group, R is a methoxy or ethoxy group in positions 6 and S* 35 7, m is 2, o -o R 4 and R 5 are hydrogen atoms, 51 R 6 is a NHR 8 group, wherein R 8 is a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group; d) compounds of formula I, wherein A is a benzo group, R is a methoxy group in positions 6 and 7, m is 2, R 4 is a methyl group, R 5 is a phenyl group and R 6 is an ethoxy group; or ii) a compound of general formula Ih, H(Ih) 0 wherein R 6 is an ethoxy group or a -NHCH 2 CH(CH 3 2 group, or pharmaceutically acceptable salts thereof; 25 in association with a pharmaceutically acceptable carrier, diluent or excipient.
3. A compound of general formula I (R)m 4 (I) 6 *ii 52 or the pharmaceutically acceptable salts thereof with an inorganic or organic acid wherein A, R, m, R 4 R 5 and R 6 are as hereinbefore defined, with the exception of: compounds of formula (Ic) R 6 R R 0 wherein R represents a hydrogen atom, or a hydroxy or methoxy group, m is 1, 2 or 3, R 4 and R 5 are hydrogen atoms and R 6 is a hydroxy or ethoxy group; or compounds of formula (Ic) wherein m is 2 and R represents methoxy groups in positions 6 and 7, and R 4 is a hydrogen atom, R 5 is an ethyl group and R 6 is a 25 methoxy group; or R 4 is a methyl group, R 5 is a hydrogen atom and R 6 is a hydroxy or ethoxy group; or R 4 is a hydrogen atom, R 5 is a methyl group and R 6 is an S. ethoxy group; (ii) compounds of formula (Id), *ee 53 A 6 (Id) 0 wherein R is a hydrogen atom or a methoxy group, R 4 is a methyl group, R 5 is a hydrogen atom or a phenyl group and R 6 is an ethoxy group; (iii) compounds of formula (Ie), R x- Y- R H (Ie) C R8 II 0 wherein 25 R represents a hydrogen atom, or a (C_ 4 )alkyl, hydroxy or (C 1 4 )alkoxy group, or two adjacent R substituents together represent -O-CH R 8 represents a hydrogen atom, or an alkenyl or alkyl group which may be substituted by hydroxy, methoxy, 30 dimethylamine or phenyl, and wherein R 8 represents a phenyl, fluorophenyl, pyridyl or N-benzylpiperidyl group; (iv) compounds of formula (If), C. C All jii 54 R N N V6 (If) wherein R represents a hydrogen atom, a (Cl.
4 )alkyl group, a halogen atom or a (Cl 4 )alkoxy group; R 4 represents a hydrogen atom or a (Cl_4)alkyl group; R 6 represents a (Cl_ 4 )alkoxy or an -NHR 8 group, in which R 8 represents a hydrogen atom or a (C 1 4 )alkyl group, whilst the alkyl may be substituted by phenyl. 4. A method of treatment as claimed in claim 1, wherein A is a benzo group and one or more of the following applies: a) R is a hydrogen atom, a hydroxy, (C 14 )alkoxy or 25 methylthio group; *4 b) R 4 is a hydrogen atom or a methyl group; Sc) R 5 is a hydrogen atom, or a (C 1 5 )alkyl, phenyl, S 30 phenyl (C 15 )alkyl or (Cl 4 )alkoxy group; d) R 6 is a hydroxy or ethoxy group; or R 6 is an NR 7 R 8 group wherein R 7 and R 8 are as 35 hereinbefore defined.
5. A method of treatment as claimed in claim 4, A method of treatment as claimed in claim 4, 55 wherein one or more of the following applies: a) R is a methoxy group; b) R 5 is a hydrogen atom, or a 5)alkyl, phenyl, phenethyl, or methoxy group; c) R 7 and R8 are both (C 1 5 )alkyl groups; d) R 7 is a hydrogen atom and R 8 is an alkenyl or alkynyl group with 3 carbon atoms; e) R 7 is a hydrogen atom and R 8 is an alkyl group with 1-8 carbon atoms; f) R 7 is a hydrogen atom and R 8 is an alkyl group with 1 to 3 carbon atoms, which may be substituted by a hydroxy, methoxy, dimethylamino, furyl, pyridyl, pyrrolidinyl, morpholino, or phenyl group or a phenyl which is mono-, di- or tri- substituted by hydroxy or methoxy groups; or g) R 7 and R 8 together with the nitrogen atom, to which they are bound, represent a pyrrolidinyl, 25 morpholino or piperazinyl group.
6. A method of treatment as claimed in claim wherein one or more of the following applies: 9 30 a) R is a methoxy group, m is 2, and the R substituent is in positions 6 and 7; 9. So: b) R S is a (C 4 5 )alkyl or a phenethyl group; or 35 c) R is a -CH 2 CH=CH 2 group.
7. A method of treatment as claimed in claim SAe 7. A method of treatment as claimed in claim 1, wherein 56 A is a thieno group and R is a hydrogen atom.
8. A method of treatment as claimed in claim 7, wherein R 4 is a hydrogen atom or a methyl group; or R 5 is a phenyl or phenethyl group; or R 6 is a -NRR 8 group.
9. A method of treatment as claimed in claim 8 wherein R 7 is a hydrogen atom, a methyl or ethyl group and R 8 is a methyl or ethyl group which may be substituted by a morpholino or thienyl group; or R 7 and R 8 together with the nitrogen atom to which they are bound form a morpholino group. A pharmaceutical preparation as claimed in claim 2 comprising a compound of formula I which is defined as in claims 4 to 9, with the exception of: S a) compounds of formula I, wherein A is a benzo group and R is a methoxy group (in positions 6 and 7), 30 m is 2, R 4 is a hydrogen atom, R 5 is a hydrogen atom and R 6 is a NH(CH 2 3 0H, NH(CH 2 2 0H or NH(CH 2 3 0CH 3 group; and b) compounds of formula I, wherein A is a benzo group, R is a methoxy group in positions 6 and 7, m is 2, R 4 is a 57 methyl group, R 5 is a phenyl group and R 6 is an ethoxy group. 11. A compound of formula I as claimed in claim 3, wherein A, R, m, R 4 R 5 and R 6 are defined in any one of claims 4 to 9, with the exception of: a) compounds of formula Ic RX 1 4 I c 0 wherein R represents a hydrogen atom, or a hydroxy or methoxy group, m is 1, 2 or 3, R 4 and R 5 are hydrogen atoms and R 6 is a hydroxy or ethoxy group; and compounds wherein m is 2 and R represents a methoxy group in positions 6 and 7, and 25 R 4 is a hydrogen atom, R 5 is an ethyl group and R 6 is a methoxy group; *or R 4 is a methyl group, R 5 is a hydrogen atom and R 6 is a hydroxy or ethoxy group; S 30 or R 4 is a hydrogen atom, R 5 is a methyl group and R 6 is an ethoxy group; b) compounds of formula (Id), R NR S 35 NR 4 (Id) c I /rr'" 58 wherein R is a hydrogen atom or a methoxy group, R 4 is a methyl group, R 5 is a hydrogen atom or a phenyl group and R 6 is an ethoxy group; c) compounds of formula (Ie), R H H (Ie) 1C- .R8 II 0 wherein R represents a hydrogen atom, or a (C 1 4 )alkyl, hydroxy or (C 1 4 )alkoxy group, or the two adjacent R substituents together represent -O-CH 2 R 8 represents a hydrogen atom, an alkenyl, or alkyl group which may be substituted by a hydroxy, alkyloxy, dimethylamine or phenyl group. 12. A process for preparing a compound of general formula I as claimed in claims 3 or 11, wherein a Scompound of formula II, wherein A, R, m, R, R' and R6 are defined as in the .i desired compound of formula I, is reduced and the resulting compound is, if desired, subjected to one or 35 more of the following reactions: .ar r R wherein A, R, m, R 4 R 5 and R 6 are defined as in the desired compound of formula I, is reduced and the resulting compound is, if desired, subjected to one or e: 35 more of the following reactions: a) conversion of a compound of general formula I wherein 59 R 6 is a hydaroxy or a (Cl. 4 )alkoxy group, into the corresponding amide wherein R 6 is the group NR 7 R 8 b) N-alkylation of a compound of general formula I wherein R 4 is a hydrogen atom to obtain the corresponding compound of formula I wherein R 4 is a (C. 4 ,)alkyl group; c) conversion of a compound of formula I wherein R 6 is a hydroxy group into the corresponding ester (R 6 (Cl. 4 )alkoxy); d) hydrolysis of a compound of formula I wherein R 6 is a (C 1 ,4)alkoxy or NR 7 R 8 group into the corresponding free acid; e) isolation of any individual diastereoisomers; f) isolation of the compound in free form or in the form of its acid addition salt. 13. Process for preparing a compound of general formula I', a a a. a a a a (R) R 9 H 2 SNHR a wherein A represents a benzo, thieno or indolo group; 35 R represents a hydrogen atom, a (C 14 )alkyl group, a halogen Cl, Br, I) atom, or a hydroxy, (Cl. 4 )alkoxy, amino, methylthio, methanesulphonyloxy A q 60 or methanesulphonamido group, or two adjacent R substituents together represent -0-CH 2 or -O-CH 2 -CH 2 m represents 1, 2 or 3 if A is a benzo or indolo group, and 1 or 2 if A is a thieno group; R 9 represents a hydrogen atom or a (C 13 )alkyl group; R 5 represents a hydrogen atom, a (C 1 _,,)alkyl, phenyl, phenyl(Cl. 5 )alkyl, 4 )alkoxy group or a -NHCOX group (wherein X is a (C 1 5 )alkyl group); R 8 represents a hydrogen atom, a branched or unbranched alkenyl group with 3 to 6 carbon atoms; or a branched or unbranched alkynyl group with 3 to 6 carbon atoms; or a branched or unbranched alkyl group with 1 to 12 carbon atoms, whilst the alkyl group may be substituted by one or more of the following substituents: hydroxy, 25 (C1. 4 alkoxy, di (C l) alkylamino, furyl, pyridyl, pyrrolidinyl, morpholino, indolyl, nitrilo, thienyl, phenyl or phenyl which is mono- or poly- 35 substituted by hydroxy, methoxy or fluorine; or e) a phenyl, fluorophenyl, pyridyl or N- benzylpiperidyl group; 61 in which a compound of general formula V (R) M wherein A, R, m, R 5 R 8 and R 9 are defined as in the desired compound of formula is reduced and the resulting compound is, if desired, subjected to one or more of the following treatments: a) isolation of the individual diastereoisomers; b) isolation of the compound in free form or in the form of its acid addition salt. 14. A compound of formula II R S S S S S 4 SS S S .9 S. S S or a salt thereof with an inorganic or organic acid, wherein A is an indolo group, R, m, R 4 R 5 and R 6 are as defined in claim 1 except compounds wherein 30 m is 1, R represents a hydrogen atom, a (Cl. 4 )alkyl group, a halogen atom or a (Cl, 4 )alkoxy group, R 4 represents a hydrogen atom or a (C 1 4 )alkyl group, R 5 represents a hydrogen atom, 62 R 6 represents a (Cl. 4 )alkoxy or an -NHR 8 group, wherein R 8 represents a hydrogen atom or a 4 )alkyl group, in which the alkyl group may be substituted by a phenyl group. A process for preparing a compound of formula II as claimed in claim 14, wherein a malonic acid diamide of general formula IV H r CH-- CH2-- NHCO C CO R (IV) R wherein R, m, R 5 and R 6 are defined as in the desired compound of formula II, and Ar represents a 2- or 3- indolyl group, is cyclised to obtain the corresponding compound of formula II. 16. A process as claimed in claims 12 or 13 substantially as hereinbefore described and with reference to any of the Examples. 17. A compound of formula as claimed in claims 3 or 25 11 whenever prepared by a process as claimed in claims S: 12 or 13. a 18. Each and every novel compound, process, composition, method and use herein disclosed. DATED this 6th day of April 1993 a a BOEHRINGER INGELHEIM INTERNATIONAL GmbH by their Patent Attorneys CALLINAN LAWRIE too* oap s a** ^•oQ