AU609121B2

AU609121B2 - Benzo- and thieno-3,4-dihydro-pyridine derivatives

Info

Publication number: AU609121B2
Application number: AU15090/88A
Authority: AU
Inventors: Dietrich Arndts; Franz Josef Kuhn; Walter Losel; Otto Roos; Gunther Schingnitz; Gerd Schnorrenberg; Georg Speck; Ilse Streller
Original assignee: Boehringer Ingelheim International GmbH
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 1987-04-24
Filing date: 1988-04-22
Publication date: 1991-04-26
Anticipated expiration: 2008-04-22
Also published as: DK219488A; IL86131A0; ATE107921T1; AU1509088A; EP0288048B1; CA1330798C; PT87300B; DE3850437D1; FI881889A0; HUT47915A; PL271963A1; JP2669468B2; HU208673B; FI881889A; JPS63280069A; KR880012594A; NO174548B; FI91750B; YU80488A; NO881759L

Abstract

Benzo- and thieno-3,4-dihydropyridine derivatives of the formula I <IMAGE> in which D denotes a group of the formula Ia or Ib <IMAGE> and A and B denote a benzo or thieno radical; and R4 denotes (C1-C4)alkoxy or an -NR9R10 group in which R9 and R10 independently of one another denote (a) hydrogen, (b) branched or unbranched alkyl, alkenyl or alkynyl (where the alkyl can be substituted, for example by the group <IMAGE> (c) cycloalkyl having 3-7 ring members, (d) dimethylamino, (e) amino(C2-C4)alkyl, (f) phenyl, (g) morpholinyl or (h) pyridinyl, or R9 and R10, together with the nitrogen atom to which they are bonded, denote a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl radical; and their pharmaceutically acceptable salts. The compounds have cardioprotective and/or cerebral protective action.

Description

Australia Form PATENTS ACT 1952 ("VO MPLETE SPECIFICATION (ORI GI NAL) FOR OFFICE USE 609121 Short Title: Int. CI: -Application Number: CI*Lodged: I This docum ent ltai s i e C1 'lefdjflcil ts Izide ULdc Isectij)I 49 and is crec for L7I g cPrinting. neor omplete Specification-Lodged: 0 Accepted: :0 0 Lapsed: Published: *riority: Related Art: of Applicant: Address of Applicant: Actual Inventor: Address for Service:, TO BE COMPLETED BY APPLICANT BOEHRINGER INGELHEIM INTERNATIONAL GmbH D-6507 Ingeihein am Rhein, Federal Republic of Germany.

WALTER LOSEL, OTTO ROOS, GERD SCHNORRENBERG, DIETRICH ARNDTS, GEORG SPECK, ILSE STRELLER, FRANZ JOSEF KUHN and GUNTHER SCHINGNITZ.

CAINLINNSS Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

CoplteSpciictin ort ivetin nttld:" BENZO AND THIENO-3,4-DIHYDRO-PYRIDINE CoplteSpciictin o t'~inenio etile:DERIVATIVES" The following statement is a full description of this inventiont, Including the best method of performing it known to me:- Noe: The description Is to bo typed In double spacing, pica typo face, In on aroa not exceeding 250 mm in depth and 160 mm in width, on tough white paper of good quality and It Is to be Inserted Insido this form, la The present invention relates to new benzo- and thieno-3,4-dihydro-pyridine derivatives, their preparation and pharmaceutical compositions containing them.

A compound of general formula VIII R*

VIII

(R12)n-

R

1 0r (wherein R 1

R

2

R

3

R

5

R

6 and R 7 represent hydrogen and the substituted groups A and B represent the group 20 CH 3 0 and the preparation thereof have been described by Kobar, Jeno in Szegedi Tonarkepzo Foiskala Ind.

Kozl. 1985, pages 145-153 (cf. Chem. Abstr. 87; 134980Z). This publication does not however make any mention of the physiological effects of this compound.

According to one aspect of the present invention we provide a compound of formula I -2- A

R

[wherein A represents a benzo or thieno group; Rand R 3 independently of each other each represent 10 a hydrogen atom or a (C 1 5 )alkyl group, or together *with the carbon atom to which they are bound R and R 3 together represent a 5- or 6-membered carbocyclic ring; 0: 15 R 11 represents a hal~ogen atom (preferably F, Cl, Br or 1) or a (C 1 )alkyl, hydroxy, (C 1 )alkoxy, amino, thiomethyl, methanesuiphonyloxy or methanesuphon-' *amido group, or two adjacent substituents R 11 together .represent -O-CH 2 or -O-CH 2 -CH 2 m represents 0, 1, 2 or 3 if A is a benzo group, or 0, 1 or 2 if A is a thieno group; D represents a group of formula Ia or lb 25 R

N

R

1

R

6 Ia Rl5 b (R B 12 n 8 R. -1 0 (wherein in the group of formula la B represents a benzo or thieno group; R 1 represents a hydrogen atom, or a (C 1 1 1 0 )alkyl, phenyl, phenyl-(C 1 5 )alkyl, 'C 1 aloyr -NHiCOX (wherein X is (C 1 )alkyl) group; R 5 represents a hydrogC-7 atom, or a (C 1 4 )alkyl or hydroxymethyl group; -3- Rand R 7 independently of one another each represent a hydrogen atom or a

(C

1 5 alkyl group, or together with the carbon atom to which they are bound R and R 7 together represent a 5- or 6-membered carbocyclic ring;

R

12 represents a halogen atom (preferably F, Cl, Br or I) or a (C 1 4 )alkyl, hydroxy,

(C

1 4 )alkoxy, amino, thiomethyl, methanesuiphonyloxy or methanesuiphonamido group, or two adjacent substituents R 12 together represent -O-CH 2 or

-O-CH

2

-CH

2 n represents 0, 1, 2 or 3 if B is a benzo group, or 0, 1 or 2 if B is a thieno group; and in the group of formula lb t: R, represents hydrogen, (C1_ 10 )alkyl, phenyl-(C 1 5 )alkyl, (C 1 4 )alkoxy or -NHCOX (wherein X is (C 1 9,alkyl), and preferably represents hydrogen,

(C

1 .1 0 )alkyl, phenyl-C 1 5 )alkyl, or -NHCOX (wherein X is (C 1 _)alkyl);

R'

5 represents a hydrogen., atom or a (C 1 )1kyl group; fee* 0. fee R 4 represents a (Cl 1 4 )alkoxy or an -NR 9

R

10 group, wherein R9and R 10 independently of each other represent hydrogen, branched or unbranched (Cl 1 2 )alkyl, (C 2 12 )alkenyl or (C 2 1 2alkynyl (wherein the alkyl may be substituted by hydroxy, (C 1 4 )alkoxy, di(C 1 4 )alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl, indolyl, or the grottw AI (1R12)n, wherein R, 2 is as defined above; Ar is phenyl or CO thienyl; n! is 0, 1, 2 or 3 if Ar is phenyl, or 0, 1 or 2 if Ar is thienyl)) -c~eq x- b 4 (C3- 7 cycloalkyl dimethylamino, amino-

(C

2 4 )alkyl (wherein the amino group may be unsubstituted or is mono- or di-(C 1 4 )alkylamino), phenyl, morpholinyl, or pyridinyl, with the proviso that R9 and R 10 cannot simultaneously represent hydrogen, dimethylamino or di(CI_ 4 )alkylaminomethyl; or R 9 and R 10 together with the nitrogen atom to which they are bound together represent a pyrrolidinyl, 10 piperidinyl, morpholinyl or piperazinyl group, the piperazinyl ring optionally being N-substituted .s by unsubstituted phenyl, mono- or di-(C1- 4 )alkoxyphenyl, pyrimidinyl or phenyl(C 1 _4)alkyl)] or the pharmaceutically acceptable salts thereof, preferably with inorganic or organic acids; with the exception of the compound of formula I wherein D is the group Ia and i, R2 R 3 R5, R 6 20 and R 7 each represent a hydrogen atom and A and B together represent the group and with the exception of the compound of formula I wherein D is the group of formula I and Ri, R2' R 3 and R' 5 represent a hydrogen atom, represents the group CH 0

CH,

7Cl

OCH

3 and R 4 represents the group -NH-CH 2

-CH

2 OCH3 The carbocyclic ring which may be formed by R 2 and R 3 or R 6 and R 7 and the associated carbon atom to which they are bound'is preferably a saturated or 6-membered carbocyclic ring.

Compounds of formula I wherein D is the group of formula la are hereinafter referred to as compounds of formula VIII a.

*e Su (RII m

VIII

(wherein Ri, R 3

R

5

R

6

R

7

R

1 1

R

1 2 A and B are defined as hereinbefore).

Compounds of formula VIII wherein R 5 is hydrogen form tautomers of formulae VIIIa and VIIIb, U. U

U.

U. S

U

(R

11 )m

(R

11 m VIIIa VIIIb

(R

1 2 n wherein R 5 is also hydrogen. The definition of all formulae I and VIII and the invention also include the above-mentioned tautomers.

6- Compounds of formula I wherein D is a group of formula Ib are hereinafter referred to as compounds of formula IX lo 0 .::::.Compounds of formula IX wherein R' 5 is hydrogen form tautomers of formula IXa ::R2

,,R

3 RII)m7 A Z Ix

R

0 se* 20 which also form part of the present invention.

The tautomers may be separated byknown methods, o.o.

e.g. by column chromatography or selective reduction (NaBH 4 or catalytic reduction). Compounds of both 25 structures wherein R 5 represents (C 1 4 )alkyl are stable.

b- taken to include the compounds of structure IXa wherein R' 5 represents hydrogen or (Cl_ 4 )alkyl.

We have surprisingly found that the new compounds of formula Y and, particularly, the above-mentioned compound and the intermediate of formula II formed in the preparation of compounds of formula VIII and described hereinafter have valuable therapeutic properties th as free bases and also in the form of their salts.

~1 I_ 7 Moreover, compounds of general formula IX wherein R4 is the group of general formula X R6 NH CH2 2)n 2

R

7 are important intermediates in the preparation of compounds of general formula VIII, the tautomers 10 and salts thereof.

Of the compounds of formula VIII, the following are preferred: 15 Compounds of formula VIII wherein R 1 represents hydrogen, (C1- 0 )alkyl, phenyl(Cl- 5 )alkyl or -NHCOX (wherein X is (Cl_ )alkyl); R11 and R12 independently of each other represent 20 (Cl_4)alkyl, hydroxy, (C 1 4 )alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents RII or R 12 together represent -O-CH 2 or -O-CH 2

-CH

2 25 Compounds of formula VIII, wherein Ri represents hydrogen, (C1- 10 )alkyl or -NHCOX (wherein X is (C 1 l 5 )alkyl); R2' R 3 Rg and R 7 independently of one another represent a hydrogen atom or R 2 together with R 3 and/or R 6 together with R7 and the associated carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring; R11 and R 12 independently of each other represent hydroxy, (Cl- 4 )alkoxy, methanesulphonyloxy I I I I 8 O or methanesulphonamido, or two adjacent substituents Rll or R 12 together represent -O-CH 2 or

-O-CH

2

-CH

2 particularly preferred are compounds wherein

R

1 represents a hydrogen atom, or a (C 1 6 )alkyl or -NHCOCH 3 group; and/or

R

5 represents a hydrogen atom, or a methyl 10 or hydroxymethyl group; and/or R, R 3

R

6 and R 7 independently of each other represent a hydrogen atom or R 2 together with R 3 and/or R 6 together with R 7 and the 15 associated carbon atom to which they are bound represent a 5-membered carbocyclic ring; and/or *o R, and R 12 independently of each other represent 20 hydroxy, methoxy, methanesulphonyloxy or Stmthanesulphonamido, or two adjacent substituents RiI or R,2 together represent -O-CH-O-.

Further generally preferred compounds are those 25 of formula VIII wherein m and/or n represents 2, particularly those wherein A and/or B is a benzo group, whilst the two substituents R 11 and/or R 12 are preferably in the meta- or para- position relative to the fusion points of the group A or B, respectively.

Compounds wherein R 11 and R12 are methoxy are particularly preferred.

Examples of specific compounds according to the invention are listed in the Tables which follow; l-(3,4-dihydro -6,7-dimethoxy-isoquinolin-lyl) -1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-lylidene)-ethane or a physiologically acceptable F salt thereof is especially preferred.

I

9 Of the compounds of formula IX, the following particularly preferred: Compounds wherein R4 is methoxy or ethoxy; wherein R 4 represents an -NR 9

R

10 group, wherein R9 and R 10 independently of each other represent hydrogen, (C 1 8 )alkyl, (C 2 3 alkenyl or (C2- 3 )alkynyl (whilst the alkyl may be substituted 10 by hydroxy, (C1- 4 )alkoxy, di(C 1 4 )alkylamino, furyl, pyrrolidinyl, morpholinyl, sees pyridinyl or the group (R12) atwherein see asses: 15 Ar, R1 and n are defined as hereinbefore), (d) dimethylamino, (1f) phenyl, morpholinyl, (h) pyridinyl, whilst R and Rl cannot simultaneously .9 10 represent hydrogen, dimethylamino or di(C 1 4 )alkylaminomethyl; or R 9 and Rio together with the nitroger atom to which they are bound represent a pyrrolidinyl, morpholinyl Or piperazinyl group, whilst the piperazinyl ring may optionally be N-substituted by unsubstituted 25 phenyl, mono- or di(C 1 -4)alkoxyphenyl, pyrimidinyl or phenyl (C 1 4 alkyl; more particularly compounds wherein R4 is an -NR 9RIO group, wherein Rg and/or RIO each represents unsubstituted phenyl, fluorophenyl, morpholino or 2- or 3-pyridinyl; or wherein RP.

4 is an -NR 9 RRi group, wherein R5 and/or RIO represents (C 1 4 )alkyl, preferably methyl or ethyl; or wherein R 4 is an -NR 9

R

10 group wherein R 9 and/or Rio each represents (C 2 or C 3 )alkyl, which may ii I Y1 a hydrogen or a (C 5 alkyl group, or together with the carbon atom to which they are bound R and R 3 together represent a 5- or 6-rnembered carbocycliL! ring; Ala I be substituted by hydroxy, methoxy, dimethylamino, furyl, morpholino, pyrrolidinyl or pyridinyl; or wherein Ris an -NR R 10 group wherein R 9 is hydrogen.

4 9 other compounds of formula IX which are particularly preferred are those wherein R 4 is an -NR 9

R

10 group wherein R 9 is hydrogen and RP 10 is a substituted alkyl of formula VII, w0hearoein or is 0, )aky or 2;ehrwthtecro 0 04: atom towhich they are bound R 6 and R 7 together represent a 5- or 6-membered carbocyclic ring; Ar represents phenyl or thienyl; R 12 represents (C 1 )alkyl,. halogen Cl, Br, I), hlimAoxv. (C 1 Qalkoxy, amino, thiomethyl, methane- SulphonyloLXY or methanesulphonamido, or two adjacent substituents R 11 together represent O-CH 2 or -O-CH 2 -CH 2 and n~represents 0, 1, 2 or 3 if Ar is phenyl, or 0,I or 2 if Ar is thienyl.

Especially prefered are those compounds of formula IX wherein R., 2 is (C 1 )alkyl, hydroxy, (C 1 4 alkoxy, ~s~L/~methnesulphonyloxy or methavesuiphonamido, or, thiomethyl, methanesuphoyo>7y or meth, nesulphonamnido group, or two 11/3 adjacent substituents R 1 2 together represent

-O-CH

2 or -O-CH 2

-CH

2 wherein R 12 represents hydroxy, (C 1 4 )alkoxy, methanesuiphonyloxy or methanesulphonami,,1,o, or two r~ic'jacent substituents R 1 together represent -O-C1_H 2 or

-O-CH

2

-'CH

2 or wherein R.

2 represents hydroxy, methoxy, methanesuiphonyloxy or methanesuiphonamido, or two adjacent 'substituents

R

1 together represent -O-CH see* **toPartica.larly preferred compounds are t'hose compounds 15 wherein R2is metoxy; wherein n' is zero; wherein Ar is phenyl and n' is 2, preferably wherein Se *the two substituents R2are in positions 2- and 3-.

Particular mentior, should also be made of compounds of formula (IX) wherein Ris an -NRR, ghoup, wherein R 9 and RIO together with the nitrogen atom to which they are bound represent morpholino, pyrrolidinyl or piperazinyl (which is N-substituted by me, hoxypheny1, phenethyl or 2-pyrimidinyl).

of the above-mentioned groups of compounds, especially preferred are those wherein R 1 represents hydrogen, (C 1 10 )alkyl, phenyl (C 1 5 )alkyl or -NUCOX (wherein X is

(C

1 and

R

11 represents'(Cl 1 4 )alkyl, hydroxy, ((l 14 )alkoxy, methanesuiphonyloxy or methanesuiphonamidop or two adjacent substituents R 11 together.

represent -O-CH or -O-CH -CHl--

A

12 wherein R 1 represents hydrogen, (Cl_-1 0 )alkyl or -NHCOX (wherein X is (C1- 5 )alkyl);

R

2 and R 3 each represent hydrogen or together with the carbon atom to which they are bound

R

2 and R 3 together represent a 5- or 6-membered carbocyclic ring;

R

11 represents hydroxy, (Cl_ 4 )alkoxy, methane- 10 sulphonyloxy or methanesulphonamido, or two adjacent substituents R 1 1 together represent

-O-CH

2 or -O-CH 2

-CH

2 wherein R 1 represents hydrogen, (Cl- 6 )alkyl, or -NHCOCH 3 S- wherein R' represents hydrogen, methyl or S. ethyl;

S*

20 wherein R2 and R 3 represent hydrogen or together with the carbon atom to which they are bound R 2 and R 3 together represent a 5-membered saturated carbocyclic ring; S" 25 wherein R 11 represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R 11 together represent -O-CH 2 wherein, if A is a benzo group, m represents 2 and preferably the two substituents RI are in the meta- and para- positions, respectively, to the fusion points of the group A; wherein R 11 is methoxy.

Other preferred compounds are those wherein A represents -13benzo, Rll represents methoxy, m is two, R, is hydrogen or (C 1 5 )alkyl, R 2

R

3 adR 5 represent hydrogen and R 4 represents morpholino, methylamino, diethylamino or phenethylamino.

Examples of specific compounds falling within the present invention are listed in the Tables hereinafter, but particularly preferred are morpholinocarbonylmethyl-6 ,7-dimethoxy-3 ,4-dihydroisoquinoline, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid methylamide, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid diethylamide and 15 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid too**: pheny ,ethylamide and the physiologically acceptable salts thereof.

The compounds of formula I ac.cording to the invention may be prepared in a manner known per se.

In another aspect the present invention provides a process for preparing the compounds of the invention.

The process comprises at least one of steps A? 25 B and C hereinafter.

A. (to prepare a compound of formula I wherein D is a group of formula Ia, i.e. to prepare a compound of formula VIII) cyclising an amide of formula II Rz R (R 11 )M A I -R R RI

IN

1 Ar (R 1 2 ns I IJIX|I±L V iL- .L V r l The following statement is a full description of this invention, including the best method of performing it known to me:-* SNote: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 mm in width, on tough white paper of good quality and it is to be inserted inside this form.

'I 1 14 14 (wherein A, R 1

R

2

R

3

R

6

R

7

R

11

R

12 and m I are defined as hereinbefore, Ar represents a phenyl or thienyl group and n' represents 0, 1, 2 or 3 if Ar is a phenyl group, or 0, 1 or 2 if Ar is a thienyl group, and R 5 represents a hydrogen atom or a (C 1 -4)alkyl group) in the presence of a condensing agent.

Suitable condensing agents are, for example, strong Lewis acids such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride, tin tetrachloride, and also inorganic acids such as polyphosphoric, sulphuric, fluorosulphonic and 15 hydrofluoric acid, or mixtures of condensing agents I such as, for example, a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C 1 4 )alkylsulphonic acid, e.g. containing about 10% by weight of P 205 If a compound of formula II wherein R is hydrogen *0 5 is cyclised in the presence of a mixture of phosphorus apentoxide and (C 1 4 )alkylsulphonic acid, there is obtained, in addition to the corresponding compound of formula VIII wherein R 5 is hydrogen, the analogous ,i compound of formula VIII wherein R 5 is (Cl,4)alkyl.

Preferably, this variant of the process is carried out with methanesulphonic acid.

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

toluene, xylene), chlorobenzenes, chloroform, acetonitrile and decalin. In a preferred embodiment of the CD A\ process, the condensing agent, such as phosphorus According to one aspect of the present invention we provide a compound of formula I SL -I-II I 15 oxychloride or a mixture of (Cl 1 4 )alkylsulphonic Sacid and phosphorus pentoxide, is used without the addition of solvent.

Cyclisation is preferably effected 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 yide temperature range, preferably with heating to 500C -p to about the boiling point of the reaction mixture.

The reaction time required is generally between 15 several days and several hours, depending on starting compound II.

The compounds of general formula II defined above are new compounds.

Thus, a further aspect of the present invention provides a compound of formula II

R

2

R

2 5 R A I R R* R7 (II) R Ar 12) n (wherein A, RI, R 2

R

3

R

6

R

7

R

1

R

12 and m 30 are defined as hereinbefore, Ar represents a phenyl or thienyl group and n' represents 0, 1, 2 or 3 if Ar is a phenyl group, or 0, 1 or 2 if Ar is a thienyl group, and R 5 represents a hydrogen atom or a (Cl_4)alkyl group) or a physiologically acceptable salt thereof.

There is further provided a process for the preparation ~it- .i 16 of a compound of a formula II which comprises cyclising 0 the corresponding malonic acid diamide of general formula R3 RI7 !r II a (wherein R 5 is hydrogen, RI, 2

R

3

R

6

R

7

R

11 and

R

12 are defined as hereinbefore, Ar represents phenyl or thienyl and m' and n' independently of each other represent 0, 1, 2 or 3 if the associated Ar is phenyl, or 0, 1 or 2 if the associated Ar is thienyl) 0* The reaction may be carried out as described above for the cyclisation of compound II to form a compound of Sformula VIII. If the reaction is carried out with a mixture of phosphorus pentoxide and (C1- 4 )alkylsulphonic acid, there is obtained, in addition to the corresponding compound of formula II wherein R5 is hydrogen, the analogous compound of formula II wherein R is (C 4 )alkyl.

e"e: (See also process step C).

B. (to prepare a compound of formula I wherein D is a group of formula Ia) condensing a compound of formula IIIa r C/?l)mb--cH,-N H co-- co-N -cH- 8flW Sn I O- I- RI Rs R sIa.

(wherein R 5 is hydrogen, R 1 R21 R, R R7 R 11 and R12 are defined as hereinbefore, Ar represents phenyl or thienyl and m' and n' independently of each other

(R

1 2)n, wherein R 12 is as defined above; Ar is phenyl or thienyl; n' is 0, 1, 2 or 3 if Ar is phenyl, or 0, 1 or 2 if Ar is thienyl))

L/

17 represent 0, 1, 2 or 3 if the associated Ar is phenyl, or 0, 1 or 2 if the associated Ar is thienyl) in the presence of a condensing agent, without isolation of the intermediate product of formula (II).

The reaction in which compound of formula III is used as starting material may be carried out without isolating the intermediate compound of formula II in situ up to the preparation of the compound of formula VIII.

Since the isoquinoline or thienopyridine ring cyclises only with very great difficulty in many compounds, the intermediate compound of formula II formed during the cyclisation reaction or the tautomers thereof may be isolated, the base may be liberated and subjected to the second cyclisation reaction, if necessary or desirable. In this case, phosphorus oxychloride will preferably be used in the first step, with gentle heating.

In the second step, cyclisation is preferably effected with phosphorus pentachloride, a mixture of phosphorus oxychloride and phosphorus pentachloride or with a mixture of methanesulphonic acid and P 2 0 5 The compounds of general formula Ilia are substantially known compounds and may be prepared by methods known .oi per se.

C. (to prepare a compound of formula I wherein D is a group of formula Ib, i.e. to prepare a compound of formula IX) condensing a compound of formula III K 3

R

18 O (wherein R' 5 Js hydrogen, Rl, R 2

R

3

R

4 and Rl are defined as hereinbefore, Ar represents phenyl or thienyl and m' represents 0, 1, 2 or 3 if Ar is phenyl, or 0, 1 or 2 if Ar is thienyl) in the presence of a condensing agent to form corresponding compounds of formulae IX and IXa. The process used will be described in greater detail hereinafter. If the reaction is carried out with a mixture of phosphorus pentoxide and (C 1 4 )alkylsulphonic acid, there are obtained, in addition to the corresponding compounds IX and IXa wherein R' is hydrogen, the analogous compounds IX and IXa wherein R' is (C 1 )alkyl.

If desired, one or more of the following treatments may be carried out after either one of steps A, B and

C:

alkylating a compound of formula wherein R 5 or R' is a hydrogen atom to form a compound of formula (I) wherein R 5 or is a (C 1 )alkyl group;

C

hydroxymethylating a compound of formula wherein D is a group of formula Ia and R 5 is a hydrogen atom to yield a compound of formula wherein R 5 is hydroxymethylene; *5 C S S isolating the individual tautomprs of compounds of formula I; isolating the free compound of formula from its salt; reacting a compound of formula to yield a pharmaceutically acceptable salt thereof.

j WLv t L.L formulae I and VIII and the invention also include the above-mentioned tautomers.

III I n

SORIGINAL

19 Suitable condensing agents for this process are strong Lewis acids such as phosphorus oxychloride, 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, for example, a mixture of phosphorus oxychloride and phosphorus pentachloride, or a S* 10 mixture of phosphorus pentoxide and (C, 1 4 )alkylsulphonic acid, e.g. containing about 10% by weight o of P205.

If a compound of formula III wherein R5 is hydrogen is cyclised in the presence of the mixture of phosphorus pentoxide and (C_-4)alkylsulphonic acid, there are obtained, as mentioned above, in addition to the S*corresponding compounds IX and IXa wherein R' 5 is hydrogen, the analogous compounds IX and IXa wherein R' 5 is alkyl. This variant of the process is preferably carried out with methanesulphonic acid.

Cyclisation may be carried out in the presence or absence of a solvent. Any inert solvent is 25 suitable provided that it has sufficient solubility for the reactants and a sufficiently high boiling point, for example benzene, alkylbenzenes (e.g.

toluene, xylene), chlorobenzenes, c-roform, acetonitrile and decalin. In a preferred embodiment of the process, the condensing agent, such as phosphorus oxychloride or a mixture of (C_1 4 )alkylsulphonic acid and phosphorus pentoxide, is used without the addition of solvent.

Cyclisation is preferably effected with phosphor-s oxychloride or, in difficult cases, with a mixture -7 of phosphorus pentoxide and (C 1 4 )alkylsulphonic SA/ acid (preferably methanesulphonic acid).

20 The reaction may be carried out within a wide temperature range, preferably with heating to 50 0 C up to about the boiling point of the reaction mixture.

The reaction time required is between 2 and hours, depending on the starting compound III.

The tautomers of general formulae IX and IXa wherein is hydrogen may be separated by known methods, e.g. by column chromatography or selective reduction with, for example, NaBH 4 (reduces the tautomer of formula IX). Tautomers of formulae IX and IXa are reduced by catalytic reduction.

15 Compounds of formula I wherein R 5 is hydrogen are optionally N-alkylated. N-alkylation may be carried out, in principle, with any known alkylating agents provided that they have sufficient reactivity, e.g. active alkylesters such as dialkylsulphate, 00'. 20 alkylesters of toluenesulphonic acid or alkylesters 0 of fluoromethanesulphonic acid. The reaction is conveniently carried out at temperatures up to the boiling point of the reaction mixture (in this case, alkyl represents (C1- 4 )alkyl).

'*The N-hydroxymethylation may be carried out under the conditions of aminoalkylation according to Leuckart-Wallach (Ber. Dtsch. Chem. Ges. 18, (1885) 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) No. 352; 4 (1950) No. 378). Generally, the substance is treated with a 30% formalin solution, for example, in the presence of formic acid at ambient temperature.

The free base of general formula I may be conveited into the acid addition salts thereof in a manner known per se.

I .i .i ~i R11 and R 12 independently of each other represent hydroxy, (C1- 4 )alkoxy, methanesulphonyloxy 11 i 21 Suitable acids for salt formation include, for example, inorganic acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, or nitric acids, or organic acids such as acetic, propionic, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, cinnamic, ascorbic and methanesulphonic acid.

The new bis-(3,4-dihydro-l-pyridinyl)-methanes of formula I have valuable therapeutic properties, as already mentioned hereinbefore, both ar. bases and in the form of their salts.

In particular, these substances have a significant *o 15 cardioprotective activity which was determined as follows: 6 As is well known, the myocardial Ca level is a measure of hypoxic heart damage or heart damage 20 caused by toxic doses of catecholamine (Higgins et all, Mol. Cell. Cardiol. 10: 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242: 437-449, as* 1982; Fleckenstein Vortrage der Erlanger Physiol.

Tagung 1970, Edit. Keidel, Springer Verl. Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenalin-induced myocardial calcium uptake is a measure of the cardioprotective efficacy of calcium antagonists (Fleckenstein loc.

cit.), of calmodulin inhibitors (Higgins) and other drugs, e.g. beta-adrenolytics (Arndts, Arzneimittel Forsch. 25: 1279-1284, 1975). The cardioprotective activity was determined in conscious rats after subcutaneous or oral administration of the active substance using the method dscribed by Arndts (loc.cit.) and the potency of the test substances was given as the H 50 value; this value corresponds 4 to the dose which results in a 50% inhibition of m L_ 22 the myocardial radio-calcium uptake caused by administration of 30 mg/kg s.c. of isoprenalin.

The new compounds tested were found to be up to times more effective than the known commercial product propranolol.

Compound H50 value* A 1.25 B 2.26 C 1.34 D 2.25 E 2.29 F 1.41 G 2.23 H 2.15 15 oral administration of active substance.

655 05 6 If an isolated heart kept for a fairly long time under ischaemic conditions is then subjected S' to normal perfusion again, heart function is not S* 20 immediately normalised. Rather there is a period of transition characterised by contracture and arrhythmia.

This phase of arrhythmia is caused by changes in the function and structure of the myocardiac cell with intracellular calcium overloading (Hess and s 25 Manson, J.Mol.Cell.Cardiol, 16, 969, 1984). Compounds with a cardioprotective activity such as Verapamil and Diltiazem decrease the calcium overloading and improve the contraction characteristics on re-perfusion (Watts et al, Am. J. Physiol. 238, H 909, 1980; Meno et al, Am. J. Physiol., 247, H 380, 1984). The cardioprotective activity was investigated on isolated rat hearts with ischaemia and subsequent re-perfusion. Under controlled conditions after one hour's ischaemia (flow rate 0.15ml/min) there is a period of irregular heart activity lasting for 10-15 minutes. Infusion of cardioprotective compounds shortens this period significantly.

.)jJ or wherein R 4 is an -NR 9

R

10 group wherein R 9 and/or R1 each represents (C2or C )l~,which may 23 Compound Concentration [pg/mlu sb~.ei~ of the arrhythmici phase fropt 11-13 tan rutes to 3.3 13.3 6.6 3.3 4 .0 min 3~ ,5 ~un 5.0 -min .00.

*o 0 of Compounds in the test results Compound A Compound of Table 1 R ('F-0 R" CH 0 113

R

2

-R

3 (CH 2 R 5

R

6 R 7

H

CH

3 0

CH

3 0

(CH

2 1) 4- .J..ttA U.flflLrflfl.L%.,,

'VJ.

ud s o Comounds of Table 4 (Structural Type I) Corn Ft4 Sali ,f o Em L 4 I 9 9 *r 9 9. z 9 99 99 99 99 CH 3 0 3 CH 3 CH 3 CH 3 CH3 Cu:;? CH 0 3 c3 CH3 0 CR 0 CH3 0 CH 0 3

CH

3 0 CH 3 0 CH 3 0 cU 0 CH30 Cu 0 CH 3 CU 0 C3 0 C3 CH 3 -(CH CH3

(CH

2 )3 CH 3 2)3 CH 3 3 Cu 3

NH-N-

-(CR )2 N5H-CH 2 -CH (CH-3

NH-CH-

-(CH )z

(CHZZY

2 2,

NHCII{

3 NiH- (CvU 2 2-OCR* NH-CH 2 22 -CH(OH)-Cu 3 N O

NH-CH(C'

3 -(CH 2 -CH(CH3)

NH-

(CH

2 )2 HC1 B S Bs

BS

S

s XC1

BS

99 9 9 .9 9 99 94 9 9 9.

CH'

C

(Qjj (CH2) 2

H

represent 0 v.l 2 'J vJ 2 2 I I I 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: Calcium antagonists inhibit the transmembranal influx of calcium ions into the cells. This inhibition affects the voltage-dependent (slow) calcium channel in the cell membrane. The detection of transmembranal calcium ion currents on strips of tissue with potassium depolarisation using the method described by van Breemen clearly indicates a calcium antagonist (van Breemen et al., Chest. 78, 157 S 165 S, 1980; van Breemen et al., Am J. Cardiol. 49, 507 510, 1982; Casteels et al., Pfltgers Arch. 392, 139 145, S 15 1981; Deth. and van Breemen, J. Membrane Biol.

30, 363 380, 1977). These investigations show that the compounds according to the invention are not conventional calcium antagonists.

20 In view of th^se findings, the compounds of formula I and the acid addition salts thereof may be considered for use as active substances for pharmaceutical compositions for the treatment of coronary heart disease and acute myocardial infarction.

In tests on the survival of animals in a sealed chamber (hypoxia tolerance test) through which a gas mixture consisting of 96.5% nitrogen and oxygen was passed, the animals pretreated with the substances according to the invention showed a statistically highly significant increase Other preferred compounds are those wherein A represents '26 in survival over the control animals or animals which had been pretreated with diltiazem, nifedipin or verapamil. The cerebroprotective activity tested by this method was noticeable even at a dosage of 5 mg/kg p.o. Thus, the compounds according to the invention are clearly superior to the known substances mentioned above both in terms of the effective doje and in the improved performance obtained in animal experiments.

In view of these findings, the compounds of general formula I or the acid addition salts thereof may be used as active substances for preparations to Streat cardiac insufficiency and cerebral metabolic *9og 15 disorders or organic brain psychosyndrome and posttraumatic and alcoholic brain damage.

o Thus, according to a further aspect of the present invention there is provided a pharmaceutical composition 20 comprising a compound of formula I as hereinbefore defined or a physiologically acceptable salt thereof, preferably with an organic or inorganic acid together with at least one pharmaceutical carrier or excipient.

The pharmaceutical compositions are suitable for oral or parenteral administration. They may be *.administered chiefly in the form of tablets, coated tablets, ampoules and syrup preparations. The single dose of these preparations is conveniently between 1.0 and 200 mg, preferably between 20 and 50 mg per 75 kg of body weight. Depending on the gravity of the case, 1 to 3 doses will generally be administered per day.

According to further aspects of the present invention there are provided a method for the treatment of coronary heart disease acute myocardial infarction S and/oL o--ae i cardio- and/or cerebroprot.e .,'on r o 27 in a subject which comprises administering to said subject a compound of formula I (as defined hereinbefore) or a compound of formula II as defined hereinbefore or a physiologically acceptable salt thereof, and the use of a compound of formula I (as defined hereinbefore) or a compound of formula II (as defined hereinbefore) or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent -fo=-se in a method for the treatment of coronary heart disease and/pr acute myocardial infarction, and/or Aor=us-e=4i cardio- and/or cerebroprot .ction in a subject.

The following Examples are intended to illustrate the invention in a non-limiting manner (unless 15 otherwise stated, all percentages and ratios are by weight): Oo 0 0

L

process, the condensing agent, such as phosphorus 28 Example 1 1- (3,4-Dihydro-6,7-dimethoxy-isoquiflolin-l-yl) 1- 2,3, 4-tetrahydro-6 ,7-dimethoxy-isoquinolin- 1-ylidene) -pentane and 1- (3,4-Dihydro-6,7-dimethoxy--isoquinolifl-1-yl) 1- (1,2,3 ,4-tetrahydro-6 ,7-dimethoxy-2-N-ntethylisoquinolin-1-ylidene) -pentane 4.9 g of n-butylmalonic acid-di-N-[2-(3,4-dimethoxyphenyl) -ethyl] -amide are heated, to 100 0 C for 1 *to 2 hours in 20 ml of a methane suiphon ic acid/P 2 0 mixture (10% by weight ofP0). Atrheeaio Oso2 Atrth eato e...has ended (monitored by thin layer chromatography) the reaction mixture is poured onto ice, made alkaline 6:00*: 15 with saturated soda solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, evaporated down in vacuo and the residue is separated on silica ***gel (eluant: methylene chloride: methanol 100:5, V:V) The N-H compound is eluted first.

N-H coflpounOl: m.p. 158-159 0 C (hydrochloride)

N-CH

3 compound: m.p. 136-137 0 C (hydrochloride) Example2 1- (3 ,4-Dihydro-6 7-dimethoxy-isoquinolin-l-yl) 1 4--d ih yd ro-6 7-d ime th oxy- 2-N-me thyl isoqu inol in 1-ylidene) -pentane-hydrochloride 1 g of the l.-(3,4-dihydro-6,7-di-ltet-hoxy-isoquinolinl-yl) ,4-tetrahydro-6 ,7-dimethoxy-isoquinolin- 1-ylidene) -pentane prepared in Example 1 is heated to boiling for 6 hours in 2 ml of freshly distilled

L.

There is further provided a process for the preparation -29 dimethylsuiphate. After working up in the usual 0 way, the product is chroinatographed on silica gel (eluant: CH 2 Cl 2 MeOH 100:5, V:V) the hydrochloride is formed and crystallised from ethanol/ether.

Example 3 1- (3 ,4-Dihydro-6 ,7-dimethoxy-isoquinolin-l-yl) 1- 4-dihydro-6 ,7-dimethoxy-l-N-hydroxymethylisoquinolin-1-ylidene) -ethane-hydrochloride 12 g of l-(3,4--dihydro-6,7-dimethoxy-isoquinolinl-yl) -1-(3,4-dihydro-6,7-diiidethoxy-isoquinolin- 1-ylidene) -ethane are left to stand for 20 hours at ambient temperature in a mixture consisting of 20 ml of 30% formalin solution and 10 ml of 98% formic acid. The mixture is evaporated to dryness in a. water ,Jet vacuum, the reaction product is taken up in CH 2 Cl 2 washed with dilute soda solution and then with water, the organic phase -is dried over Na 2

SO

4 the solvent is eliminated in vacuo, the residue is taken up in just sufficient ethanol and precipitated as the hydrochloride by the addition of ethereal hydrochloric acid. M.p.

CC* 25 =155*C Example 4 a- 4-Dihydro-6 ,7-dimethoxy-isoquinolin-1-yl) 1, 2,3,4-tetrahydro-6,7--dimethoxy-l-benzylideneisoquinoline 4.9 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-l-a- (2- (3 ,4-dimethoxyphenyl) -ethyl I-aminocar bonyl3-benzvlor thienyl and W~n and n' independently at each other

II

isoquinoline are heated to boiling for 4 hours in 20 ml of freshly distilled phosphork.L oxychloride.

After the reaction has ended (monitored by thin layer chromatography) excess POC1 3 is distilled off, the residue is distributed between CH C1 2 and dilute soda solution, the organic phase is washed with water, dried over Na 2

SO

4 and evaporated down. The residue is chrornatographed on 6,ilica gel (eluant: CH 2 Cl 2 :MeOI 100:10, The fastrunning yellow fraction yields c-(3,4-dihydro-6,7dime-thoxy-isoquinolin-1-yl) 2,3 ,4-tetrahydroabove 270 0 C (hydrochloride)) whilst the subsequent red zone, yields the N-H compound (mi.p.

15 95-100*C) given in the title.

Example 20tetrahydro-1-methylidene-thieno[2,3-clpyridine 19 g of malonic acid di-N-[2-(3-.thieno)-ethyllamide are heated to boiling for 3 hours in 25 ml of phosphorous oxychloride. As soon as no further starting material 25 can be detected, the mixture is worked up in the usual way, the reaction product is purified on A1 2 0 3 neutral, activity stage III (made by Woelm) (eluant: CH 2 Cl 2 and the hydrochloride is formed.

233-.235-C) Exampl1e 6 c-Isobutylaminocarbonyl-l-pentyl-6 ,7-dimethoxy- 3, 4-dihydro-isoquinoline 3.8 g (10 mmol) of c-isobutylaminocarbonyl-valeric cid-N-[2-(3,4-dimethoxyphenyl) -ethyl]-amide are

L

31 dissolved in 120 ml of acetonitrile and 18 ml of 0 phosphorus oxychloride are added. The reaction mixture is heated to reflux temperature for about 2 hours. It is then evaporated down, the residue is taken up in 200 ml of methylene chloride and made alkaline by stirring into an ice water/potash solution. After working up in the usual way -extracting with methylene chloride, drying the organic phase over Na 2

SO

4 eliminating the solvent, etc. the product is purified over a silica gel column (CH 2

CI

2 /MeOH 100:2). 158-160°.

Example 7 o* g 15 Methyl 2-ethyl-2-(3,4-dihydro-5,6-dimethoxy-l-isoquirolinyl)-butane-carboxylate 6 22 g of methyl 2- [2-(3,4-dimethoxyphenyl)-ethyl]aminocarbonyl -2-ethyl-butane carboxylate are heated 20 to boiling in a mixture of 100 ml of acetonitrile and 12 ml of phosphoros oxychloride until total conversion of the substance is obtained (about 2 hours). The mixture is then worked up in the usual way, the reaction product is purified on 25 silica gel (eluant: CH2Cl 2 CH30H 100:2) and the hydrochloride is formed.

M.p. 141-143 0 C (ethanol/ether) Examples of some compounds according to the invention which may also be prepared analogously to the Examples described above are listed in the Tables which follow.

32 Table 1 R 2 R3

R

Rili I

S

S.

S S

S

5.

S S 56 6* S S

S.

S. S

S

S.

S. S S 5* R 1 2

R

1

Z

L I a 6 0 S *5 0 6 a. a a. 6* aa 6 a R7 MD OC/Salt form- Ri i' Rii'' Ri R2 R3 Rs R 1 2 C11 2 0 CH30 CH3SO2NH CH30 CH3O CH30 CH2O CH30 CH! C11 3 0 C2 3 0

CH

3 0 CH30 CH2O CH3O CH3S0 CH0 CHIO

CH

3 0 CH30 CH3O CH0 CH30 CH30 CR130 CH0 CH3O CH2O CH30 -O-CH O- CH30 CH 2-0

H

n-C.AH n-C4Hg CH3 CH2

H

CH3 n-Csllai C2Hs CGHs CH3

CHS

C2Hs

H

CI3 CONH C6Hs (CH2)4-

H

H,

H

CH3

H

CH3

H

CH3 CH3 CH20H CH3

CH

3

H

CH30 CH3O CH30 CH3SO 2

NH

CH30 CR30 CH30 CR30 CH0 CH30 CH30 C1130 CH3SO2O HO CH30 CH30 HO C130 CH30 C1130 CH0 CR20 113 0 C11 3 0 CH30 CR30 -0-CH2-0- CH2-0- CH30 CH30 C2-0- C2-0- CR30 CR30 -0-CH2-0-

-(CH

2 j-

H

119/BS 233-238 (D)/BS 136-137/Cl 158-159/Cl 180/Cl 177/BS 182-186/BS 138-140/BS 222-?25/BS 155Cl 75-79(aorplus) lBS 80 (amorphous) /BS 95-100/BS 156-158/Cl 148-155/Cl 177-179/Cl 251-253/C 251-253(D)/Cl 171-172/Cl 191-195/BS wi 0 o c -0 M V

D

M 0 M tl

C:

0 Rr Srr (D 0 rt x V' H- 0 C C D 0 0 o Di D o H 0'' BS Base C1 Chloride D Decomposition 34 Table 2 H R 6* Salt form Mp 0 c) H 3 C c 0 H 3

CO

218-222 9* 9* 239-235 was given as the H 50 value; this value corresponds to the dose which results in a 50% inhi.bition of 35 Table 3 H 9*@9 9~ 9. 0 9 9 9's S 9 9

AS

99 9 59 6* 9 .9 Salt form MP( 0

C)

H

3

CO)

H

3

C

162-17 2

S

99 9 5 99 9. 9 9 59 237-2 39 s 6 250-253 0.15m1/min) there is a period of irregular heart activity lasting for 10-15 minutes. Infusion of cardioprotective compounds shortens this period significantly.

36 Table 4 Structural type I *9* 0**S a a a a.

a a a a.

a a a.

a *s a a.

a a* a a a a.

a. a a a a.

R-

11 R2

-R

R'~

1 Rf

R

Structural type II BS =Base 1 S C

~I

bE C 4 a i R,11 R t11 R I RR 2 R" R4 Structural type Salt form m p. C)

CH

3 0

CH

3 0 C83 0 C14I30 cH 3 0

CH

3 0

CH

3 0

CH

3 0

CH

3 0

CH

3

O

CH

3 0

CH

3 0 CH 30

CH

3 0 cH 3 0 C Hi3 0

CH

3

C

CH

3 0 CH 30 3

U(CH

3 2 NHC

H

IlH-(CH 2 2

-CH

3

(CH,

2 -CH3) 2 tIl (CH 2)3- CH 3 NlH-(CH 2) 4

-CH

3 11- H C 3 W-,C 8CI -C2CH(U3 2 2 fIR-CCH 12) CH(CH 3) HH -C H -C CH,2 HC1 HC1 HCl HCi7

HCI

fIC I i s

HCI

!HCI

196-197 149-150 212-217 199-204 94- 98 198 126-128 198-199 221-222 113-114

L~

II S S S S S *5 4 5 S S S SS (O O S S S S S S S S 5 4. .5 It R' 1 R''1 1 R 1 R 2 R 4 Structural type Salt fo rn m (0 C)

CH

3

O

cr 3 0 CM 0 CH 3 3

CH

3 0 CH.0 H H H

CH

3 O0

CH

3 0

CH

3 0

CHO

CH

3 0

CH

3 0

CH

3 0

CH

3 0

CH

3

O

CH 0 CH 3 3

CH

3 0 3 CH 0 3 CH 0 CH 3 0 CH 3 3 CM 0 3

CH

3

O

H H H H -(CH 2 4

H

H H H Ii H H H H H It NH-CM 2-CCH N(C8 3

)-C,-CM

2

OII

UH(CtH 3

-Q~-CH

UH-(HCH

32 2

OCM

HHCH(

11 (CH 3 N(C 2 H9 2 HH(C )4-CH N H{C,2) 3 OCH NM-iCH 2 3

-N(CH

3 2 HC1

MCI

216-217 202-203 HC1 132-134

BS

HC1

BS

196-198 224-226 88- 91 115-121 i 136 144-147 -i a a a a a a a a a a a a a a. a a a a a a *a a a a a *a a a a a a a a a a R'11 CH 3 0

CH

3 0 C H. 0

C

3

O

CH

3 0 CH1 3 0

CH

3 0 CH130

CH

3 0 11 RI R 2 R 3 R 4 Structural type

H

HI

H

P.

H

O1 C 2H52 NH(CH 2 )3 2 N(CH 3) NH(CH 2 3 OCH 3 N 0 Salt f orm 11vS B S B S

HCI

B S BS5 MP. (0 C) 170-177 178-180 158-161 160-164 197-199 207-208 HO H H H HH(CH 2) 2-CH 3 UH(CH 2)-CH 3 UH(CH CH 2 4 3 NH(-CH 2) 2OCH3 22 173- 180 148-155 152-155 181- 182 24 5-2 48 Ho H H H U.S S S S S S U

S

0 S. S *S U S, S 55 a. 5* S S 5 6 ~ii R 1 R'111

R

1

R

2

R

3 R 4 0-CH 2 -0 0-C H 2 0 0-CH 2 -0 0-CH 2 -0 0-CH 2 0-CH 2 -0 NH-CH -CH(G3H)-CH1 3 NH-N 0 QC zH5

M[C:H

2 )301 NH(CH 2-CH(C1 3 2 HH-(CH 22fP

OCH

3

'N

11 0 2 2SOCH 23 NH-(cH2~ i C Structural Salt type form I iBS I HC1 II Bs II 85 II BS I I BS mip P C) 134-1.46 180-193 143-152 133-134 129-133 142-146

'A)

I

C

1

C

I

C

r 0 3 c a 1' Il 3-

C

at a-

C

H it H H H H 89-105 (7) 176 UHiSOCH 3

CH

3 0

S

S. p. 9 99 0@ 9 *5 5 9 0 99 S. aS S 5 9 5 S S 0 4 59 11 1 2

R

3

R

4 Structural type Salt form Mp. C) CM3 0 3

CH

3 0 C H 3 0

CH

3 0 CI30

CH

3 0 CH3 0 3

CH

3 0 CI30

CH

3 0 CH3 0

CH,O

CH

3 0

CH

3 0 CH30

CH

3 Cu 3 Cu 3

CH~

CH

3

CH

3 H H

NH-CH

2

-CH(CH

3 2 H H NH-(CH2) 4

-CH

3 H H N[(CH2 2

CH

3 2 H H NC(CH 2 YCH 3] H H HH-CH(CH )3-CH(CH 3 H H

NH-(CH

2 2

-OCH

3 H H NH-CH H H 1H F H H N -CHi 2 2K

OCHJ

H H NH-(CH 2 2 OCH 3 138-141 114-116 6 1 g 51 i g 61i g 136-139 189- 193 146-148 115-119

CH

3 O CH 3 0 CH 3

CH

3 0

CH

3 0

CH

3

CH

3 0 CH 3 0

CH

3

CH

3 0

CH

3 0

CH

3

CH

3 0

CH

3

CH

3 O

CH

3 0

CH

3 H H IHH--CH YON H H NH-(CH9 2 )27 H

NH-(CH

2 3 -H(CH 3 2 128-132 185-190 131-13 102-105 *r IP3 Il-~ S t o t o 0".

0 0 0,0 0: 40J 55 4r 5

S

R'I R 1 R R 2 Structural type CM 3

O

CH

3 0 CH 3 CH3 0

CH

3 0 CH 0 3

CM

25

C

2

M

5 C 2

H

5 1H-(CH 2 4 -CH 3 NH-CH 2 -CH(C

H

3 2 NH-CM C H Salt form

BS

Mp. C) 99-103.

111-115 85- 95 CH3 0

C

3

O

CH 3 0 CH3 0

C

3

CH

3

O

CH

3 0

CH

3 0 CH3 0

CH

3 0

CH

3 0

CHM

3 0 3

CH

3 0

CH

3

O

CH 0 3 C30

CM

25g

CM

25 H5

C

2

M

5

C

2

H

5 C2H 25 H H

OCH

3 NH-CM -CH 2-6 OCI 3 2 2 3 N H1 F HH-CH 2- CH 2 OCH

NH-(CM

2 3

-N(CM

3 NH-C H 2 NH-(CH 2 HH-(CH 2 2 NH-CH(C 3-CHC )2 121-125 137-139 110-113 108-148 182-184 218-220 198-204 85- Ln: 0I1

I-

CD

t h 0 Q :r m 0 II ti 91

~I

(D

m x

DI

(D C Ca r(

HCD

(D Q

O

R.

2

R

3 a a a a aa* a a a a,

R'

11 R 1111 Wa aS a a a a a. aa a Structural type a.

Salt form MP- (0 C)

CH

3 0

CH

3 0

CH

3 0 CH 30

CH

3

O

CH 30 CH30

CH

3 0 CM! 0 3-

CM

3

O

CM 0 C30 CM

(CHM

CH3 (H23)

CH

3

(CH

2 )3

CH

3 (CH)3

C

3

CH

2 )3 CH 3( H 2 3

CH

3 0

CH

3 0 CH 3

(CH

2 3

CH

3 0 CH 3 O

CH

3 (CH 2 3

CH

3 0

CH

3 0 CH 30 CH 3

CH

1 30 CH 0 3-

CM

3 0 CH 30

CH

3

(CH

2 13 CH3(CHM 3CH 23

CH

3

(CH

2 3 H H NH(CH2 1 3

OH

H H

NH-CH

2

-CH(OH)-CM

3 H H NH-(CH 2 2 OH 3 H H

NH-(CM

2 3

-OCH

3 H H NH-(CH I 2 2 N(CH 3 2 H H HH-(CH 2 -N(CH 3 H H 1H-CH 4 H H MH-(H 2 2 j\ H H H(CH 3 2 H H H H N((CH C H H (C -C H H 11 CH 2Of 3 2 H H iJ H H N 0 H H N OCH3 H H H N-(CH 2YK2 H H N 14 ii MCi HC1

BS

Es

OS

101-103 156-158 93- 96 93- 94 87- 87- 76- 115-117

BS

HCI

HC1

HCI

HC1

HCI

HC1

CH

3 0 C!,0 CH (CH 3 0H 3 O CH 3 O CH 3 (Cli 3

CH

3 0 CH 3 O CH 3

(CH

2 3

CH

3 0 C 3 0 CH 3

(CH

2 3

CH

3 O CH 3 0 CH 3

(CH

2 108- 109 175-177 107-110 amorphous 193-195 195-198 103-128 (amorphous) 93-106 (amorphous) 92-116 (amorphous)

I

S

*S S *r S S. 5* 5 S. S 55 5 S *5 S S 5 5 R 111 R' s11 RI

R

2 R 3 R 4 0@0 C) Structural type

CH

3 0 CH 30

CH

3 0 CH3 cH 3 0

CH

3 0

CH

3 0 cH 3 0

CH

3 0

C

3

O

CH 3 CH 3 CH39 CH 0 CH30 CH 0 3.

CH 0 3 CH30

CH

3

O

CM 0 CH (CH I 3 2 CH

C

3 9

'H

2 U3 C 3(CHR CH 3 (C 2 )3 CH (CH 2)

CH

3 (CH 2 13

CH

3

(CH

2 3 c11 3

(CH

3

CH

3

(CH

2 13 CH 3 (CH 2 3 CH 3 (CH 2 )3 H H

NHCH

3 i H NHC2H5 A5 H HH(CH 2 CH 3 H H NH(CH 2 )3-CH F. NH (CH 4-CH 3 H H NHCH 3)3 H H

NH-C

2

-H(H

3 H H NH(CH 2 Y LCI 2 H H NH-CH(CH i H Hi NH-CH(CH 3)-(CII 2 3- CH(CH 3 H H X-HC (CCH(C H H NH(C CH(CM 3 OCH3 H H

NH-C(CH

2 -6 CH 3 H H NH-(C 2-P 3 1 OCH 3 H H II-(C 2 Cl='fH H H NH-(CH I 2-OH Salt form

BS

Bs Bs

BS

Bs Bs B35

BS

94-102 119-123 100-103 110-112 108-109 126-128 158-160 93- 110-112 108-110 88- 92 77- 80

CH

3 O C 3 0 CH 3

(CH

2 3

CH

3 0 CH 3 O CH 3 (CH2)3

CH

3 0 CH 3 0 CM 3 (CH2

CH

3 O CH 3 0 CH 3

(CH

2 3

C;

ci z

NJ

U.)

ID

Vt' 5e I i1 iii

ID

111-113 120-125 HCI 158-160 105-107

I

R 2 R3 R111 Re 1 11 R 1 CH 130

CH

3 0

CM

3 0

CH

3 O0

CH

3 0

CHM

3 0

CH

3 0 CH 3

(CH

2 1 3 CH 13 (CH H 2 3

CH

3

(CH

3 23

H

NH

NH(CH 2 4- -CH 3 N \/0 Structural salt type form I~ BS Mp. (0 C) 167- 169 108-156 (amorphous) 85- 87 83

F

a

R

2

R

3 S. 5

S

a. S S a S S S. *a a *r R a 11

R

1 Structural type CH3 0 CH 3 0 CH 30 CH 0 CH 0 3

CH

3 0 CH 0 3 CU 0 3

CH

3 0 3

CH

3 0

CU

3 0 CU 0 3 CH 30

C

3

O

C H 3 CU30 CU 0 3

CU

3 0

CU

3 0

CUH

3 0

CHO

CH

3

O

CU

3 0

CU

3 0

CH

3 0

C

C H 3

CH

3 (CH 2 )4

CH

3

(CH

2 4

CUH

3 (CU 2 I

CH

3 (CH 2 4 C H 3(CU 2) C3 (H2 4 CH 3 (CH 2 4 C3 (C 24

CH

3 (CH2) 4 C H 3

(CH

2 14

CU

3 (C1 2 14 C H 3 (CH 2 4

CH

3

(CH

2 14 N H- O 2 4- Cif3

NH-CH

2 -CH(CH 3 )2 NH-(CH2 2 (CH 3 2

HH-CH(CU

3 )-CH 2 3

-CH(CH

3 ]2 NH-CU 2 N -C U: 2 -CH C: H 2

NH-(CH

2 0

NH-CH

2

I

2 K2~A NH-IC 1 2 20 NH-(C 2) 2-N(C 1I NH-(CH 1 2 2 N H- (C H2 3 N Ci 3 2 NH- (CH 2 Of 3, Salt form

BS

8S B5

BS

8S

BS

B 5

BS

Mp. C) 100-102 76- 79 92- 06 amorphous 111 102-103 88- 141-142 74- 78 102- 104 amorphous 865- 87

CH

3 O CH 3 0 CH (CH 2 4 H H IM(CH,2 CH 3 157-160 c-

S

S *5 0 S 0 0 S. S1 S S S. S S S S S S S S S

S

Rt11

R'&

1 1

R

1

R

2 R 3 R 4

CH

3 0

CH

3 0

CH

3 0

CH

3

O

CH 30

CH

3 0

CH

3 0 CH 30

CH

3 0

CH

3 0

CH

3

O

CH

3

O

CH 3

CH

3 0

CH

3 0

CH

3 0 C 30 CH3 0 C H 3 0 CH 0 .3 CH30

C

6

H

5

-(CH

2 2 C H -(CH 2

C

6

H

5

-(CH

2 2 C 6ii 5-(CH C 6 H5- (CH 22 C 6H 5- (CH 2 2 C H 5-(CH 22 C-0

C

6

H

5

-CH

2 2 C 6H -(CH22 C 6 H 5 (CH 2 NH-(CII1)

NH-CH

2 G N H 2C N H- C11 2

)Z

Nl1-(CH 2 2 H 2 2 -i

HH-(CH

2 2

N

IIH-CH 2 27 Structural type

I

i

:I

I

Salt f orm

BS

Bs

BS

Mp. (0 C) 133-135 133 152-153 137-139 128-130 107-108 85- 86 86- 87 141-142

I

_I

:t j r j

I

CH

3 0 CH3SO 2

NH

Cif 3 0

CH

3 0

CH

3 0

CH

30

CH

3

CH

3 0

CH

30

CH

3 0

C

3 0

CH

2

CH

3 0 CH 2 BS Base C1 Chior D =Deco.

H H NH-CH 2 -CH 2

OH

99-101 e a. a a a a a. a a a a. a a a a. a a. a a a a *aa a aa Table 12

IV

Rui' R i RL R2 R3 I Rs R 2' -I CH30

CH

3 0 CH 3 0 CH30 CHO CH30 CH3O CH3O CH-3S0 CH30 C11 3 0 CH30 CHO CH30 CH30 CH3O CH30

C

2 0- CH0 CH30

H

n-CA H, CH2

H

f-Cs5ri C2 Rs CA3

H

CH3CONH -(gH2 )A H I H H H H H H H H Ht H H H 11 H if H I t I iI 11

H

CH3

CR,

H

CH

CH3 Ci3 CI1,

H

CH30 CH30 CR130 CH30 CH30 C1130

CH

3 S0I Ho CH30 CH30 HO C1130 C1130 C11 3 0 CH30 C1130 Cil 2 0

CHI

2 0- -0---CII2- O- CI2 0- CH,0 -(CR2

H

It 49 Table 6 H

R

C-N-CH

2 -H A r 0 6. Ar (R 1 *1 n see.% 66A B 6 50 Table 7

S

\K-N

C-H HR

VI

C11H 2

-CH

2 A 12 n' 0 6S~( U r C 12 n a 0 06* 0 0SH es 0964

OCH

955055 000.

55 4Q, 51 Examples of pharmaceutical applications 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 9 9 0*S* 9 o9 Preparation A mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous 15 gelatine solution through a 1 mm mesh screen, dried at 40 0 C and rubbed through a screen again, The granules thus obtained are 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 tablets are polished with beeswax.

6 e 9 9 9 99 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 Preparation The active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and intimately mixed with lactose and corn starch. The mixture is thun compressed to form tablets weighing 210 mg.

52 c) Capsules Active substance according to claim 1 20.0 mg Lactose 230.0 mg Corn starch 40.0 mg Talc 10.0 mg 300.0 mg Preparation The aotive substance, lactose and corn starch are A,2irst mixed together in a mixer and then in a grinding machine. The mixture is returned to the mixer, thoroughly combined with the talc and -transferred by machine into- hard gelatine capsules.

.00, 1 In these Examples, compounds such as **set: 1- (3,4-dihydroxy-6,7-dimethoxyiso4ui nolin-" -1- 4-dihydro-6 7-dimethoxyiso zinolin-1--yi dene) ethane, morphol inocarbonylmethyl-6 ,7-dimethoxy-3 ,4-dihydtroisoquinoline, 6,7-dimethQ,,Ty-3,4-dihydro-isoquinoline acetic acid methylamide, 6,7-dimethoxy-3 4-dthydro-isoquinoline acetic acid 1 25 diethylamide or

S..

6,7 -dimethoxy'-3,4-dihydro-isoqu~noline acetic acid phenylethylamide or b:armaceutically acceptable s&lts thereof may for examnple be used as active substance.

-I

Claims

1. A compound of formula I (R11im S S S* b S O a a LS 10 [wherein A represents a benzo or thieno group; R2 and R 3 independently of each other each represent a hydrogen atom or a (Cl,5)alkyl group, or together 15 with the carbon atom to which they are bound R 2 and R 3 together represent a 5- or 6-membered carbocyclic ring; R11 represents a halogen atom or a (Cl_ 4 )alkyl, hydroxy, (C1- 4 )alkoxy, amino, thiomethyl, methane- sulphonyloxy or methanesulphonamido group, or two adjacent substituents R 1 1 together represent -O-CH 2 -O- or -O-CH 2 -CH 2 m represents 0, 1, 2 or 3 if A is a benzo group, or 0, 1 or 2 if A is a thieno group; D represunts a group of formula Ia or Ib "1 0 0 (R12) (wherein in the group of formula la 00 0 000 0 00000 Q-t- o 0 a (a 0 0 0 -54- 9 9 C C C C *9C B represents a benzo or thieno group; R 1 represents a hydrogen atom, or a (C 1 ,lo)alkyl, phenyl, phenyl-(C 1 (C 1 4 )alkoxy or -NHCOX (wherein X is (Cl_5)alkyl) group; Rg represents a hydrogen atom, or a (C 1 4 )alkyl or hydroxymethyl group; R 6 and R 7 independently of one another each represent a hydrogen atom or a (C 1 5 )alkyl group, or together with the carbon atom to which they are bound R 6 and R 7 together represent a 5- or 6-membered carbocyclic ring; R 12 represents a halogen atom or a (C.4)alkyl, hydroxy, (C 1 4 )alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphonamido .oup, or two adjacent substituents R 12 together represent -O-CH 2 or -O-CH 2 -CH 2 n represents 0, 1, 2 or 3 if B is a benzo group, or 0, 1 or 2 if B is a thieno group; and in the group of formula Ib R 1 represents hydrogen, (C 1 1 o)alkyl, phenyl-(C 1 .5)alkyl, (C 1 4 alkoxy or -NHCOX (wherein X is (C 1 5 )alkyl); R' 5 represents a hydrogen atom or a (C. 4 )alkyl group; R 4 represents a (C 1 4 )alkoxy or an -NRqRlo group, wherein R 9 and Ro independently of each other represent hydrogen, branched or iunbranched (C. 12 )alkyl, (C 2 12 )alkenyl or (C212)alkynyl (wherein 99CCC* C eg. C P 9* CC S 9 C.

9.. I i UI C~) 0 0 1 00 C 0 0 0 La (a 55 the alkyl may be substituted by hydroxy, di (C 1 4 alkylamino, furyl, pyrrolidinyl, pyridinyl, indolyl, or the group (C 1 4 alkoxy, morpholinyl, a a. a a a. a a a. a a. Ar& (R 12 (wherein R 12 is as defined above; Ar is phenyl or thienyl; n' is 0, 1, 2 or 3 if Ar is phenyl, or 0, 1 or 2 if Ar is thienyl)) (C 3 7 )cy(.ioalkyl, dimethylamino, amino(C 2 4 alkyl (wherein the amino group may be unsubstituted or is mono- or di-(Cl 1 4 )alkylamino), phenyl, (g) morpholinyl, or pyridinyl, with the proviso that R 9 and Rocannot simultaneously represent hydrogen, dimethylamino or di (C 1 4) alkylaminomethyl; or R9and Rio together with the nitrogen atom to 15 which they are bou!-,d together represent a pyrrolifinyle. piperidinyl, morpholinyl or piperazinyl qroup, the piperazinyl ring optionally being N-substituted by unsubstituted phenyl, mono- or di-(C 1 4 )alkoxyphenyl, pyrimidinyl or phenyl(Cl 1 4 )aLkyl)] or the pharmaceuticp,-lly acceptable salts thereof; with the exception of the compound of formula I 25 wherein D is the group of formula Ia and Rl, R 2 1 R 3 R r R 6 and R 7 each represent a hydrogen atom and A and B taqe~h f\represent the group CH CH3 a. a a a a. a. a aS a. j 0 C) 00 CD n- C t" Cn r= n 01:c3: 3 Q; <J 0C) 0 00 0 0 C. 0 z o C c., =1 C.) 56 S and with the exception of the compound of formula I wherein D is the group of formula Ib and RI, R 2 R 3 and R' 5 represent a hydrogen atom? A represents the group CH 3 0- CHO0 S r OCH 3 and R 4 represents the group -NH-CH 2 -CH 2 OCH 3 2. A compound of formula I as claimed in claim 15 1, wherein D represents a group of formula Ia as defined in claim 1; R 1 represents a hydrogen atom, or a (C 1 1 0 )alkyl, phenyl(C 1 5 )alkyl or -NHCOX (wherein X is (C 1 group; R11 and R 12 independently of each other represent 25 (C1- 4 )alkyl, hydroxy, (Cl_ 4 )alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents RI, or R 12 together represent -O-CH2-O- or -0-CH 2 CH 2 3. A compound of formula I as claimed in either of claims 1 and 2, wherein S S. S S D represents a group of formula Ia; R 1 represents a hydrogen atom, or a (Cl_ 1 0 )alkyl or -NHCOX (wherein X represents (C 1 I 5 )alkyl) group; I 57 R 2 R 3 R 6 and R 7 independently of one another represent a hydrogen atom or R 2 together with R 3 and/or R 6 together with R 7 together with the carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring; R 1 1 and R1 2 independently of each other represent hydroxy, (C1- 4 )alkoxy, methanesulphonyloxy or methane- sulphonamido, or two adjacent substituents R 11 or R 1 2 together represent -O-CH 2 or -O-CH 2 -CH 2 4. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and m and/or n represents 2. 15 5. A compound of formula I as claimed in claim 4, wherein when A and/or R is a benzo group the two substituents 'R 1 and/or R L2 are each methoxy *and/or are in the meta-or para- position, respectively, to the fusion points of the group A or B. 6. A compound of formula I as claimed in claim being l-(3,4-dihydro. -6,7-dimethoxyisoquinolin- 1-yl)-1-(3,4-dihydro-6,7-dimethoxy-isoquinolin- 1-ylidene)-ethane or a physiologically acceptable 25 salt thereof. 7. A compound of formula I as claimed in claim 1 wherein D represents a group of formula Ib and R 4 is methoxy or ethoxy. 8. A compound of formula I as claimed in claim 1, wherein D represents a group of formula Ib and R 4 represents an -NR 9 R 1 0 group, wherein R 9 and RI0 independently of each other represent hydrogen, (C 1 8 )alkyl, (C2_ 3 )alkenyl or (C 2 3 )alkynyl 1 (whilst the alkyl may be substituted by hydroxy, f 0 -58- 4 alkoxy, di (C- 4 alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl or the group Ar~ (Rl2)nI! wherein Ar, R 1 2 and n' are defined as in claim 1) dimethylamino, phenyl, morpholinyl, pyridinyl, whilst R 9 and R 1 0 cannot simultaneously represent hydrogen, dimethylamino or di (C- 4 alkylaminomethyl; or R9and R 1 together with the nitrogen atom to which they are bound represent a pyrrolidinyl, morpholinyl or piperazinyl group, whilst the piperazinyl ring may optionally be N-substituted by unsubstituted phenyl, mono- or di(C 1 4 alkoxyphenyl, pyrimidinyl phenyl (C 4 )alKyl,- or R 9 and/or R 1 0 each represents unsubstituted phenyle fluorophenyl, morpholino )r 2- or 3-pyridinyl; *or R 9 and/or R 1 0 each represents (C 1 4 )alkyl;- or R~9 and/or R 1 0 each represents (C 2 or C 3 )alkYl which may be substituted by hydroxy, methoxy, dimethylamino, furyl, morpholino, pyrrolidinyl or pyridinyl, .:or R is hydrogen. 9 9. A comipound of formula I as claimed in claim 8, wherein Pis an -NR R 1 0 group wherein Ris hydrogen and R 0is a substituted alkyl of formula ViI R (C 16-c A 352) p I R12)n- VII K 7 '-I C0 0 oom c L o 0 0 Co1 0o C., C) C) C- 4.J t I 59 0 0 00 06 *5 S S. (wherein p is 0, 1 or 2, and Rg, 6 R 7 Ar, R1 2 arid i' are as defined in claim 1). A compound of formula I as claimed in claim 5, wherein R 1 2 represents hydroxy, methoxy, methanesul- phonyloxy or methanesulphonamido, or two adjacent substituerats R 12 together represent -O-CH 2 and/or n' is zero; or Ar is phenyl and n' is 2? and/or two substituents R 1 2 are in positions 2- anid 3-* and/or p is 1; and/or R and R7 are hydrogen.

11. A compound of formula I as claimed in any 20 one of claims 1 and 7 to 10, wherein D represents a group of formula Ib, R 1 represents hydrogen, (C 1 0 )alkyl, phenyl(C 1 alkyl or -NICOX (wherein X is 5 )alkyl); and 25 P 1 1 represents (C 4 )alkyl, hydroxy, (C 1 4 )alkoxy, methanesulphonyloxy or methanesuiphonamido, or two adjacent substituents R 1 1 together represent -O-CH 2 or C CJ2--0; and/or R 2 and R3 each repreent a hydrogen atom or together with the carbon atom to which they are bound R 2 and R 3 together represent a 5- or 6-membered carbocyclic ring.

12. A compound as claimed in either of claim 11 wherein R 1 represents hydrogen, (C 1 6 )alkyl or -NHCOCH 3 and/or S SS S5 4 J 4 (11 CI 0 60 R' 5 represents hydrogen, methyl or ethyl.

13. A compound as claimed in either of claims 11 and 12 wherein Rl 1 represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R 11 together represent -0-C- 2

14. A compound as claimed in any one of claims 1 and 7 to 13, wherein m represents 2; and/or A is a benzo group and the two substituents R 11 are in the meta- or para- position relative to the fusion points of group A; and/or R 11 is methoxy. A compound as claimed in claim 1, wherein D represents a group of formula Ib, A represents benzo, R1 is methoxy, m is two, R 1 is hydrogen t or (C1- 5 )alkyl, R 2 R 3 and R' 5 represent hydrogen and R 4 represents morpholino, methylamino, diethylamino or phenethylamino. 25 16. A compound as claimed in claim 15, being morpholinocarbonylmethyl-6,7-dimethoyv-3,4-dihydro- isoquinoline, 6,7-dimethoxy-3,4-dibydro-isoquinoline acetic acid metbylamide, 6,7-dimethoxy-3,4-dihydro-isoqtUinoline acetic acid diethylamide, or 6,7-dimethoxy-3,4-diydro-isoquinoline acetic acid phenyle.hylamide, or a physiologically acceptable salt thereof.

17. A compound as claimed in any one of the preceding claims being in the form of physiologically acceptable salts with inorganic or organic acids. Q 61

18. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 17 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.

19. A process for preparing a compound of formula I as claimed in any one of claims 1 to 16, comprising at least one of the following steps: A) (to prepare a compound of formula I wherein 1D is a group of formula Ia) condensing a compound r of formula II 4.R IN 20* N e* *6 SS 9* "s 7 (i (wherein A, Rif R2r R3' RG, R7, Rjl, R 12 and m are defined as in any one of claims 1. to 6t Ar represents a phenyl or thiewi0b group ,Ind n' represents 4 aOa 1, 2 or 3 if Ar is a phenyl group or 0, 1 or i A is thinyl group, and R representv a hydrogen atom or a (a 1-4)alkyl group) in the pvese!,., of a condensing agenbi o prepare a compound Of formula whearein 1 is a group of formula a) condensing a compound of formula 1,a at oe R, R h) c- Nis COCO-N Hof f-o Ct u")a 3 cRt. N IC--O-UCHC I 62 (wherein R 5 is hydrogen, Rl, R 2 R 3 R 6 R 7 R 1 and R12 are defined as in any one of claims 1 to 6, Ar represents phenyl or thienyl and m' and n' independently of each other represent 0, 1, 2 or 3 if the associated Ar is phenyl, or 0, 1 or 2 if the associated Ar is thienyl) in the presence of a condensing agent, without isolation of the intermediate product of formula (II); or (to prepare a compound of formula I wherein ~D is a group of formula Ib) &Sa condensing a compound of formula III 6R 00000 R1 1I C- C- 140c- c- C0- Ri, (wherein R5 is hydrogen, R, R 2 R 3 1 R 4 and are defined as in any one of claims 1 and 7 to 16, Ar 09 rpresents phanyl or thilonyl and m' rcopresents 0, 1, s 2 or 3 if AV is phoenyl, or 0, 1 or 2 if Ar is thinyl) in the presence of a condensing agent; and, if desired, carrying out one or more of the follow- 44 ing after- reatmenas; alkylainj a compound of formula wherein 11 or i1 1 is a hydrogen atom to form a compound of formula (1) wherein Rg -or RI io a (0 1 -4)alkyl group; hydroxymehylating a compound oe formula wherein D is a group of formula Ta and R9 is a hydrogen atom to yield a compound of formula wherein R is hIydroxy- mothylenet i 63 isolating the individual tautomers of compounds of formula I; isolating the free compound of formula from its salt; reacting a compound of formula to yield a pharmac- eutically acceptable salt thereof.

20. A compound of formula II *see 3 R7 *09 99 9. (R 1 A I -Rk- '1Z7 1wherein AR R2 R, R6, R7 1 RII, RI, and m are as defined in claim It Ar repres ents a phenyl or 4 thienyl group and n' represents Oel2 or 3 if Ar is a phenyl group, or 0,1 or 2 if At is a thienyl group$ and R5 represents a hydrogen atom or a (c I 25 4) alkyl group) or a physiologically acceptable salt thereof. 412 n 21, A compound of formula It substantially a4 herein disclosed-

22. A prochs or t h e preppration of a compound of formula I as claimed in claim 20 which comprises cthylng the corraespndin maloni acid dimide of foarmula ru Al CQMIA'=JU0 %IJL .J.L 641C ;*j.LUU LJ. starch, the granules are dried and intimately mixed with lactose and corn starch. The mixture is thji, compressed to form tablets weighing 210 mg. 64 Mia (wherein R 5 is hydrogen, R 1 RZ, R 3 R 6 R 7 1 R 11 and R 1 are defined as in claim 1, Ar represents phenyl or thienyl and mn' and n' independently of each other represent 0, 1, 2 or 3 if the associated Ar is phenyl, or 0, 1 or 2, if the associated Ar is thienyl),

23. A method for the treatment of coronary heart disease and/or acute myocardial infarction and/or conditions In which cardlo- and/or cerebroprotection is required in a su~bject which comprises administering to said subject a compound of formula I (as. defined in any one of claims 1 to 17) or a compound of formula 11 (as defined In claim 20) or a physiologically acceptable salt thereof. 24, Compounds of formula I as defined in claim 1 and salts, thereof, substantially as herein disclosed. ft... 6 0 ft... ft... ft. ft ft 0O 'ft.. ft ft ft... oft ft. ft S ft ft.. ft ft eft.... ft ft... ft ft. ft ft ft. ft ft S ft ft ft. ft ft... ft ft... ft ft.. ft D A TED this day of February 1991 BOEH-RINGER INGELHEIM INTERNATIONAL GMBH By their Patent Attorneys:, CALLINAN LAWM