NZ224356A

NZ224356A - 3,4-dihydro benzo- and thieno- pyridine derivatives and pharmaceutical compositions containing such

Info

Publication number: NZ224356A
Application number: NZ22435688A
Authority: NZ
Inventors: Walter Losel; Otto Roos; Gerd Schnorrenberg; Dietrich Arndts; Ilse Streller; Franz Josef Kuhn; Gunther Schingnitz
Original assignee: Boehringer Ingelheim Int
Priority date: 1987-04-24
Filing date: 1988-04-22
Publication date: 1991-07-26

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £24356 VWWImvw. m NO DRAWINGS 22 4 3 5 6 Priority Date<8):. •Mmptete Specification Filad: . o £> b~i Co"7D • • • • 4 •7T««« •••£•• •?▼•••• •Sm*«• •• • < /kJ«ss* (SI o . .Cq7D.S).c. ., ~-*fc»Wcatlon Date: ^.0. Journal, Mo: ....r. Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION BENZO - AND THIENO-3,4-DIHYDRO-PYRIDINE DERIVATIVES X/Ve, BOEHRINGER INGELHEIM INTERNATIONAL GMBH, a body corporate of the Federal Republic of Germany of D-6507 Ingelheim am Rhein, Federal Republic of Germany, hereby declare the invention, for which ^2f?we pray that a patent may be granted to yt6/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) - la- 224356 NZ 52-737 Benzo- and thieno-3,4-dihydro-pyridine derivatives 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 (wherein 1^, R2r Rg* Rg, Rg and R7 represent hydrogen and the substituted groups A and B represent the group 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 VIII Re (followed by page 2) K^^rBSIJJWWoiwu. - 2 - 22 4 3 5 6 [wherein A represents a benzo or thieno group; R2 and R3 independently of each other each represent 10 a hydrogen atom or a (C^_g)alkyl group, or together with the carbon atom to which they are bound R2 and Rg together represent a 5- or 6-membered carbocyclic ring? O 15 Rj^ represents a halogen atom (preferably F, CI, Br or I) or a (C1-4)alkyl, hydroxy, (C1-4)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphon-amido group, or two adjacent substituents R^ together represent -O-CHj-O- or -0-CH2-CH2-o-; 20 25 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 la or lb la 30 (wherein in the group of formula la B represents a benzo or thieno group; lb Rj^ represents a hydrogen atom, or a (C1_1Q)alkyl, 35 phenyl, phenyl-(C1-5)alkyl, (C1_4)alkoxy or -NHCOX (wherein X is (Cj^g) alkyl) group; Rg represents a hydrogen atom, or a (C^_4)alkyl or hydroxymethyl group; 224356 - 3 - 10 Rg and R^ independently of one another each represent a hydrogen atom or a alkyl group, or together with the carbon atom to which they are bound Rg and together represent a 5- or 6-membered carbocyclic ring; r12 represents a halogen atom (preferably F, CI, Br or I) or a (C1-4)alkyl, hydroxy, (C1..4)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphon-amido group, or two adjacent substituents R^2 together represent -O-CHj-O- or -O-CHj-CJ^-O-; n represents 0, 1, 2 or 3 if B is a benzo group, or 0, 1 or 2 if B is a thieno group; I5 and in the group of formula lb Rj represents'hydrogen,(C1_jQ)alkyl, phenyl-(C1_5)alkyl, (C1_4>alkoxy or -NHCOX (wherein X is (Cj.g) alkyl), " and preferably represents hydrogen, (Cj_10) alkyl\ phenyl- 20 ^1.5)alkyl : or -NHCOX (wherein X is (C1-5)alkyl); R's represents a hydrogen atom or a (C^_4)alkyl group; 25 R4 represents a (C^_4)alkoxy or an -NRgR^g group, wherein Rg and R1Q independently of each other represent 30 (a) hydrogen, (b) branched or unbranched alkyl, (C2_12) alkenyl or (C2 _12) alkynyl (wherein the alkyl may be substituted by hydroxy, (C^_4) aTlcOxy di(C^_4)alkylamino, furyl, pyrrolidinyl, morpholinyl pyridinyl, indolyl, or the group 35 AH 'R12^n' (w^ere^n Ri2 *s as 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)) - 4 - <56 (c) fCj_7) cycloalkyl (d) dimethylamino, (e) amino-(C2_4)alkyl (wherein the amino group may be unsubstituted or is mono- or di-(C1-4)alkylamino), (f) phenyl, (g) morpholinyl, or (h) pyridinyl, with the proviso that Rg and R^q cannot simultaneously represent hydrogen, dimethylamino or di(C^_4)alkylaminomethyl; or Rg and R10 together with the nitrogen atom to which they are bound together represent a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, the piperazinyl ring optionally being N-substituted by unsubstituted phenyl, mono- or di-(C1_4)alkoxyphenyl, pyrimidinyl or phenyl(C1-4)alkyl)] or the pharmaceutical^ acceptable salts thereof, preferably with inorganic or organic acids; with the exception of the compound of formula I wherein D is the group la and R^, R2, Rg, R,., Rg and R^ e^ch represent a hydrogen atom and A and b each represent the group ch30 and with the exception of the compound of formula I wherein D is the group of formula lb and_R, , the group and R4 represents the group or an ethoxy group; (followed by page 4a) 724^6 - 4a - G G and with the exception of the compound of formula I wherein D is the group of formula lb, and R' represent a methyl group., R2 and R^ represent a hydrogen atom, A represents the group CH. ^3° CH30 and R4 represents an ethoxy group. (followed by page 5) mmarn A J ?24S56 - 5 - The carbocyclic ring which may be formed by R2 and Rg or Rg and R7 and the associated carbon atom 5 to which they are bound is preferably a saturated 5- or 6-membered carbocyclic ring. C Compounds of formula I wherein D is the group of formula la are hereinafter referred to as compounds 10 of formula VIII R- R, 15 VIII 20 (wherein R^, R^, Rg, Rg, Rg, R?, Rn» Ri2' A and B are defined as hereinbefore). Compounds of formula VIII wherein Rg is hydrogen form tautomers of formulae Villa and Vlllb, e 25 30 1*12*n villa Vlllb 35 wherein Rg is also hydrogen. The def|niti'oh of all ^ formulae I and VIII and the invention alsc ~ the above-mentioned tautomers. MAY 1*91-« , / 22 4 3 5 6 Compounds of formula I wherein D is a group of formula lb are hereinafter referred to as compounds of formula IX j?, IX 10 Compounds of formula IX wherein R's is hydrogen form tautomers of formula IXa 0 20 which also form part of the present invention. The tautomers may be separated by known methods* e.g. by column chromatography or selective reduction (NaBH4 or catalytic reduction). Compounds of both 25 structures wherein Rg represents (C^_4)alkyl are stable. The definition of general formula I or IX should be taken to include the compounds of structure IXa wherein R*5 represents hydrogen or (C^_4)alkyl. 30 We have surprisingly found that the new compounds of formula I and, particularly, the above-mentioned compound and the intermediate of formula II formed in the preparation of compounds of formula VIII 35 and described hereinafter have valuable therapeutic properties both as free bases and also in the form of their salts. aw. 22 4 3 5 6 - 7 - Moreover, compounds of general formula IX wherein R4 is the group of general formula X R6 - NH - CH2 - c (Ar) ^12^' x *7 are important intermediates in the preparation of compounds of general formula VIII, the tautomers and salts thereof. Of the compounds of formula VIII, the following are preferred: -) Compounds of formula VIII wherein R^ represents hydrogen, (C1-10)alkyl, phenyl(Cj^g)alkyl or -NHCOX (wherein X is (C1_5)alkyl); R^ and R12 independently of each other represent (C1-4)alkyl, hydroxy, (C^_4)alkoxy, methane-sulphonyloxy or methanesulphonamido, or two adjacent substituents R^ or R^2 together represent -0-CH2-0- or -0-CH2-CH2-0-; -) Compounds of formula VIII, wherein Rj^ represents hydrogen, (C^_10)alkyl or -NHCOX (wherein X is (C1_5)alkyl)? R2/ Rgr Rg and R7 independently of one another represent a hydrogen atom or R2 together with Rg and/or Rg together with R7 and the associated carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring; R^ and R^2 independently of each other represent hydroxy, (C^_4)alkoxy, methanesulphonyloxy - 8 - 224356 or raethanesulphonamido, or two adjacent substituents R^ or R12 together represent -0-CH2-0- or -0-CH2-CH2-0-; -) particularly preferred are compounds wherein R^ represents a hydrogen atom, or a (C^_g)alkyl or -NHCOCHg group; and/or r5 represents a hydrogen atom, or a methyl or hydroxyraethyl group; and/or R2, R3, R6 and R7 independently of each other represent a hydrogen atom or R2 together with Rg and/or Rg together with R7 and the associated carbon atom to which they are bound represent a 5-membered carbocyclic ring; and/or R13. and Ri2 independently of each other represent hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R11 or r12 to9ether represent -0-CH2-0-. Further generally preferred compounds are those 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^ and/or R^2 are preferably in the meta- or para- position relative to the fusion points of the group A or B, respectively. Compounds wherein R11 and R^2 are methoxy are particularly preferred. Examples of specific compounds according to the invention are listed in the Tables which follow; 1~(3,4-dihydro-6,7-dimethoxy-isoquinolin-l- yl) -1- (3,4-dihydro-6,7-dimethoxy-isoquinnl i n-1- . ylidene)-ethane or a physiologically acc apfel^|;i'^rEislT0FF!'"E— salt thereof is especially preferred. 22NOV 19tlu RECEIVED 224356 - 9 - Of the compounds of formula IX, the following are particularly preferred: Compounds - wherein R4 is methoxy or ethoxy; - wherein R4 represents an -NRgR^g group, wherein Rg and R^g independently of each other represent (a) hydrogen, (b) (C1-g)alkyl, (C2_3) alkenyl or (C2_3)alkynyl (whilst the alkyl may be substituted by hydroxy, (C^_4)alkoxy, di(C^-4)alkylamino/ furyl, pyrrolidinyl, morpholinyl, pyridinyl or the group (R12} n'' wherein Ar, R12 and n' are defined as hereinbefore), (d) dimethylamino, (f) phenyl, (g) morpholinyl, (h) pyridinyl, whilst Rg and R^g cannot simultaneously represent hydrogen, dimethylamino or di (C1-4)alkylamino-methyl; or Rg and R^g 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^_4)alkoxyphenyl, pyrimidinyl or phenyl(C1-4)alkyl; more particularly compounds wherein R4 is an -NRgR^g group, wherein Rg and/or R10 each represents unsubstituted phenyl, fluorophenyl, morpholin-4-yl or 2- or 3-pyridinyl; or wherein R4 is an -NRgR^g group, wherein Rg and/or R10 represents (Cj_4)alkyl, preferably methyl or ethyl; or wherein R4 is an -NRgR^g group wherein Rg and/or R10 each represents (C2 or C3)alkyl, wh ■ ch mav M.Z. PATENT OFF ICE 22 NOV 1990 RECEIVE o 5 224356 - 10 - be substituted by hydroxy, methoxy, dimethylamino, furyl, morpholin-4-yl pyrrolidinyl or pyridinyl; or wherein R4 is an -NRgR10 group wherein Rg is hydrogen. Other compounds of formula IX which are particularly preferred are those wherein R^ is an -NR^R^q group wherein Rg is hydrogen 10 and R^g is a substituted alkyl of formula VII, R« —fCH2)p-C-vii 15 — R' wherein p is 0, 1 or 2; Rg and R^ independently of each other represent 20 hydrogen or alkyl or together with the carbon atom to which they are bound Rg and R7 together represent a 5- or 6-membered carbocyclic ring; 25 Ar represents phenyl or thienyl; r12 represents CC1_4)alkyl, halogen (F, CI, Br, I), hydroxy, (C^_4)alkoxy, amino, thiomethyl, methane-sulphonyloxy or methanesulphonamido, or two adjacent /-s. substituents R^ together represent -0-CH2-0- or ^ 30 -0-CH2-CH2-0- and n' represents 0, 1, 2 or 3 if Ar is phenyl, or 0, 1 or 2 if Ar is thienyl. 35 Especially prefered are those compounds of formula IX wherein R12 is (C1-4)alkyl, hydroxy, (C1_4)alkoxy, methanesulphonyloxy or methanesulphonamido, or. fi.Z. PATENT OFFICE 22N0V Ibou RECEIVED - 11 - 224356 two adjacent substituents R-^ together represent -O-CHj-O- or -O-CHj-CHj-O-; wherein R^2 represents hydroxy, (C^ 4)alkoxy, methane-O 5 sulphonyloxy or methanesulphonamido, or two adjacent substituents R^2 together represent -0-CH2-0- or —0—CH2""CI?2 -0—; or wherein R^2 represents hydroxy, methoxy, methanesulphonyl-10 oxy or methanesulphonamido, or two adjacent substituents r12 to9ether represent -O-CHj-O-. Particularly preferred compounds are those compounds wherein R12 is methoxy; 15 wherein n' is zero; wherein Ar is phenyl and n' is 2, preferably wherein the two substituents R^2 are in positions 2- and 3-. 20 Particular mention should also be made of compounds of formula (IX) wherein R4 is an -NRgR1Q group, wherein Rg and R^Q together with the nitrogen atom Cj) to which they are bound represent morpholin-4-yl, pyrrolidinyl 25 or piperazinyl (which is N-substituted by methoxyphenyl, phenethyl or 2-pyrimidinyl). Of the above-mentioned groups of compounds, especially preferred are those 30 - wherein R^ represents hydrogen, (C^_^q)alkyl, phenyl (C1_5)alkyl or -NHCOX (wherein X is (C^_g)alkyl); and R11 rePresents ^1-4) al^yl, hydroxy, (C1__4) alkoxy, 35 methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R^ together represent -0-CH--0- or -0-CH?-CH,.-0-; ": z. PATENT OFFICE 2 2 NOV 1990 RECEIVED - 12 - 22 4 3 5 f - wherein represents hydrogen, alkyl or -NHCOX (wherein X is (C1-5)alkyl); R2 and Rg each represent hydrogen or together with the carbon atom to which they are bound R2 and Rg together represent a 5- or 6-membered carbocyclic ring; R11 rePr®sents hydroxy, (C^_4)alkoxy, methane-sulphonyloxy or methanesulphonamido, or two adjacent substituents R^ together represent -O-CHj-O- or -O-CHj-CHj-O-; wherein R^ represents hydrogen, (Cj_g)alkyl, or -NHCOCHg; wherein R*5 represents hydrogen, methyl or ethyl; wherein R2 and Rg represent hydrogen or together with the carbon atom to which they are bound R2 and Rg together represent a 5-membered saturated carbocyclic ring; wherein R^ represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R^ together represent -0-CH2-0-; wherein, if A is a benzo group, m represents 2 and preferably the two substituents R^ are in the meta- and para- positions, respectively, to the fusion points of the group A; wherein R^ £S methoxy. Other preferred compounds are those wherein A represents 5 O 10 15 20 O 224356 - 13 - benzo, represents methoxy, m is two, R1 is hydrogen or (C1-5)alkyl, R2, R3 and R's represent hydrogen and R^ represents morpholin-4-yl, methylamino, diethylamino or phenethylamino. Examples of specific compounds falling within the present invention are listed in the Tables hereinafter, but particularly preferred are morpholin-4-yl-carbonylmethyl-6,7-dimethoxy-3 ,Tl-dihydro-isoquinoline, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid methylamide, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid diethylamide and 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid phenylethylamide and the physiologically acceptable salts thereof. The compounds of formula I according 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, B and C hereinafter. A. (to prepare a compound of formula I wherein D is a group of formula la, i.e. to prepare a compound of formula VIII) cyclising an amide of formula II <RU) II N.Z. PATENT OFFICE 2 2 NOV 19 90 PECEIV7D i I a 224356 _->t! - 14 - (wherein A, R^i R2, R3' ' Rll' R12 ® are defined as hereinbefore, Ar represents a phenyl | or thienyl group and n' represents 0, 1, 2 or 3 I if Ar is a phenyl group, or 0, 1 or 2 if Ar is 5 a thienyl group, and R- represents a hydrogen atom 'w' or a (C^_4)alkyl group) in the presence of a condensing agent. i Suitable condensing agents are, for example, strong ! ^ 10 Lewis acids such as phosphorus oxychloride, phosphorus | pentachloride, phosphorus trichloride, phosphorus <j 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 such as, for example, a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and (C^_4)alkylsulphonic acid, e.g. containing about 10% by weight of P2°5* 20 If a compound of formula II wherein Rg is hydrogen is cyclised in the presence of a mixture of phosphorus pentoxide and (C1-4)alkylsulphonic acid, there is obtained, in addition to the corresponding compound 25 of formula VIII wherein Rg is hydrogen, the analogous compound of formula VIII wherein Rg is (C1-4)alkyl. Preferably, this variant of the process is carried out with methanesulphonic acid. c 30 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. 35 toluene, xylene), chlorobenzenes, chloroform, acetonitrile and decalin. In a preferred Amhnriinpnfr nf fchg process, the condensing agent, «|imfr'^a^iph'aflphiogus| 2 2 NOV 1900 JJeceiv'D o 15 22 4 3 5 6 oxychloride or a mixture of (C1-4)alkylsulphonic acid 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 a wide temperature range, preferably with heating to 50°C up to about the boiling point of the reaction mixture. The reaction time required is generally between several days and several hours, depending on starting compound II. The cqmpounds of general formula II defined above are new compounds. Thus, a further aspect of the present invention provides a compound of formula II (wherein A, ? R2r Rg# Rg, R^, R^, R12 ^^d ® 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^ represents a hydrogen atom or a (C^_4)alkyl group) or a physiologically acceptable salt thereof. (II) There is further provided a process for the preparation ^2.4- 36k - 16 - of a compound of a formula II which comprises cyclising the•corresponding malonic acid diamide of general formula Ilia <Rll)B.-^)-^-CH2'NHCO"{:"CO"NH"CK2"f"@,"(Ri2>Bi' ltl* (wherein Rg is hydrogen? r R2' R3' R6' R7' R11 and 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). The reaction may be carried out as described above for the cyclisation of compound II to form a compound of formula VIII. If the reaction is carried out with a mixture of phosphorus pentoxide and (C^^Jalkyl-20 sulphonic acid, there is obtained, in addition to the corresponding compound of formula II wherein Rg is hydrogen, the analogous compound of formula II wherein Rg is (C^^) alkyl. (See also process step C) . 25 B. (to prepare a compound of formula I wherein D is a group of formula la) condensing a compound of formula I lie* r2 <RnV-0T R3 CH -NHCO 2 CO-NH-CHJ-?-^-(Ru)n, R- R- Ilia ; ti'< T / (wherein Rg is hydrogen, R^, R2, R3/ Rg* R7# Rjj and R12 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)( \i jVlUW* 1 V o o c - 17 - 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, 10 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 15 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, 20 cyclisation is preferably effected with phosphorus pentachloride? a mixture of phosphorus oxychloride and phosphorus pentachloride or with a mixture ^ of methanesulphonic acid and P2°5' 25 The compounds of general formula nia are substantially known compounds and may be prepared by methods known per se. C. fto prepare a compound of formula I wherein 30 D is a group of formula lb, i.e. to prepare a compound of formula IX) condensing a compound of formula , /' V- x III C) r I:'SJ .„o^ vhi' m■'-©4"CH2-meo-f-co-«4 R3 »'i nr $ -/8> %W>$\o (wherein Rg is hydrogen? Rj ? Rj, R3? R4 and Rn are defined as hereinbefore? Ar represents phenyl or thienyl and in' represents 0,1,2 or 3 if Ar is phenyl, or 5 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 10 and (Cj_4)alkylsulphonic acid, there are obtained? in addition to the corresponding compounds IX and IXa wherein R'g is hydrogen? the analogous compounds IX and IXa wherein R'g is (Cj_4)alkyl. 15 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 (I) wherein Rg 20 or R'g is a hydrogen atom to form a compound of formula (I) wherein Rg or R'g is a (C^_4)alkyl group; hydroxymethylating a compound of formula (I) wherein 25 0 is a group of formula la and Rg is a hydrogen atom to yield a compound of formula (I) wherein Rg is hydroxymethylene; isolating the individual tautomers of compounds 30 of formula I; isolating the free compound of formula (I) from its salt; * . - 19 - 224356 Suitable condensing agents for this process are strong Lewis acids such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron 5 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 10 mixture of phosphorus pentoxide and (Cj^jalkyl- sulphonic acid, e.g. containing about 10% by weight of P2°s. If a compound of formula III wherein Rg is hydrogen is cyclised 15 in the presence of the mixture of phosphorus pentoxide and (C^_4)alkylsulphonic acid, there are obtained, as mentioned above, in addition to the corresponding compounds IX and IXa wherein R's is hydrogen, the analogous compounds IX and IXa wherein R'5 is (C1-4)alkyl. 20 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, chloroform, aceto-nitrile and decalin. In a preferred embodiment 30 of the process, the condensing agent, such as phosphorus oxychloride or a mixture of (C^_4)alkylsulphonic acid and phosphorus pentoxide, is used without the addition of solvent. 35 Cyclisation is preferably effected with phosphorus oxychloride or, in difficult cases, with a mixture of phosphorus pentoxide and (C^-4)alkylsulphonic acid (preferably methanesulphonic acid T7~:—- P'U EIMTOFRCE 2 2 NOV 1S< bo RECEIVED o o - 20 - 22 4 3 5 6 The reaction may be carried out within a wide temperature range, preferably with heating to 50°C up to about the boiling point of the reaction mixture. 5 The reaction time required is between 2 and 15 hours, depending on the starting compound III. The tautomers of general formulae IX and IXa wherein r'5 is hydrogen may be separated by known methods, 10 e.g. by column chromatography or selective reduction with, for example, NaBH4 (reduces the tautomer of formula IX). Tautomers of formulae IX and IXa are reduced by catalytic reduction. 25 15 Compounds of formula I wherein Rg 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, 20 alkylesters of toluenesulphonic acid or alkylesters 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 (Ci_4)alkyl). The N-hydroxymethylation may be carried out under the conditions of aminoalkylation according to Leuckart-Wallach (Ber. Dtsch. Chem. Ges. J18, (1885) 2341) or Eschweiler-Clarke (Teilheimer 2, (1948) 30 No. 352; £ (1950) No. 378). Generally, the substance is treated with a 30% formalin solution, for example, in the presence of formic acid at ambient temperature. 35 The free base of general formula I may be converted into the acid addition salts thereof in a manner known per se. 224356 c o /"A O - 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, 5 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 10 of formula I have valuable therapeutic properties, as already mentioned hereinbefore, both as bases and in the form of their salts. In particular, these substances have a significant 15 cardioprotective activity which was determined as follows: 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 al., J.Mol.Cell. Cardiol. 10: 427-438, 1984; Nakanishi et al., Am. J. Physiol. 242: 437-449, 1982; Pleckenstein A., VortrSge der Erlanger Physiol. Tagung 1970, Edit. Keidel, Springer Verl. Berlin, 25 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 (Pleckenstein loc. cit.)f of calmodulin inhibitors (Higgins) and other 30 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 described by Arndts 35 (loc.cit.) and the potency of the test substances was given as the Hgg value; this value corresponds to the dose which results in a 50% inhibition of .'"'Vi'FriTOFFICE 2 2 my 1990 HECEIVED 22 4 3 5 - 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 C^} 5 times more effective than the known commercial 5 product propranolol. Compound H50 ~ value* A 1.25 B 2.26 O c 1,34 ^ 10 D 2.25 E 2.29 P 1.41 6 2.23 H 2.15 15 * oral administration of active substance. If an isolated heart kept for a fairly long time under ischaemic conditions is then subjected to normal perfusion again, heart function is not 20 immediately normalised. Rather there is a period of transition characterised by contracture and arrhythmia. This phase of arrhythmia is caused by changes in J the function and structure of the myocardiac cell with intracellular calcium overloading (Hess and 25 Manson, J.Mol.Cell.Cardiol, JL6, 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, 30 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 35 0.15ml/min) there is a period of irregular, heart activity lasting for 10-15 minutes. Infusion of cardioprotective compounds shortens this period significantly. 22 4 3 5 6 - 23 - Compound Concentration [jig/ml ] shortening of the arrhythmia phase from 11-13 minutes to A I K L 3.3 13.3 6.6 3.3 4.0 min 3.5 min 3.1 min 5.0 min Conpounds in the test resulta Compound A : Compound of Table 1 r. R11 <*3° R5 5 H R11 CH30 Ri2 ! CH3O R1 H R12 5 CH3O VR3 -«s2)4- r6~R7 : -(CH2) 22 4 - 24 - Compounda of Table 4 (Structural Type I) f / CompowL r'n r,'u *1 r2 r3 R Salt 4 :f ocm b ch30 chjo H h h nh-n--(ch3>2 hc1 o c ch3o ch.o ch3- -(ch2>3 k h nh-ch2--ch(ch3)2 bs D chjo ck3o CV -(ch2)3 h b nh-ch--(ch3)2 bs c ch30 cb3o CV "<ch2>3 h h nh- -(ch2>2-0 bs f ch30 cbao ch3- -<ch2>3 h h NHCHj bs o G ch3o chjo CV -<ch2>3 h h nh- "(CH2)2~OCK: bs h chjo ch30 cn3--(ch2,3 h K nh-ch2--ch(oh)-ch3 hc1 f* I ch3o CH 0 h h H r-\ n 0 \ / K ch3o CHjO CH3" -(ch2>3 h h nh-ch(ch )- -<=H2,3--ch(ch3)2 BS L ch3o CH3O C6H5--(ch2>2 h h nh- (=H2)2-0 BS m - 25 - 22 4 3 5 6 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 r 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., Pflflgers Arch. 392, 139 - 145, 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. In view of these 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 3.5% oxygen was passed, the animals pretreated with the substances according to the invention showed a statistically highly significant increase .j¥SSSWSWJ5SJ^-T-',•'v' 22 4 3 5 * - 26 - % I in survival over the control animals or animals which had been pretreated with diltiazem, nifedipin or verapamil. The cerebroprotective activity tested 5 by this method was noticeable even at a dosage ft | 5 of 5 mg/kg p.o. Thus, the compounds according j to the invention are clearly superior to the known i substances mentioned above both in terms of the effective dose and in the improved performance obtained in animal experiments. C 10 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 treat cardiac insufficiency and cerebral metabolic 15 disorders or organic brain psychosyndrome and posttraumatic and alcoholic brain damage. 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 25 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 30 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 35 there are provided a method for the treatment of coronary heart disease, acute myocardial infarction and/or for use in cardio- and/or cerebroprotection 1 - 27 - 2 2 L * * in a subject which comprises administering to said subject a compound of formula I fas 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 5 hereinbefore) or a compound of formula II (as defined hereinbefore) or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for use in a method for the treatment of coronary heart disease and/or acute myocardial infarction, 10 and/or for use in cardio- and/or cerebroprotection 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): O c i - 28 - Example 1 2 2 4 3 5 6 1- (3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl) -1- (1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-(^) 1-ylidene)-pentane and 5 1- (3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-N-methyl-isoquinolin-l-ylidene)-pentane 4.9 g of n-butylmalonic acid-di-N-[2-(3,4-dimethoxy-10 phenyl)-ethyl]-amide are heated to 100°C for 1 to 2 hours in 20 ml of a methanesulphonic acid/PjO^ mixture (10% by weight of P205). After the reaction has ended (monitored by thin layer chromatography) the reaction mixture is poured onto ice, made alkaline 15 with saturated soda solution and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, evaporated '■j down in vacuo and the residue is separated on silica gel (eluant: methylene chloride: methanol = 100:5, 20 V:V). The N-H compound is eluted first. \ Q_J N-H compound: m.p. = 158-159°C (hydrochloride) N-CHg compound: m.p. ■ 136-137°C (hydrochloride) 25 Example 2 1- (3,4-Dihydro-6,7-dimethoxy-isoquinolin-l-yl)-1- (3,4-dihydro-6,7-dimethoxy-2-N-methyl-isoquinolin-30 1-ylidene)-pentane-hydrochloride 1 g of the 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl) -1-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-l-ylidene) -pentane prepared in Example 1 is heated 35 to boiling for 6 hours in 2 ml of freshly distilled - 29 - ?? 4 3 dimethylsulphate. After working up in the usual way, the product is chromatographed on silica gel feluant: CH2C12: MeOH ■ 100:5, V:V) , the hydrochloride is formed and crystallised from ethanol/ether. 5 Example 3 1-(3,4-Dihydro-6,7-dimethoxy-isoguinolin-l-yl)-1-(3,4-dihydro-6,7-dimethoxy-l-N-hydroxymethyl-10 isoquinolin-l-ylidene)-ethane-hydrochloride 12 g of 1-(3,4-dihydro-6,7-dimethoxy-isoguinolin-l-yl) -1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-ylidene)-ethane are left to stand for 20 hours 15 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 CH2C12, washed with dilute soda 20 solution and then with water, the organic phase is dried over Na2SO^, 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. 25 = 155°C Example 4 a-(3,4-Dihydro-6,7-dimethoxy-isoguinolin-l-yl)-30 1,2,3,4-tetrahydro-6,7-dimethoxy-l-benzylidene-isoquinoline 4.9 g of l,2,3,4-tetrahydro-6,7-dimethoxy-l-a-^[2-(3,4-dimethoxyphenyl)-ethylJ-aminocarbonyl^-benzyl- •*?/ 224356 - 30 - isoquinoline are heated to boiling for 4 hours in 20 ml of freshly distilled phosphorus oxychloride. After the reaction has ended (monitored by thin layer chromatography) excess POClg is distilled 5 off, the residue is distributed between CH2C12 and dilute soda solution, the organic phase is washed with water, dried over Na2so4 and evaporated down. The residue is chromatographed on silica gel (eluant: CH2ci2:MeOH = 100:10, V:V). The fast-CD 10 running yellow fraction yields a-(3,4-dihydror6,7- dimethoxy-isoquinolin-l-yl)-1,2,3,4-tetrahydro-6,7-d ime thoxy-l-benzylidene-2-N-phosphono-i soqu i noline (m.p. above 270°C (hydrochloride)), whilst the subsequent red zone yields the N-H compound (m.p. 15 95-100°C) given in the title. Example 5 (4,5-Dihydro-thienor 2,3-c]pyridin-l-yl)-4,5,6,7-20 tetrahydro-l-methylidene-th ieno f 2,3-c]pyridine 19 g of malonic acid di-N-[2-(3-thieno)-ethyl]amide are heated to boiling for 3 hours in 25 ml of phosphorus oxychloride. As soon as no further starting material can be detected, the mixture is worked up in the usual way, the reaction product is purified on Al2Og neutral, activity stage III (made by Woelm) (eluant: CH2C12) and the hydrochloride is formed. (M.p. = 233-235#C) Example 6 a-Isobutylaminocarbonyl-l-pentyl-6,7-dimethoxy-3,4-dihydro-isoquinoline 3.8 g (10 mmol) of a-isobutylaminocarbonyl-valeric acid-N-[2-(3,4-dimethoxyphenyl)-ethyl]-amide are N.Z. P-Vi'EiMT OFFICE 2 2 NOV 1990 f:eceiv-d u 25 o 30 4SWT"" 224356 - 31 - dissolved in 120 ml of acetonitrile and 18 ml of phosphorus oxychloride are added. The reaction mixture is heated to reflux temperature for about 2 hours. It is then evaporated down, the residue 5 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 Na2S04, eliminating the solvent, etc. - the 10 product is purified over a silica gel column _(CH2ci2/MeOH » 100:2). M.p.: 158-160°. Example 7 15 Methyl 2-ethyl-2-(3,4-dihydro-5,6-dimethoxy-l-iso-quinolinyl)-butane-carboxylate 22 g of methyl 2- [2-(3,4-dimethoxyphenyl)7ethyl]-aminocarbonyl -2-ethyl-butane carboxylate are heated 20 to boiling in a mixture of 100 ml of acetonitrile and 12 ml of phosphorus 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: CH2C12 : CH3OH = 100:2) and the hydrochloride is formed. M.p. = 141-143°C (ethanol/ether) Examples of some compounds according to the invention 30 which may also be prepared analogously to the Examples described above are listed in the Tables which follow. o Table 1 - 32 - o c «g*r<rr •6»,t^«WaAT *-r.n3>-i.>j.V^w-v '•AwM^^VeS,^ C; • O Rl i1 Rn" Ri Ra Ra Rs CHaO CHaO H -(CHa) 4 - H CHJSOJHH CHaO H H H H CHaO CHaO n-C*H» H H CHa CHaO CHaO n-C4H« H H H CHaO CHaO CHa H H H CHaO CHaO CHa H H CHa CHaO CHaO H H H H CH iO CHaO H H H CHa CHaO CH a S0> H H H CHa CHaO CHaO CHa H H CHa OH CHaO CHaO n-CsHu H H CHa CHaO CHaO CaHs H H CHa CHaO CHaO CtH) H H H CHaO CHaO CHa . H H H CHaO CHaO CaHs H H H CHaO CHaO CaHs H H H CHaO CHaO H H H H -0—CHa 0- H H H H CHaO . CHaO CHaCONH H H H -0—CHa- —0- CeHs H H H BS = Base CI = Chloride D = Decomposition o o % 81 a■' r. r, Mp #C/Salt formw CHiO CHaSOaNH CHaO CHaO CHaO CHaO HO CHaO CHaO CHaO CHaO CHaO CHaO 0-0-CHaO 0-0-CHaO 0- - (CH a ) 4 • H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H 119/BS 233-238 {DJ/BS 136-137/Cl 158-159/C1 180/C1 177/BS 182-186/BS 138-140/BS 222-225/BS 155/C1 75-79(amorphous) /B6 80 (amorphous)/BS 95-100/BS 156-158/C1 148-155/C1 177-179/Cl 251-253/Cl 251-253(D)/C1 171-172/Cl 191-195/BS I 8 I ro ro 4>-cm cji o> Table 2 - 34 - 22 4 3 5 6 i o op. H-^R :::x)6 Salt form CI M p(°C) 218-222 1 06" ci 239-235 H«w*iiiuimj* 'i-ui'wawwimasiimm 1 - 35 - Table 3 22 4 3 5 6 r> w Salt form Mp ( C) h3co H3C0 CI 162-172 G ci 237-239 CI 250-253 I Table 4 „. .v».^y>-i,c^..>^>-gsr- ?+•+>.+r.„-w. - < ->.-,'•>• >*>•-<» 22 4 3 5 6 - 36 - /n Structural type I J ^ ft Structural type II v—' BS = Base ««!?=<■ o o r'n d ' « r n r1 r2 r ch3o ch3o h h h ch3o ch3o h h h CHjo ch3o h h h chjo ch3o h h h ch3o ch3o h ii h CHjO ch3o h h h ch30 ch3o h h h CHjo ch30 h h h ch3o ch30 h ii h CHjo ch30 h h h ch3o ch30 h ii h nhch3 n(ch3)2 NHC2«5 nh-(ch2)2-ch3 n((ch2)2-ch3)2 nh(ch2)3-ch3 hh-(ch2)4-ch3 mh-ch(ch3)2 hh-ch2-ch(ch3)2 nh-(ch2)2-ch(ch3)2 hh-ch2-c»ch2 I O o t Structural Salt up. (° C) type form hc1 196-197 hc1 149-150 hc1 212-217 hc1 199-204 hc1 94- 98 # hc1 196-198 ' bs 126-128 hc1 198-199 hc1 221-222 hc 1 hc1 113-114 ro ro -r> CM CJI a> tA. O G r,11 r,,ll r1 *2 *3 r4 ch30 ch30 h h h nh-ch2-c=ch ch30 ch30 h h h n(ch3)-ch2-ch20h ch30 ch30 h h h »H(C«2>3-O0CH ch30 ch30 ii h h nh-n(ch.) ch30 ch30 h h h oc2h5 ch30 ch30 h -{ch 2*4*' oc2h5 ch3o ch30 h h h nhch3 ch30 ch30 h h h n(ch3)2 ch3o ch30 h h h n(c2h5)2 ch30 ch30 h h h nh(ch2)4-ch3 ch30 ch30 h h h nh-(ch2)3-och3 ch3o ch30 h h h mh-(ch2)3-m(ch3) O O Structural Salt Mp. (° C) type form hc1 216-217 hc1 202-203 hc 1 132-134 bs hc1 bs bs bs bs 196-198 224-226 88- 91 115-121 135-136 144-147 ro ro 04 <jn o> r'n r ' 1 R 11 r1 r chjo ho h h chjo ho h ' ' h ch3o ho h h CHjO ho h h chjo ho h h ch3° ho h h ch3° ho h h ch3° ho h h ch3o ho h ii ch3° ho h h ch3o ho h h »3 r4 ii oc2h5 h n(c2h5 *2 h nh(ch2 )2n(ch3) h nh(ch2 )3n(ch3) h nh(ch2 h0ch3 h /-a n 0 \ ( h wh(ch2 )2_ch3 h nh(ch2 h nh(ck2 Vch3 h nh(ch2 )20chj h o o o Structural Salt MP. (° C) type form i bs 170-177 i bs 178-180 1 bs 158-161 i hc1 160-164 1 bs 197-199 I BS 207-208 I! BS 173-180 ii BS 148-155 ii BS 152-155 II BS 181-182 II 8S 245-248 «<o ro ro CM CXI O* r' 11 o-ch2-o o-ch2-o o-ch2-o o-ch2-o o-ch2-o o-ch2-o o-ch2-o 11 nhso2ch3 ch30 o h h h h h H h tl h h h II h h h O nh-ch2-ch(oh)-ch3 nh-n 0 v / OC2H5 hh(ch2)3oh mh{ch2)2-chich3)2 nh-(ch2)2 p och. Structural Salt type form nh-(ch2)2 <s nhs02ch3 och. 11 I II 11 II 11 11 II bs HC1 bs bs bs bs, bs bs O Mp. ( C) 134-146 180-193 143-152 133-134 129-133 142-146 89-105 (7) 176 # ro ro i & i CM cn <9 r,u R"ll «1 r2 r ch30 chjo 1 ch3 . h h ch3° chjo ch3 h h CHjO chjo ch3 h h chjo ch3o ch3 h h ch3o ch3o ch3 h h CHjO ch3° CH3 h h ch3o CHjO ch3 H h CHjO CHjO ch3 H h ch3o ch3o ch3 H h CH3° CHjO ch3 h h ch3o ch3° ch3 h h ch3o CH3o' ch3 h h ch,0 ch3o ch3- h h Structural Salt type form M p. ( c ) nh-ch2-ch(ch3)2 nh-(ch2)4-ch3 nc(ch2 )2ch3d2 nc(ch2 )3-ch332 nh-ch(ch3)-(ch2)3-ch(ch3)2 nh-(ch2)2-0ch3 nh-ch. ToJ nhOf »h-,C„2,20 MH-(CH2)2 /0Ch3 O0CH3 nh-(ch2)2/> N nh-(ch2)2^i H nh-(ch2)3-n(ch3)2 X BS 138-141 X BS 114-116 X BS 611g X. BS 611 g X BS 611 g X BS 136-139 X HC 1 189-193 X. BS 146-148 BS 115-119 X • BS 128-132 X HC 1 185-190 X BS 131-133 X BS 102-105 4* |H ro ro 0*1 CXI o o o o R' 11 R" 11 R1 r2 r3 Structural type Salt form Mp. (° C) ch3o ch3° ch3o ch3o ch3o ch30 ch3° ch3o ch3o ch30 c2h5 c2h5 c2h5 c2h5 c2h5 h h h h h h ch3o ch3o c2h5 h ch3o ch3o c2h5 h h h ch3o ch3o c2h5 CH3O CHjO C2Hg ch30 ch3o c2h5 ch30 CHjO c2h5 h - h K h h h h h »h-(ch2)4-ch3 nh-ch2-ch(ch3)2 mh-ch2-ch2 -o och. NH-CH2-CH2-^J-OCH3 nhOf nh-ch2-ch2-och3 nh-(ch2)3-n(ch3)2 nh.CH2^ NH-KV.O nh-ch(ch3)-(ch2)3-ch(ch3)2 bs bs bs bs bs BS bs bs bs bs bs 99-103 111-115 85- 95 121-125 137-139 110-113 108-148 182-184 218-220 198-204 85- 95 B ro ro -IN CM cji o> I c: R'n R"ll R 1 R2 R CHjO CHjO CHjICHj 3 H H CHjO CHjO CHj(CH2 1 3 H H CHjO CHjO CHj(CH2 3 H >1 CHjO CHjO ch3(ch2 3 H H CHjO CHjO chj(ch2 3 H H CHjO CHjO CHj(CH2 3 H H ch3o CHjO chj(ch2 3 H H CHjO CHjO CHj(CH2 3 H H CHjO CHjO CHj(CH2 3 H H CHjO CHjO CHjtCHj 3 H H CHjO CHjO CHj(CH2 3 H H CHjO CHjO CHj(CH2 3 H H CHjO CHjO CHj(CH2 3 H H CHjO CHjO CHjICHj 3 H II CHjO CHjO CHj(CH2 1 3 H H CHjO CHjO CH3(CH2 3 H H CHjO CHjO CH3(CH2 3 H H s-' ( NH(CH2)3OH NH-CH2-CH(OH)-CM3 NH-(CH2)2-OCH3 NH-(CH2)3-OCH3 NH-(CH2)2'N(CH3)2 NH-(CH2)3-H(CH3)2 nh-ch2^ hh'uh2]2-q H(CH3)2 h(c2h5)2 M((CH2)2CH3J2 N((CH2)3-CH3)2 a /—\ n 0 o o Structural Salt type form HC 1 HC1 BS BS BS BS BS BS BS HC1 HC t HC 1 HC 1 HC 1 HC 1 HC 1 HC1 0 mp. r c) 101-103 156-158 93- 96 93- 94 87- 90 87- 90 76- 80 115-117 108-109 i 175-177 107-110 i amorphous 193-195 195-198 103-128 (amorphous) ro 93-106 {amorphous)p^ 92-116 (amorphous) 4* Ol Ul c r,u r"u «l chjo chjo cH3<cy3 ch3o chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3 < ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 CHjO chjo ch3(ch2)3 ( . • ' i- , J^'Jy 4 byp. , ,yy^ 3 nhch3 nhc2h5 hh(ch2)2-ch3 nh(ch2)3-ch3 nh(ch2)4-ch3 nh-ch(ch3)2 hh-ch2-ch(ch3)2 nh(ch2)2ch(ch3)2 nh-ch(c2h5)-ch3 nh-6h(ch,)-(cM,-ch(ch,) hhc(ch3)3 nh-(ch2)2 2 3 3 2 Structural type 1 i i i 1 1 1 i i I i •O nh-(ch2)2-^_^-0ch. nh (ch2)2 P och. och nh-ch2-ch«ch2 nh-(ch2)2-oh Salt form bs bs bs bs bs bs bs bs bs bs bs bs bs bs hc 1 bs Mp. r o 94-102 119-123 100-103 110-112 108-109 126-128 158-160 93- 95 110-112 108-110 88- 92 77- 80 111-113 120-125 158-160 10S-107 ro ro 4N CaI o> R'll R,,11 R1 R2 R3 R4 ch3o ch3o ch3(ch2)3 h h oc2h5 ch3o ch30 ch3 (ch2) 3 h h hh*{^ ch30 ch30 ch3 (ch2)3 h h nh-/^ ch30 h ch3(ch2)3 h h nh(ch2)4-ch /~~\ ch30 ch30 h h h nv^° ^ __ _ , . o o # Structural Salt Mp. (0 C) type form i hc1 167-169 II HC1 108-156 (amorphous) 11 BS 85- 87 1 BS 83 1 I ro ro 4N CM CJIs o>, o r ' K n r 1 1 K 11 R1 R2 R, ch3o ch3o ch3(ch2)4 h • h CHjO ch30 ch3(ch2)4 h h CHjO ch30 ch3(ch2)4 h H CHjO ch30 ch3(ch2)4 h H CHjO ch30 ch3(ch244 K H CHjO ch30 CH3<CH2 )4 H H CHjO ch30 ch3(ch2)4 H H CHjO ch30 ch3(ch2 )4 H H CHjO ch30 ch3(ch2)4 h H CHjO ch30 ch3(ch2)4 h H CHjO ch3o ch3(ch2)4 h h CHjO ch30 ch3(ch2)4 H H CHjO ch30 ch3(ch2)4 H H CHjO ch30 ch3(ch2)4 h H o o Structural Salt type form nh-(ch2)4-ch3 nh-ch2-ch(ch3i2 nh-(ch2)2-ch(ch3)2 nh-ch (ch3mch2)3-ch(ch312 ■o NH nh-ch -o nh-(CV20 nh-ch2-ch«ch2 nh-CH2^ nh-(ch2)2-<0 ■h-cch,^ nh-(ch2)3-n(ch3)2 nh-(ch, n ch, n((ch2)3ch3)2 bs bs bs bs bs bs bs bs bs bs bs bs bs o Mp. { C) 100-102 76- 79 92- 96 amorphous 111 102-103 80 88- 90 141-142 74- 78 102-104 amorphous 865- 87 ro ro bs 157-160 chi CJG r'n r"n r1 R2 r3 ch3o ch3o c6h5-(ch2)2 h h ch3o chjo c6h5"(ch2 )2 h h ch3o ch3o c6h5-(ch2)2 h h ch30 ch30 cgh5-(ch2)2 h ch3o ch30 cghg-(ch?)2 h ch30 ch30 c6h5-<ch2,2 h ch30 ch30 c6h5~{CH2 ^ H ch3o ch3o c6h5-(ch2)2 h ch3o ch3o c fih 5-(c h2)2 h ch30 ch30 c6h5-(ch2 >2 h h h h h h O » mp. r c) 133-135 133 152-153 137-139 128-130 107-108 85- 86 86- 87 141-142 99-101 I* N: IV) Cm u o o o Table 5 IV Ri 1' Rn" Ri Ra Ra "12 Rs Ri a' Ria" R* Ri CHaO CHaO H -(CHa )4- H CHaO CHaO - (CH a )« - CHaO CHaO n-CdHt H II CHa CHaO CHaO H H CHaO CHaO CHa H H CHa CHaO CHaO H H CHaO CHaO H H H H CHaSOaO HO H H CHaO CHaO H H H CHa CHaO CHaO H H CHaO CHa SO H H H CHa HO CHaO H H CHaO CHaO n-CsHi i II li CHa CllaO Cll >0 H H CHaO CHaO CaHs H H CHa CHaO CHaO H H CHaO CHaO CHa H H H •0— — CH » 0- H . H CHaO CHaO CaHs H H H -0 — - CHa * o- H H CHaO CHaO H H H H "0— — CH a o- H • H -0— CHa—0- k 11 II H -0— -CHa o- H H CHaO CHaO CHaCONH 11 H H CH jO CHaO H H ro ro CM Ul m i #' Table 6 - 49 - iy^QS5tiIeSIl5^ww*£I^<*e**2www2w«ww2*«*»*i*22^* 22 4 35 6 c c -N-CH2-CH2-(^-(R12)n. Ar T~''"ll'n- // V CH, och, o 1> J - 50 - Table 7 ^2.4 3 5 6 n C-CH2-CH2-^Ar^- <vRl2*n' VI —(R12)n1 (f y—ocHj OCH, o £> ,v, n&^MCtow * 22 4 3 W _ 51 _ Examples of pharmaceutical applications a) Coated tablets 1 tablet core contains: 5 Active substance of general formula I 30.0 mg Lactose 100.0 mg Corn starch 75.0 mg Gelatine 3.0 mg Magnesium stearate 2.0 mg ^ 10 210.0 mg 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°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 20 by means of an aqueous suspension of sugar, titanium dioxider talc and gum arable. The finished coated tablets are polished with beeswax. O 30 b) Tablets 25 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 35 starch, the granules are dried and intimately mixed with lactose and corn starch. The mixture is then compressed to form tablets weighing 210 mg. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> f s O' - 52 - 22 4 356 c) Capsules Active substance according to claim 1 20.0 mg Lactose 230.0 mg <0 5 Corn starch 40.0 mg w Talc 10.0 mg 300.0 mg Preparation ^ 10 The active substance, lactose and corn starch are v"~' first 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. 15 In these Examples, compounds such as 1-(3,4-dihydroxy-6,7-dimethoxyisoquinolin-l-yl) -1-(3,4-dihydro-6,7-dimethoxyisoquinolin-l-ylidene)-ethane, 20 morpholinocarbonylmethyl-6,7-dimethoxy-3,4-dihydro-isoquinoline, 6,7-din»ethoxy-3,4-dihydro-isoquinoline acetic acid methylamide, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid 25 diethylamide or 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid phenylethylamide or pharmaceutically acceptable salts thereof may .^} for example be used as active substance. WHAT/TfWE CLAIM IS:- - 53 - n alma. 22 4359

1. A compound of formula I n p R 3 5 I 10 [wherein A represents a benzo or thieno group; R2 and independently of each other each represent a hydrogen atom or a (C^g) alkyl group, or together 15 with the carbon atom to which they are bound R2 and R3 together represent a 5- or 6-membered carbocyclic ring? R11 rePresents a halogen atom or a (Cj^) alkyl, 20 hydroxy, alkoxy, amino, thiomethyl, methane- sulphonyloxy or methanesulphonamido group, or two O adjacent substituents R^ together represent -0-CH2-0-or -0-CH2-CH2-0-t 25 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 la or lb 30 R 6 la lb 35 (wherein in the group of formula la 224356 - 54 - B represents a benzo or thieno group; represents a hydrogen atom, or a (Cj^q)alkyl, phenyl, phenyl-(C^.g)alkyl, (C1-4)alkoxy or -NHCOX 5 (wherein X is (C1_5)alkyl) group; Rg represents a hydrogen atom, or a (C^_4)alkyl or hydroxymethyl group; 10 Rg and R^ independently of one another each represent a hydrogen atom or a (C^.g)alkyl group, or together with the carbon atom to which they are bound Rg and r7 together represent a 5- or 6-membered carbocyclic ring; 15 r12 rePresents a halogen atom or a (Cj_4)alkyl, hydroxy, (C1-4)alkoxy, amino, thiomethyl, methane-sulphonyloxy or methanesulphonamido group, or two adjacent substituents R^2 together represent -0-CH2-0-20 or -0-CH2-CH2-0—; 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 25 Rx represents hydrogen, (C1_1Q) alkyl, .phenyl- (C^) alkyl, (cl_4) alkoxy or -NHCOX (wherein X is (C1_5)alkyl); R'g represents a hydrogen atom or a (C^_4)alkyl 30 group; R4 represents a (Cj^) alkoxy or an -NR^R^q group, wherein 35 Rg and R^g independently of each other represent (a) hydrogen, (b) branched or unbranched alkyl, (C2_12)alkenyl or (C2_12)alkynyl (wherein _ N.Z. PATENT OFFtrF 2P.nQV 1390 j*z£r\yeo 0 24 - 55 - the alkyl may be substituted by hydroxy, (Cj^) alkoxy, di(Ci_4)alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl, indolyl, or the group Ar) ^R12*n' fwherein Ri2 *3 as defined 5 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) (C3_7)cycloalkyl, (d) dimethylamino, (e) amino(C2_4) alkyl (wherein the amino group may be unsubstituted or is mono- or di-(C^_4)alkylamino), (f) phenyl, (g) 10 morpholinyl, or (h) pyridinyl/ with the proviso that Rg and R^q cannot simultaneously represent hydrogen, dimethylamino or di(C^_4)alkylaminoraethyl; or Rg and R^g together with the nitrogen atom to 15 which they are bound together represent a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, the piperazinyl ring optionally being N-substituted by unsubstituted phenyl, mono- or di-(C1-4)alkoxyphenyl, pyrimidinyl or phenyl(C1-4)alkyl)] 20 or the pharmaceutical^ acceptable salts thereof; with the exception of the compound of formula I 25 wherein 0 is the group of formula la and R^, R2, **3? Rg* Rg and R^ each represent a hydrogen atom and A and B each represent the group - 55a - ?24<56 and with the exception of the compound of formula I wherein D is the group of formula lb, and R' represent a methyl group, R2 and R3 represent a hydrogen atom, A represents the group and R4 represents an ethoxy group; ?24 - 56 - and with the exception of the compound of formula I wherein D is the group of formula lb and R^r R2» R3 and R*5 represent a hydrogen atom, A represents the group ch CH,0 10 OCHj and represents the group -MH-CH2-CH2 —ft y OCH, or an ethoxy group. 2. A compound of formula I as claimed in claim 15 1, wherein D represents a group of formula la as defined in claim 1; 20 R^ represents a hydrogen atom, or a (Cj^g) alkyl, phenyl(C^_5)alkyl or -NHCOX (wherein X is (C1-5)alkyl) group; Rjj and R12 independently of each other represent 25 (C1-4>alkyl, hydroxy, fC^_4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R^l or R^j together represent -O-CHj-O- or -0-CH2- ch2-o-. 30 3. A compound of formula I as claimed in eithe, of claims 1 and 2, wherein D represents a group of formula la; 35 R^ represents a hydrogen atom, or a (Cj^g) alkyl or -NHCOX (where^ X represents (C^_5)alkyl) group; 22 4 3 5 6 10 - 57 - R2' r3' R6 and r7 Independently of one another represent a hydrogen atom or R2 together with R3 and/or Rg together with R7 together with the carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring; Rj^ and R12 independently of each other represent hydroxy, (C^_4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R^ or R12 together represent -0-CH2-0- or -0-CH2-CH2-0-. 4. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula la and R^ represents a hydrogen atom, 15 or a (C1_g)alkyl or -NHCOCH3 group. 5. A compound of formula I as claimed in any one of claims 1 to 4, wherein D represents a group of formula la and Rg represents a hydrogen atom, 20 or a methyl or hydroxymethyl group. 6. A compound of formula I as claimed in any one of claims 1 to 5, wherein D represents a group of formula la and R2, R3, Rg and R7 independently 25 of each other represent a hydrogen atom or R2 together with R3 and/or Rg together with R7 and the carbon atom to which they are bound represent a 5-membered carbocyclic ring. 30 7. A compound of formula I as claimed in any one of claims 1 to 6, wherein D represents a group of formula la and R^ and R^2 independently of each other each represent hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent 35 substituents R11 or R12 together represent -0-CH2-0-. 224356 58 8. A compound of formula I as claimed in any one of claims 1 to 7, wherein D represents a group of formula la and A and/or B is a benzo group. 5 9. A compound of formula I as claimed in any one of claims 1 to 7, wherein D represents a group of formula la and A and/or B is a thieno group. 10. A compound of formula I as claimed in any 10 one of claims. 1 to 9, wherein D represents a group of formula la and m and/or n represents 2. 11. A compound of formula I as claimed in claim 10, wherein when A and/or B is a benzo group the 15 two substituents Ri;l and/or R12 a" *n the meta-or para- position, respectively, to the fusion points of the group A or B. 12. A compound of formula I as claimed in any 20 one of claims 1 to 11, wherein D represents a group_ of formula la and and R^2 are each methoxy. 13. A compound of formula I as claimed in claim 1 being l-(3,4-dihydro-6,7-dimethoxyisoquinolin- 25 1-yl)-1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-1-ylidene)-ethane or a physiologically acceptable salt thereof. 14. A compound of formula I as claimed in claim 30 1 wherein D represents a group of formula lb and r4 is methoxy or ethoxy. 15. A compound of formula I as claimed in claim 1, wherein D represents a group of formula lb and 35 R4 represents an -NR9r1q group, wherein Rg and R^g independently of each other represent (a) hydrogen. fci-8)alkyl, (C .Tu:\!T OFFICE 2 2 NOV 1990 I # !f - 59 - 224356 (whilst the alkyl may be substituted by hydroxy, 2 (C^_4)alkoxy, di (C1_4) alkyleunino, furyl, pyrrolidinyl, | morpholinyl, pyridinyl ] 5 or the group (at) ^12^" wherein Ar' Ri2 a"d n1 are defined as in claim 1), (d) dimethylamino, (f) phenyl, (g) morpholinyl, (h) pyridinyl, whilst Rg and R^g cannot simultaneously represent hydrogen, N 10 dimethylamino or di(C^_4)alkylaminomethyl? ! O i or Rg and R10 together with the nitrogen atom to | which they are bound represent a pyrrolidinyl, morpholinyl or piperazinyl group, whilst the piperazinyl 15 ring may optionally be N-substituted by unsubstituted phenyl, mono- or di(C1-4)alkoxyphenyl, pyrimidinyl ? or phenyl (C1-4)alkyl. i 20 16. A compound o£ formula I as claimed in claim 15, wherein R4 is an -NRgR^g group wherein Rg and/or R10 each represents unsubstituted phenyl, fluorophenyl, morpholin-4-yl or 2- or 3-pyridinyl. 17. A compound of formula I as claimed in claim ^ 25 15, wherein R4 is an -NRgR10 group wherein Rg and/or R^g each represents (C^_4)alkyl, 18. A compound of formula I as claimed in claim 15, wherein R4 is an -NRgR^g group wherein Rg and/or 30 R10 each represents (C2 or C3)alkyl which may be substituted by hydroxy, methoxy, dimethylamino, furyl, morpholin-4-yl pyrrolidinyl or pyridinyl. 19. A compound of formula I as claimed in any 35 one of claims 15 to 18, wherein R4 is an -NRgR^g group wherein Rg is hydrogen. fv Z. PATENT OFFICE 2 2 NOV 1990 rzc~. i\ > 22 4 3 5 6 - 60 20. A compound of formula I as claimed in claim 15, wherein R4 is an -NRgR10 group wherein Rg is hydrogen and R^g is a substituted alkyl of formula VII (wherein p is 0, 1 or 2, and Rg, R?, Ar, R12 and n' are as defined in claim 1). 21. A compound of formula I as claimed in claim 20, wherein R^2 represents (Cj^)alkyl, hydroxy, (C^_4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R12 together represent -O-CH^-O- or -0-CH2-CH2-0-. 22. A compound of formula I as claimed in claim 21, wherein R12 represents hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R^2 together represent -O-CHj-O- or -0—CH2—CH2-0-. 23. A compound of formula I as claimed in claim 22, wherein R^2 represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R^2 together represent -0-CH2-0-. 24. A compound of formula I as claimed in claim 23, wherein R^2 is methoxy. VII R 7 25. A compound of formula I as claimed in any one of claims 20 to 24, wherein n' is zero. 224356 - 61 - 26. A compound of formula I as claimed in any one of claims 20 to 24, wherein Ar is phenyl and n' is 2. 5 27. A compound of formula I as claimed in claim w" 26, wherein two substituents R^2 are *n positions

2- and

3-. 28. A compound of formula I as claimed in any 10 one of claims 20 to 27, wherein p is 1. 29. A compound of formula I as claimed in any one of claims 20 to 28, wherein Rg and Rj are hydrogen. 15 30. A compound of formula I as claimed in claim 15, wherein R4 is an -NRgR10 group, wherein Rg and R10 together with the nitrogen atom to which they are bound represent raorpholin-

4-yl, pyrrolidinyl or piperazinyl (which is N-substituted by methoxyphenyl, 20 phenethyl or 2-pyrimidinyl). 31. A compound of formula I as claimed in any one of claims 1 and 14 to 30, wherein D represents a group of formula lb, R^ represents hydrogen, 25 (Ci_10)alkyl, phenyl(C1-5)alkyl or -NHCOX (wherein X is (C1-5)alkyl); and R11 rePresents (C1-4)alkyl, hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or 30 two adjacent substituents together represent -0-CH2-0- or -0-CH2-CH2-0-. 32. A compound of formula I as claimed in claim 31, wherein R^ represents hydrogen, (C^_^g)alkyl 35. or -NHCOX (wherein X is (C1-5)alkyl) ; I U j tJ.Z. PATENT OFFICE 2 2 NOV 1990 . I \ . i 10 - 62 - 22 4 3 5 6 R2 and R3 each represent a hydrogen atom or together with the carbon atom to which they are bound R2 and R^ together represent a

5- or

6-membered carbocyclic ring; 5 Rj^ represents hydroxy, CC1_4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R11 to9ether represent -O-CHj-O- or -O-CHj-CHj-O-. 33. A compound as claimed in either of claims 31 and 32, wherein R^ represents hydrogen, (C1-g)alkyl or -NHCOCH3. 34. A compound as claimed in any one of claims 31 to 33, wherein R's represents hydrogen, methyl 15 or ethyl. 35. A compound as claimed in any one of claims 31 to 34, wherein R2 and R^ each represent hydrogen or together with the carbon atom to which they 20 are bound represent a 5-membered carbocyclic ring. 36. A compound as claimed in any one of claims 31 to 35, wherein R^ represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or 25 two adjacent substituents R11 together represent -0-CH2-0-. 37. A compound as claimed in any one of claims 1 and 14 to 36, wherein A is a benzo group. 30 38. A compound as claimed in any one of claims 1 and 14 to 36, wherein A is a thieno group. 39. A compound as claimed in any one of claims 35 1 and 14 to 38, wherein m represents 2. 224356 w' - 63 - 40. A compound as claimed in claim 39, wherein A is a benzo group and the two substituents Ri;l are in the meta- or para- position relative to the fusion points of group A. 41. A compound as claimed in any one of claims 1 and 14 to 40, wherein RU 13 methoxy. 42. A compound as claimed in claim 1, wherein f7'i 10 D represents a group of formula lb, A represents benzo, is methoxy, ra is two, R^ is hydrogen or fC1-5)alkyl, R2, R3 and R*s represent hydrogen and R^ represents morpholin-4-yl, methylamino, diethylamino or phenethylamino. 15 43. A compound as claimed in claim 42, being morpholin-4-yl-carbonylmethyl-6,

7-dimethoxy-3,4-dihydro isoquinoline, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid 20 methylamide, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid diethylamide, or 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid phenylethylamide, 25 or a physiologically acceptable salt thereof. 44. A compound as claimed in any one of the preceding claims being in the form of/physiologically acceptable an salt with/inorganic or organic acid. 30 45. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 44 or a physiologically acceptable salt thereof together with at least one pharmaceutical 35 carrier or excipient. N.Z. PATENT OFF ICE 2 2 NOV 1990 224356 - 64 - 46. A process for preparing a compound of formula I as claimed in any one of claims 1 to 43, comprising at least one of the following steps: A). (to prepare a compound of formula I wherein D is a group of formula la} condensing a compound of formula II G 10 15 CRU> II (R12>n. o (wherein A, Rn *1' n2' r3' ^6' ^7' "11' are defined as in any one of claims 1 to 13, Ar represents a phenyl or thienyl group and n' represents 20 0, 1, 2 or 3 if Ar is a phenyl group or 0, 1 or 2 if Ar is thienyl group, and Rg represents a hydrogen atom or a (Cj^) alkyl group) in the presence of a condensing agent; 25 B). (to prepare a compound of formula I wherein D is a group of formula la) condensing a compound of formula IIIc» R-»f Ri R^2 a"d m ( Ru ) , -^ArVc-CH2-NKCO-|:-CO-NH-CH2-^-^A^-(R t %) ft, Ilia (wherein Rg is hydrogen, , R2, R3> Rg, R7, R^ and r^2 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 thej a£>6091 ""j is thienyl) ~~ " J ' i 22h0v 1390 %2A 3 5 ^ - 65 - . in.the presence of a condensing agent, without 5 isolation of the intermediate product of formula (II); or C). (to prepare a compound of formula I wherein D is a group of formula lb) 0 condensing a compound of formula III <RU >m1 "tAifv-CW.-NMGO-^CO-R, nr (wherein Rg is hydrogen, R^, Rj, R3, R^ and R^ are defined as hereinbefore, Ar represents phenyl or thienyl and in' 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; <a and, if desired, carrying out one or moreAthe -5 following after-treatments: alkylating a compound of formula (I) wherein Rg or R'g is a hydrogen atom to form a compound of formula (I) wherein Rg or R'g is a (C^^)alkyl 0 group; hydroxymethylating a compound of formula (I) wherein D is a group of formula la and R- is a hydrogen ,T 3 / -i atom to yield a compound of formula (I) wherein 5 Rg is hydroxymethylene; ^ ,<v 224356 66 isolating the Individual tautomers of compounds of formula I; isolating the free compound of formula (I) from 5 its salt; reacting a compound of formula (I) to yield a pharmaceutical^ acceptable salt thereof. 10 47. A compound of formula II 20 (wherein A,R3' R6' R7* Rll' R12 m are as defined in claim 1, Ar represents a phenyl or is a phenyl group, or 0,1 or 2 if Ar is a thienyl group, and Rg represents a hydrogen atom or a (C1-4) 25 alkyl group), or a physiologically acceptable salt thereof. 48. A compound of formula II substantially as herein disclosed. 30 / 49. A process for the preparation of a compound of formula II as claimed in claim 47 which comprises cyclising the corresponding malonic acid diamide of formula III 15 II thienyl group and n' represents 0,1,2 or 3 if Ar 35 • PVFE.MT OFFICE 2 7 NOV 1990 224356 (r"' m1 hi (wherein R^, R2, R3, Rg, R-j, Rj^ and R12 are defined 5 as in claim 1, Ar represents phenyl or thienyl and m' and n1 independently of each other represent 0,1,2 or 3 if Ar is phenyl, or 0,1 or 2, if Ar is thienyl). 10 50. The use of a compound of formula I as claimed in any one of claims 1 to 44 or a compound of formula II as defined in claim 47, or a physiologically acceptable salt or salts thereof in the treatment of coronary heart disease and/or acute myocardial infarction, 15 and/or in cardio- and/or cerebroprotection in a non-human patient. 51. A method for the treatment of coronary heart disease and/or acute myocardial infarction and/or for use in cardio- and/or cerebroprotection in a non-human subject 20 which comprises administering to said subject a compound of formula I (as defined in any one of claims 1 to 44) or a compound of formula II (as defined in claim 47) or a physiologically acceptable salt thereof. 25 52. The use of a compound of formula I (as defined in any one of claims 1 to 44) or a compound of formula II (as defined in claim 47) or a physiologically acceptable salt thereof for the manufacture of 30 a therapeutic agent for use in a method for the treatment of coronary heart disease, and/or acute myocardial infarction and/or for use in cardio- and/or cerebroprotection. I 35 53. Compounds of formula I as defined in claim </div>