CA1330798C - Benzo- and thieno-3,4-dihydro-pyridine derivatives - Google Patents

Abstract

Abstract Benzo- and thieno-3,4-dihydro-pyridine derivatives There is described a compound of formula I
I
[wherein A represents a benzo or thieno group;

R2 and R3 independently of each other each represent a hydrogen atom or a (C1-5)alkyl group, or together with the carbon atom to which they are bound R2 and R3 together represent a 5- or 6-mqmbered carbocyclic ring;

R11 represents a halogen atom or a (C1-4)alkyl, hydroxy, (C1-4)alkoxy, amino, thiomethyl, methane-sulphonyloxy or methanesulphonamido group, or two adjacent substituents R11 together represent -O-CH2-O-or -O-CH2-CH2-O-;

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 Ib Ia Ib (wherein in the group of formula Ia B represents a benzo or thieno group;

R1 represents a hydrogen atom, or a (C1-10)alkyl, phenyl, phenyl-(C1-5)alkyl, (C1-4)alkoxy or -NHCOX
(wherein X is (C1-5)alkyl) group;

R5 represents a hydrogen atom, or a (C1-4)alkyl or hydroxymethyl group;

R6 and R7 independently of one another each represent a hydrogen atom or a (C1-5)alkyl group, or together with the carbon atom to which they are bound R6 and R7 together represent a 5- or 6-membered carbocyclic ring;

R12 represents a halogen atom or a (C1-4)alkyl, hydroxy, (C1-4)alkoxy, amino, thiomethyl, methane-sulphonyloxy or methanesulphonamido group, or two adjacent substituents R12 together represent -O-CH2-O-or -O-CH2-CH2-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;

and in the group of formula Ib R1 is defined as for the group of formula Ia;

R'5 represents a hydrogen atom or a (C1-4)alkyl group;

R4 represents a (C1-4)alkoxy or an -NR9R10 group, wherein R9 and R10 independently of each other represent (a) hydrogen, (b) branched or unbranched (C1-12) alkyl, (C1-l2)alkenyl or (C1-l2)alkynyl (wherein the alkyl may be substituted by hydroxy, (C1-4)alkoxy, di(C1-4)alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl, indolyl, or the group , (wherein R12 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) (C3-7) 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 R9 and R10 cannot simultaneously represent hydrogen, dimethylamino or di(C1-4)alkylaminomethyl;
or R9 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 pharmaceutically acceptable salts thereof;

with the exception of the compound of formula I
wherein D is the group Ia and R1, R2, R3, R5, R6 and R7 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 Ib and R1, R2, R3 and R'5 represent a hydrogen atom, A represents the group and R4 represents the group .

Such compounds have a cardio- and/or cerebroprotective activity.

Description

.` 1- 133~798 Benzo- and thieno-3,4-dihydro-p~ridlne 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 gener~l formula VIII
P~ R~
- 1 ~>< - :-. ~Rll) Rl~ VI I I
~R6 (R~2)n~) R

R1. R2, R3~ R5, R6 and R7 represent hydroqen ~ `
and the substitu~ed groups A and B represent the group I CH~
.

and the preparation thereof have been described by Kobar, Jeno in Szegedi Tonarkepzo Foiskala Ind.
Kozl. 1985, pages 145-153 (cf. Chem. Abstr. 87; ~:~
134980~). This publication does not however make any mention of the phy~iological effects of this ~ 30 compound. ~
;;~ , '~ .
According ~o one aspect of the present inven~ion we provide a compound of ormula I
,;~ , ;~ ,,:
; '~ ' .

' - 2 - 1 3 3 ~79 8 (R~

[wherein A represents a benzo or thieno group;

R2 and R3 independently of each other each represent :'' a hydrosen a~om or a ~Cl 5)alkyl group, or together with the carbon atom to which they are bound R2 and R3 together represent a 5- or 6-membered carbo~ycl~c ring; i.

15 Rll represen~s a halogen a~om (preferably F, Cl, :~
Br or I) or a (Cl_4)alkyl, hydroxy, ~Cl_4)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphon-amido group, or two adjacent substituent Rll together ,~
represen~ -O-CH2-O- or -O-CH2-C~2-O~
' 20 m represents 0, 1, 2 or 3 if A is a benzo group, or 0, l or 2 i A is a thieno group;

D represents a group o~ formula Ia or Ib ~, ' 1 l5 , ,:

(RlZ~n~ R6 la 5>~1~ R

(wherein in the group of formula Ia ,~ ' B re,pre~ents a benzo or thieno group; '~

Rl repre~ents a hydrogen atom, or a (Cl l0)alkyl, 35 phenyl, phenyl-~cl-5)alkyl~ (Cl_4)alkoxy or -N~COX ,~
(wherein X is (Cl 5)alkyl) group;

R5 represents a hydrogen atom, or a (Cl 4)alkyl , '`
~:~ ' or hydroxymethyl group;

_ 3 _ 1 3 3 ~ 9 8 - R6 and R7 independently of one another each represent a hydrogen atom or a (Cl_5)alkyl group, or together with the carbon atom to which they are bound R6 and R7 together represent a 5- or 6-membered carbocyclic 5 ring:

R12 represents a halogen atom (preferably F, Cl, Br or I) or a (Cl_4)alkyl, hydroxy, (Cl_4)alkoxy, amino, ~hiomethyl, methanesulphonyloxy or methaneSulphon-amido group, or two adjacent sub~tituent~ R12 togetherrepre~ent -O-C~2-O- or -O-CH2-CH2-O-;

n represent~ 0, l, 2 or 3 i ~ is a benzo group, or 0, 1 or 2 if B is a thieno group; : -and in the group of formula Ib :.

Rl is defined as for the group of formula Ia, and ' preferably represents hydrogen, ~Cl_l0)alkyl, phenyl- ;~
~Cl_5)alkyl, (Cl 4)alkoxy or -N~COX ~wherein X
i8 (Cl_5)alkyl); ~:
~ ' R'5 repre~ents a hydrogen atom or a tCl-4)alkyl group;
R4 represents a ~Cl_4)alkoxy or an -NRgRlo group, wherein ~.

Rg and Rlo independentlyif each other represent (a) hydrogen, (b) branched or unbranched (Cl 12) alkyl~ (Cl_l2)alkenyl or (Cl_12)alkynyl (wherein the alkyl may be sub~tituted by hydroxy, (Cl_4)alkoxy, : di(Cl_4)alkyiamino, furyl, pyrrolidinyl, morpholinyl, ;~:
~: pyridinyl, indolyl, or the group (Rl2)n, wherein Rl2 is as deflned abo~e; Ar is phenyl or thienyl; n' is 0, 1, 2 or 3 if Ar is phenyl, or 0, l or 2 if Ar is thienyl)) ;--~' S~ ' ~ l3~a7ss ~c) (C3_7) cycloalkyl ~d) dimethylamino, (e) amino-(C2_4)alkyl (wherein the amino group may be unsubstituted or is mono- or di-(cl-4)alkylamino)~ (f~ phenyl, tg) morpholinyl, or (h) pyridinyl, with the proviso that Rg and Rlo cannot simultaneously represent hydrogen, dimethylamino or di(Cl 4)alkylaminomethyl;

or Rg and Rlo together with the nitrogen atom to which they are bound together represent a pyrrolidinyl, piperidinyl, morphslinyl or piperazinyl group, the pipera~inyl ring optionally being N-substituted by unsubs~ituted phenyl, mono~ or di-tCl_4)alkoxyphenyl, pyrimidinyl or phenyl(Cl 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 i5 the group Ia and Rl, R2, R3, R5, R6 :~
20 and R7 each repre3ent a hydrogen atom and A and ;~i~
B together represent the group -~

CH3 ~ ~;
~
CH30 ~; :

and with the exception o the compound of formula I wherein D is the group of formula Ib and R~
R2, R3 and R'5 reprèsent a hydrogen atom, A represents the group CH~O~

3 ~ ~

~' .

~" ~ , . ,~ !, . ': `, ' ', ' ' ` ;

~33~7~8 - -- 5 - ~ OCH3 and R4 represents the group~-NH-C~2-CH2 ~ OCN

The carbocyclic ring which may be formed by R2 and R3 or R6 and R7 and the associat~d carbon atom to which they are bound i~ preferably a saturated 5- or 6-memberad carbocyclic ring.

Compounds of formula I wherein D is the group of formula Ia are hereinafter referred to as compounds of formula VIII
t -, 2 ~3 ll)m~ N
,I J~ R5 VIII -R1 ~ R6 12 ) n ~) 7 n Rl~ R2~ ~3~ Rs~ R6~ R7~ Rll, Rl~, A and B are deined as hereinbefore).
Compounds of formula VIII wherein R5 is hydrogen form tautomers of formulae VIIIa and VIIIb, ~ R R~

tR11 )m~?5DN tR11 )m~N-R5 VIIIb I Z ) A~ (312 ) ~

wherein R5 is also hydrogen. The definition of all formulae ~ and VIII and the invention also include the above-mentioned tautomers.

- 6 ~ 33~ 7~
Compounds of formula I wherein D is a group of ormula Ib are hereinafter referred to a~ c~mpounds of formula IX

~X~R3 )m~ ~
~N IX
R4 ' ::

- ~:
Compounds of formula IX wherein R'~ iis hydrogen form ~au~omers o~ formula IXa PQ R3 j.
~m~N ~5 IXa~

O :.,,.:
20 which also orm part of the present invention. ~ i The tautomers may be ~eparated by known methods, e.g. by column chromatography or selective reduction ~ :, (MaBH4 or catalytic reduction). Compounds of both ~:
structures wherein R5 represents (Cl_4)alkyl are stable.

The de~inition o general ormula I or IX should be taken to include the compounds o ~tructure IXa wherein R'5 repre~ents hydrogen or (C~_4)alkyl. ~ .
:~
We have surprisingly found that the new compounds ~
of formula ~ and,lparticularly, 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 : .
proper~ies both as free bases and also in the form of their salts. ; :

'", ~ 133~98 Moreover, compounds of general formula IX wher~inR4 is the group of general formula X

C~2 ~ ~ (R12)n' X

are important intermediates in the preparation of compounds of general formula VIII, the tautomers and salt~ th~reof.

Of the compounds of formula VIII, the following are preferr~do 15 -~ Compounds of formula VIII wherein Rl represents ~:
hydrogen, (Cl_l0)alkyl, phenyltCl_5)alkYl or -N~COX (wherein X is (Cl_5)alkyl);

Rll and R12 independently of each other represent - 20 (Cl_4)alkyl, hydroxy, (Cl_4)alkoxy, methane~
~ulphonyloxy or methane~ulphonamido, or two .
adjacent substltuents Rll or R12 together repre~ent ~O-C~2-O- or -O-C~2-CR2-O-; ~ :

25 -) Compound~ of formula ~ , wherein Rl repre~ent~
; hYdrgen~ ~Cl-lo)alkyl or -NHCOX ~wherein ;~
X i~ ~Cl_5)alkyl);
~ , R2, R3, R6 and R7 independently of one another represent a hydrogen atom or R2 together with R3 and/or R6 together with R7 and the ~:~
associated carbon atom to which they are ~;
bound represent a 5- or 6-membered carbocyclic ring; :
:~: Rll and R12 independently of each other represent hydroxy, (Cl_4)alkoxy, methanesulphonyloxy :~

~33~798 - or methanesulphonamido, or two adjacent qubsti~uent~
Rll or R12 togeth0r represent -0-C~2-0- or O CH2 C~2 o -) partlcularly preferred are compounds wherein Rl represents a hydrogen atom, or a (Cl_6)alkyl or -N~COCH3 group; and/or R5 represents a hydrogen atom, or a methyl or hydroxymethyl group; and/or .

R2, R3, R6 and R7 independently of ~ach other represent a hydrogen atom or R2 together with R3 and/or R6 together with R7 and the associatea carbon atom ~o which they are bound represent a 5-membered carboc~clic :
ring; and/or :~

Rll and R12 independently of each other represent `~ -hydroxy, methoxy, me~hanesulphonyloxy or methanesulphonamido, or two adjacent 3ubstituents Rll or R12 together repre~ent -0-C~2-0-. ~

Further generally preerred compounds are tbose . .. ..
of formula VIII wherein m and/or n repre~ents 2, particularly those wherein A and/or B i~ a benzo group, whilst the two substituents Rll and/or R12 are preferably in the meta- or para- position relative to the fu~ion points of~the group A or Br respectiv~ly..
30 Compounds wherein Rll and R12 are me~hoxy are particularly :~
preferred. ~:

: Examples o~ specific compounds according ~o the : invention are listed in the Table~ which follow;
1-~3,4-dibydroxy-6,7-dimethoxy-iso~uinolin~
yl)-1-~3,4-dihydro-6,7-dimethoxy-iso~uinolin-1 : ylidene)-ethane or a physiologically acceptable ~;
salt thereof is e~pecially praferred.

9 ~33~7~8 Of the compounds of formula IX, the followlng are particularly preferred:

Compounds - wherein R4 is methoxy or ethoxy;
- wherein R~ represents an -NRgRlo group, wherein Rg and Rlo independently of each other represent (a) bydrogen, (b) (Cl_8)alkyl, (C2_3) a y (C2_3)alkynyl (whilst the alkyl may be substituted y y, ~cl-4)alkoxy~ di(Cl_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) pyrldinyl, whll~ Rg and Rlo cannot simultaneously ~
represent hydrogen, dimethylamino or di(Cl_4)alkylamino- : -methyl;
:
or Rg and Rlo together with the nitrogen atom to wh~ch they are bound represent a pyrrolidinyl t morpholinyl or piperazinyl group, whilst the piperazinyl ~:
ring may optionally be N-substituted by unsubstituted phenyl, mono- or di(Cl_4)alkoxyphenyl, pyrimidinyl or phenyl.~Cl_4)alkyl:

more partiaularly compounds wherein R4 is an -NRgRlo group, wherein Rg and/or Rlo each represents unsubstituted 30 phenyl, fluorophenyl, morpholino or 2- or 3-pyridinyl; .

or wherein R4 is an -NR~Rlo group, wherein Rg and/or Rlo represen~s (Cl 4)alkyl, preferably methyl or ethyl;
; 35 :~
or wherein R4 i~ an -NRgRlo group wherein Rg and/or Rlo each represents (C2 or C3)alkyl, which may , .
:
~ ' .

- lo 133~
be substituted by hydroxy, methoxy, dimethylamine, furyl, morpholino, pyrrolidinyl or pyridinyl;

or wherein R4 is an -NRgRlo group wherein Rg is hydrogen.
Other compounds of formula IX which are particularly preferred are those wherein R4 is an -NRgRlo group wherein Rg is hydrogen and Rl~ is a substituted alkyl of formula VII, 21P ~ ~ (æ~'~'n' VI~
R~

wherein p is 0, 1 or 2; ; r ~ ~.
R~ and R7 independently of eacb other represent hydrogen or (Cl_5)alkyl or together with the carbon atom to which they are bound R6 and R7 together represent a 5- or 6-membered carbocyclic ring;

Ar represents phenyl or thienyl;
R12 represe~ts (Cl ~)alkyl, halogen (F, Cl, Br, I) r hydroxy, (Cl ~alkoxy, amino~ thiomethyl, methane-sulphonyloxy or me,thanesulphonamido, or two adjacent :~
sub~tituents Rll together represent -O-CH2-O- or -O-CH2-~CH2-O- a n' represents 0, 1, 2 or 3 if Ar is phenyl, or ~ ~
0, 1 or 2 i~.Ar is thienyl. ~ ~ :
.
E~pecially prefered are those compounds of formula IX
wherein R1~ is (Cl 4)alkyl, hydroxy, tCl_4)alko~y, ;~
methanesulphonyloxy or me~hanesulphonamido, or , ~:
, ~ ; 7 ~ ' 11- 133~7~8 two adjacent substituents R12 together repre~ent -O-C~2-O or -O CH2-C~2-O-;

wherein R12 represents hydroxy, (Cl_4)alkoxy, methane-sulphonyloxy or methanesulphonamido, or two adjacent substituents R12 together represent -O-CH2-O- or -O-C~2-CH2-O-;
~: , or wherein R12 represents hydroxy, methoxy, methanesulphonyl- :
oxy or methanesulphonamido, or ~wo adjacent substituents R12 together represent -O-C~2~O-.

Particularly preferred compounds are those compounds wherein R12 is methoxy;
:
wherein n' is zero;

wherein Ar is phenyl and n' is 2, preferably wherein :~
the two subRtituents R12 are in po~itions 2- and 3-.
.
Particular mention i~hould also be made of compounds o~ ormula ~IX) wherein R4 i5 an -NRgRlo group, .-wherein R9 and Rlo together with the nitrogen a~om to which they are bound repre~ent morpholino, pyrrolidinyl or piperazinyl (which is N-substituted by methoxyphenyl, phenethyl or 7-pyrimidinyl).

O~ the above-mentioned groups of compounds, especially preferred are those - wherein Rl represents hydrogen, (Cl 1O)alkyl, phenyl (Cl_5)alkyl or -NHCOX (wherein X is ~Cl_5)alkyl); and ~.

Rll represents (Cl 4)alkyl, hydroxy, (Cl_4)alkoxy, ;~ 35 methanesulphonyloxy or methanesulphonamido, ;~
or two adjacent subYitituent~i Rll together :~
represen~ -O-CH2-O- or -O-CH2-C~2-O-; ~-` . i ', , . i ' ~ ` . ' '. i` , ' ~ . 'i - 12 - ~ 3 3 ~ 7 9 8 - - wherein Rl represents hydrogen, (Cl_10)alkyl or -N~COX (wherein X is (cl_5)alkyl), R~ and R3 each represent hydrogen or together with the carbon atom to which they are bound R2 and R3 together represent a 5- or 6-membered carbocyclic ring;

Rll representsi hydroxy, (Cl_4)alkoxy, methane- - . r sulphonyloxy or met~anesulphonamido, or two adjacent substi~u~nts Rll together represent --~2-- or -O-C~2-C~_o~
- wherein Rl represents hydrogen, (Cl_6)alkyl, or -NHCOC~3- ~

- wherein R'5 represents hydrogen, methyl or s ethyl;

_ wherein R2 and R3 represent hydrogen or together with the carbon atom to which they are bound R2 -~-and R3 together represent a 5-membered i3aturated aarbocyclic ring; ~ -- wherein Rll represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, .`
or two ad~acent i3ubstituenti3 ~Il together represent -O-CE~2-0 30 - whereinr i~ A is a benzo group, m represents ;~

2 and preferably the two subs~ituents R~
are ln the me~a- and para- positions, respectively, to the ~usion points of the group A;

; 3s - wherein Rll is methoxy. ~ :
: ~ ' ;'.
: Other preferred compounds are those wherein A represents . . .

~!, " ;, , i ' ' ' ' " ' ' " ' ' " ` ' ' - 13 - 1 3 ~ ~ 7 9 8 benzo, R11 represents methoxy~ m is two, Rl is g (Cl_5)alkyl, R2, R3 and R'5 represent hydrogen and R4 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-dihydro-iso~uinolin~, 6,7-dimethoxy-3,4-dihydro-isoquinoline ace~ic acid methylamide, 6,7-dimethoxy-3,4-dihy~ro-i~oquinoline acetic acid diethylamide and 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid phenylethylamide and ~he physiologically acceptable -salts thereof.

The co~pounds o formula I according to the invention may be prepared in a manner known per se.

In another aspect the pre~ent invention provides a proces~ for preparing the compounds of the in~ention.
The process comprises at least one of step~ A, 25 B and C her~nafter. ~

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

11)~5 S
¦¦ R6~R7 i~

l~ ~~ (R12 )n ~ j ' ' ': " ' - 14 _ 1 3 ~ ~7 9 8 (wherein A, Rl, R2, R3~ R6t R7~ Rll~ Rl2 an r are defined as hereinbefore, Ar represent~ a phenyl or thienyl group and n' represents 0, l, 2 or 3 if Ar is a phenyl group, or 0, 1 or 2 if Ar is 5 a thienyl group, and R5 represents a hydrogen atom or a (Cl 4)alkyl group) in the presence of a condensing agent.

Sui~able condensing agents are, for example, strong ~`
lO Lewis acids such as phosphorus oxychloride, pho~phorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium ~etrachloride, boron trifluoride, tin tetrachloride, and also inorganic acid~ such aQ polyphosphoric, sulphuric, fluoro~ulphonic and 15 hydrofluoric acid, or mixtures of condensing agents such as, for example, a mixture of phosphorous ;
oxychloride and phosphorus pentachloride, or a -~
mixture c phosphorus pentoxide and (C~ 4)alkylsulphonic acid, e.g. containing about 10% by weight of P2O5.
If a compound of formula II wherein R5 is hydrogen i8 cyclised in the presence of a mixture of phosphorus pentoxide and ~Cl_4)alkylsulphonic acid, there i8 obtained, in addition to the corre~ponding compound 25 o~ formula V~II wherein R5 is hydrogen, the analogou~
compound of formula VIII wherein R5 is (Cl_4)alkyl.
P~e~erably, this variant of the process is carried out wi~h methanesulphonic acid.

30 Cyclisation may be carried out in the presence ! ' ; ~ ~ ' or absence of a solvent. Any inert solvent is sui~able provided that it has suf~icient solubility ; for the reac~ants and a suf~iciently high boiling ~; point, for example benzene, alkylbenzenes (e.g.
toluene, xylen~), chlorobenzenes, chloroform, acetonitrile and decalin. In a pre~erred embodiment of the proce~s, the condensing agent, such a~ phosphorus ~3~7~8 oxychloride or a mixture of ~Cl_4)alkylsulphonicacid 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 (Cl 4)alkylsulphonic acid (preerably methanesulphonic acid).

The reaction may be carried out within a wide temperature range, pre~erably with heating to 50C 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 compounds of general formula II defined above are new compounds.
~hus, a further aspect of the present invention provides a compound of formula II
R2 ~ R~ ;~

t~ll)m ~ I R R7 (II) R 1~ ~ ( R12)n' twhereln A, Rl, R2, R3~ R6~ R7~ Rll~ R12 and m 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 R5 represents a hydrogen atom or a (Cl 4)alkyl group) or a phy~iologically acceptable salt thereof.
, There is further provided a process for the preparation ~.

~;

~` 133~7~8 of a compound of a formula II which comprises cyclising the corxesponding malonic acid diamide of general formula IIIa: :

12 Tl 16 ( ll)m ~ C-CH2-NHCO-f-CO-NH-CH2-C- ~ (R12)n' R3 R5 R7 (IIIa) (wherein R5 is hydrogen, Rl, R2, R31 R6~ 7~ 11 12 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, l or 2 if the associated Ar is thienyl). :1~
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 (Cl 4)alkyl-sulphonic acid, there is obtained, in addition to the corresponding compound of formula II . ~.
wherein R5 is hydrogen, the analogous compound of formula II
wherein R5 is (Cl 4)alkyl. (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:

( ll)m ~ ~ C-cH2-N~Ico-l_CO_NH_CH2_C_ ~ ( 12)n~

, (IIIa) i'''~

-17- 1 3 ~ 8 27400-90 (wherein R5 is h~drogen, Rl, R2, R3, R6, 7 11 12 defined as hereinbefore, Ar represents a phenyl or thienyl group and m' and n' independently of each other each represent 0, 1, 2 or 3 if the associated Ar is a phenyl group, or 0, 1 or 2 if the associated Ar is a thienyl group) 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 u~ed in the first step, with gentle heating. In the second step, cyclisation is preferably effected with phosphor-us pentachloride, a mixture of phosphorus oxychloride and phosphor-us pentachloride or with a mixture of methanesulphonic acid and P2O5- ~`
The compounds of general formula IIIa are sub-stantially known compounds and may be prepared by methods known per se.

-C. (to prepare a compound of formula I wherein D isa group of formula Ib, i.e. to prepare a compound of formula (IX) condensing a compound of formula III:

133~8 - R2 1l ( ll)m ~ IC-CH~-NHCO-C-CO-R4 (III) (wherein R5 is hydrogen, Rl, R2, R3, R4 and Rll are defined as hereinbefore, Ar represents a phenyl or thienyl group 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 correspond-ing 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 (Cl 4) alkylsulphonic acid, there are obtained, in addition to the corresponding compounds IX and IXa wherein R5 is hydrogen, the ;
analogous compounds IX and IXa wherein R5 is (Cl 4)alkyl.
IE desired, one or more of the following treat-ments may be carried out after either one of steps A, B and C:
alkylating a compound of formula (I) wherein R5 or R5 is a hydrogen atom to form a compound of formula (I) wherein R5 or R

is a ~Cl 4)alkyl group;
hydroxymethylating a compound of formula (I) wherein D is a group of formula Ia and R5 is a hydrogen atom to yield a compound of formula (I) wherein R is hydroxymethylene;

isolating the individual tautomers of compounds of formula (I);
isolating the free compound of formula (I) from its salt;
reacting a compound of formula (I) to yield a pharmaceutically acceptable salt thereof.
, ~' ~3~7~

Suitable condensing agents for this process are strong Lewis acids such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluvride, 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 (Cl_~)alkyl- .
sulphonic acid, e.g. containing ab~ut 10% by wei~h~ : -of P205. :~
If a compound of formula III wherein R5 is hydrogen is cyclised in the presence of the mixture of phosphorus pentoxide and (Cl 4)alkylsulphonic acid, there are obtained~ :
as mentioned above, in addition to the corresponding ~ :
compounds IX and IXa wherein R'5 i5 hydrogen, the analogous compounds IX and IXa wherein R'5 is (Cl 4~alkyl.
This variant of the proce~s is preferably carried out with methanesulphonic acid.

Cycli~ation may be carried out in the presence or absence of a solvent. Any inert solvent i8 suitable provided that it has sufficient solubility for the reactants and a su~iciently 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 condènsing agent, such as phosphorus :
oxychloride or a mixture of (Cl 4)alkylsulphonic ~ -acid and phosphorus pentoxide, is used without::
the addition of solvent. .:~

35 Cyclisation is preferably effected with phosphorous : ~;
: oxychloride or, in difficult cases, with a mixture of phosphorus pentoxide and (Cl_4)alkylsulphonic acid (preferably methanesulphonic acid). ..

- 20 - 13~7~
The reaction may be carried out within a wide temperature range, prefera~ly with heating to 50C up to about tbe boiling point of the reaction mixture.

The reaction time required is between 2 and 15 hours, depending on the s~arting compound III.

The tau~omer~ of g2neral formulae ~X and IXa wherein R'5 is hydrogen may be separated by known methods, :
e.g. by i~olumn chromatography or selective reduction with, for exampl~, NaB~4 (reduces the tautomer ~f formula IX). ~automers of formulae IX and IXa are reduced by catalytic reduction.

Compounds o~ ~ormula I wherein R5 is hydrogen are optionally N-alkylated. N-alkyla~ion may be carried out, in principle, with any known alkylatin~ agents :
provided tha~ they have suficient reactivity, e.s. active alkyle~ters such as dialkylsulphate, alkylester3 of toluenesulphonic acid or alkylesters of fluoromethanesulphonic acid. The rea~tion is convenien~ly carried out at temperatures up to the boiling point ~: .
of the reaction mixture (in this case, alkyl represents (Cl_4)alkyl).
:~
The N-hydro~methylation may be carried out under ~
the conditions o~ aminoalkylation according to ~ .
Leuckart-Wallach (Ber. Dtsch. Chem. Ges. 18, (1885) ~ :
2341) or Esahweiler-Clar,kq (Teilheimer 2, (1948) 1 , No. 352 4 (1950) No. 378). Generally, the substance :::
is treated with a 30% formalin solution, for example, in ~he presence of formi~ acid at ambient temperature.

The free bai~e of general formula I may be onverted 3S into the acid addition salts thereof in a manner known Per ~e.

- 21 - ~33~8 Suitable acids for salt formation include, for example, inorganic acids, such as hydrochloric, hydrobromic, sulphuric, phosphoric, or ni~ric acids, or organic acids such as acetic, propionic, butyric, oxalic, malonic, succinic, maleicr fumaric, lactict tartarict citric, malici benzoic, cinnamic, ascorbic and methanesulphonic acid.

The new bis-(3,4-dihydro-1-pyridinyl)-methanes of formula I have valuable therapeutic properties, as already men~loned hereinbefore, both as bases and in the form of their salts.
., In- particular, th~se ~ubstances have a significant cardiopro~ective activity which was determined ~ ~ollows~

As is well known, the myocardial Ca level is a measure of hypoxic heart damage or heart damage caused by toxic doses o~ catecholamine (Higgins et al., Mol. Cell. Cardiol. 10: 427-438, 1984;
Nakanishi et al., Am. ~. Physiol. 242: 437-449, 1982; Flecken~ein A., Vortrage der Erlanger Physiol.
Tagung 1970, Edit. Keidel, Springer Verl. Berlin, ~eidelberg, New York, 1971). Conversely, the inhibi~
tion o hypoxic or isoprenalln-lnduced myocardial c~lcium uptake is a measure of the cardioprotective efficacy of calcium antagonists (Fleckenstein loc.
cit.), of calmodulin inhibitors (~iggins) and other 30 drugs,'e.g. beta-bdrenolytics (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 ~loc.cit.) and the potency of the test substances was given as the ~50 value; this value corresponds to the dose which results in a 50% inhibition of ': ' `

- 22 - 133~7~
the myocardial radio-calcium up~ake caused by adminis-tration of 30 mg/kg s.c. of isoprenalin.

The new compounds tested were found to be up to S times more effective than ~he known commercial product propranolol.
Compound ~50 - value*
A 1.25 B 2.26 C 1.34 10 D 2 . 25 E 2.29 F 1.41 G 2.23 ~ 2.15 * oral administration of active substance.

If an isolated heart kept for a fairly long time under ischaemic conditions is then subjected to normal perfu~ion again; heart function is no~
immediately normalised. Rather there is a period o~ tran~ition characterised by contracture and arrhythmia.
Thii3 phase of arrhythmia is caused by changes in thq ~unction and ~tructure o~ the myocardiac cell with intracellular calcium overloading ~Hess and 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 characteris~ics on ~ `
re-perfusion ~Watts et al, Am. J. Physiol. 238, R 909, 1930; Meno et al, Am. J. Physiol.~ 247, 380, 1984~. The cardioprotective activity was investigated on isolated rat hearts with ischaemia and subsequent re-perfusion. Under controlled condition~ after one hour's ischaemia (flow rate 0.15ml/min) there is a period o~ irregular heart activity lasting for 10-15 minutes. Infusion o~
cardioproteative compounds shortens this period signiicantly. `~

~33~7~8 CompoundConcentration ~lug/ml] short~ning of the arrhythmia phase from 11-13 minutes to A 3.3 4.0 min I 13.3 3.5 min R 6 J 6 3.1 min L 3.3 5.0 min CODPOUnd A s Compound of Table 1 15 R / ~ C~ O R5 R11 : CEI3C~ R12 . CEI3O
R1 : El R12 : C~3O
R2-R3 : -(CH2)4 R6-R7 : -(C~2)4 20 The structure of Compound A is given on page 32. ~;
`

~ , .
, . ,~
'~
:: . ~ .' ~ ' . ' .
:.

~33~7~8 - 24 - 27~00-90 Compounds of Table 4 ~structuraL~L_~

c~rl L~ R ~ 1 2R3 R4 Sal~ S o~

B CH30 CH30 ~ H H NH-N- HCl . -(CM3)2 C ~ H3O CH30 CH3- ~ H NH-CH2- BS
- ( CH2 ~ 3 -C~ t C~13 ) 2 ~ .
D CH30 C~3o c~3- }I E~ It~l-CH- B5 ~-~c~2)3 -t~{3)2 ~ ~:

E CN30 CH30 CH3 - . H H N~I- 13S
- ~ CH2 ) 3 ~ ~ C~2 ) 2 ~~3 . ~ ~

F C~30 CH30 C~3- H H ~IKC~3 BS ::

. ( CH 2 ) 3 ' G CH30 C~3o CH3- H ~ N~- B5 ~ H
. - ~ CH 2 ) 3 - ( CE~ 2 ) 2-CH ~ ~ -H C~30 CH30 CH ~- H H NH-CE~2- HCl - ~CH2 ) 3 -CHt~H) -CH3 ~:
CH30 C~3O ~ I ~ H H N~ O

~c CH30 CH30 CH3- H H NH-CH (CH3 ~ - BS
-(CH2)3 -(C~2)3~
. -C~l ( CH 3 ~ 2 L. C~30 CH30 C6H5- H H NH- . ~S ~ :~

L . -(CH;~)2 _ , ~ . .

b . . ~ 3 ~ 3 3 ~

- 25 _ 1~79g In itro 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 volta~e-dependent (slow) calcium channel in th~ cell membrane. The detection of transmembranal calcium ion currents on strips of tissue with potassium depolari~a~ion using the method described by van Breemen clearly indicates a calcium antagonist tvan Breemen et al., Che~t. 78, 157 S - 165 S, 1980; van Breemen et al., Am J. Cardiol. 49, 507 - 510, 1982; Casteels et al., Pfl~gers Arch. 3~2, 139 - 145, 1~81; 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 ~ and the acid addition salts thereof may be considered for use as active substances for pharmaceutical composition~ for th~ treatment of coronary heart disease and acute myocardial inarction.
In tests on the survival of animals in a sealed ~hamber ~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 significan~ increase - 26 ~ U ~J ~
in survival over the control animals or animals which had been pretreated with diltiazem, nifedipin or verapamil. ~he cerebropro~ec~ive activity tes~ed 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 dose 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 sub3tances for preparatîons to treat cardiac insu~ficiency and cerebral metabolic disorders or organic brain psychosyndrome and post-traumatic and alcoholic brain damage.

Thus, according to a further aspect of the present invention there is provided a pharmaceutical composition ~0 comprising a compound o~ ~ormula I as hereinbe~ore de~ined or a physiologically acceptable salt thereof, preferably with an organic or inorganic acid together with at least one pharmaceutical carrier or exaipient.
The pharmaceutical compositions are suitable ~or oral or parenteral administration. They may be administered chie~ly in the form of tablet~, coated tablet~, ampoules and syrup preparations. The single dose o~ 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 ~or the trea~ment of coronary heart di~ease, acute myocardial infarction and/or for use in cardio- and/or cerebroprotection - 2~ - ~ 33~
in a subject which comprises administering to said subject a compound of ormula 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 o~ 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 dicease and/or acute myocardial infarction, and/or for use in cardio- and/or cerebropro~ection in a subject. ~ -The following Examples are intended to illustrate the inven~ion in a non-limi~ing manner runles~
otherwise stated, all percentages and ratios are by weight):

' - 28 - 133~798 ~m~ .

1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolin-l-ylidene)-pentane and 1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(1,2,3,4-te~rahydro-6,7-dimethoxy-2-N-methyl isoquinolin-l-ylidene)-pentane 4 9 g of n-butylmalonic acid-di-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amide are heated to 100C for 1 to 2 hours in 20 ml of a me~hanesulphonic acid/P2O5 mixture (10~ by weight of P2O5). After the reaction ha~ ended (monitored by thin layer chromatography) the reaction mixture is poured onto ice, made alkaline with saturated soda solution and extrac~ed with methylene chloride. The organic phase is washed with water, dried over sodium sulpha~e, evaporated down in acuo and the residue is ~eparated on silica gel (eluant: methylene chloride: me~hanol = 100:5, ;~
V:V). The N-~ compound is eluted first.

N-~ compound: m.p. ~ 158-159C (hydrochloride) ::~
N-C~3 compound: m.p. = 136-137C (hydrochloride) ;
Example 2 -~

1-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)-l-(3~4-dihydro-6~7-dimethoxy-2-N-methyl-isoquinolin l-ylidene)-pentane-hydrochloride 1 g of the 1-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-yl) 1-(1,2,3,4-~etrahydro-6,7-dimethoxy-isoquinolin-l-ylidene)-pentane prepared in Example 1 is heated to boiling for 6 hour~ in ~ ml of freshly distilled .~:

r~~, - 29 _ 1 3 3 ~
dimethylsulphate. After working up ln the usual way, the product i~ chromatographed on silica gel (eluant: C~2C12: MeOH = 100:5, V:V), the hydrochloride is formed and crystallised from ethanol/ether.
Example 3 1-(3~4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxy-1-N-hydroxymethyl-10 isoquinolin-l-ylldene)-ethane-hydrochloride 12 y of 1-(3,4-dihydro-6,7-dimethoxy-i~oquinolin-l-yl)-l-(3,4-dihydro-6,7-dimethoxy-isoquinolin-l-ylidene)-ethane are lef~ to stand for 20 hours a~ ambient temperature in a mixture con~isting 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 i~ taken up in C~2C12, washed with dilute soda 23 solution and then with water, the organic phase is dried over Na2S04, the solvent is eliminated in vacuo, the residue i9 taken up in just sufficient ethanol and preaipitated as the hydrochloride by ~ -~
the addition of ethereal hydroahloric acid. M.p.
25 a 155 C

Example 4 ~-(3,4-Dihydro-6,7-dimethoxy-isoquinolin-1-yl)-1,2,3,4-tetrah~drd-6,t-dimethoxy-1-benzylidene~
isoquinoline :~ ' 4.9 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-1~ [2-~3,4-dime~hoxyphenyl)-ethyl]-aminocarbonyl3-benzyl-~,'.
,:

13~79~

isoquinoline are heated to boiling for 4 hours in 20 ml of freshly distilled phosphorous oxycbloride.
After the reaction has ended ~monitored by thin layer chromatography) excess POC13 is distilled off, the residue is distributed between C~2cl2 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: CH2cl2:Meo~ = 100:10, V:V). The ~ast~
running yellow fraction yields ~-(3,4-dihydro-6,7-dime~hoxy-isoquinolin-l-yl~-1,2,3,4-tetrahydro-6,7-dimethoxy-l-ben2ylidene-2-N-phosphono-i~oquinoline (m.p. above 270C (hydrochloride3), whilst the sub~equent red zone yields the N-H compound (m,p.
95-100C) given in the title. : :

Example 5 :
.
(4,5-Dih,ydro-thienot2,3-c]pyridin-1-yl)-4,5,6,7-tetrahydro-1-methylidene-thieno[2,3-c]pyridlne 19 g of malonic acid di-N-~2-(3-thieno)-ethyl]amide . ;
are heated to boiling ~or 3 hours in 25 ml of phosphorous ::
oxychloride. As soon as no further starting material 25 can be detected, the mixture i~ worked up in the -usual way, the reaction product is puri~ied on ~
Ai2o3 neutral, activity stage III (made by Woelm) ~ -~eluant: CH2C12) and the hydrochloride is formed.
~M.p. = 233-235C) Example 6 3~Isobutylaminocarbonyl-l-pentyl-6,7-dimethoxy-3,4-dihydro-isoquinoline ~
~ :
3.8 g ~10 mmol) of ~-isobutylaminocarbonyl-valeric acid-N-r2-(3,4-dimethoxyphenyl)-ethyl]-amide are ' ~ , ! ~ ~ . , , . . ~ , - 31 - ~ 3 3 ~ 7 ~ 8 dissolved in 120 ml of acetonitrile and 18 ml of phosphorous 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 cbloride 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 Na2SO4, eliminating the solvent, etc. - the product is purified over a silica gel column (CH2C12/MeOX
= 100:2). M.p.~ 158-160. r Example 7 :
Methyl 2-ethyl-2-(3,4-dihydro~5,6-dimethoxy-1-iso- :
quinolinyl)-butane-carboxylate 22 g of methyl 2- [2-(3,4-dimethoxyphenyl)-ethyl~-aminocarbonyl -2-ethyl-butane carboxylate are heated 20 to boiling in a mixture o~ 100 ml of acetonitrile ~
and 12 ml of phosphorous oxychloride until total :~ :
conver~ion of the substance is obtained (about 2 hours). ~he mixture is then worked up in the usual way, the reaction product is purified on silica ~el ~eluant: C~2Cl~ : C~30H ~ 100:2) and the hydrochloride is formed.
M.p. ~ 141-143C (ethanol/ether) :

Example~ of some compounds according to the invention which may also~beiprepared analogously to ~he Examples described above are listed in the Tables which foll~w. ~

~ ~.

- 32 _ 1 ~ 3 ~
Table 1 -. .

11 ' ~N

R 11 ' ' ~,~ .
~ 6 J~ R ~ ~ ~
R I :
,_ R12 ,:

~ ;~

~ " I . ~ ! , i ' ~

' ' ':'';.

33 133~798 . ~
.. ~ U~
~ m tr, ,~
_, â ~ . .~ ~
~ ~ ~ O ~ ~ ~ ~ C;t ~
u~ ~ e .
O ~ c~ a o t ~ct txt O t_ t~ tJt t~t ~ t I ~ tXt .-1 ~ t~ ~ txt ~_ txt ~ c~t .~ ,rt o ~ 1 t~t ~ t CJ'~ I t.~t t~t t`
~; ~ :~ X :C X X ~ S S :~: 2 ~ ~
~ .
:~:
~'t _ ', ', .
C~ ~ X C ~ ~ ~ S T = S 3 X 3 S X T :S 3 O :
~t O C'~ O O O O O O tO O O~ O O O ~ ~ s x ~ x x ~ O ~ I s O

N
X ~ g X
o o o o o o o o o o o `I I o I I o I .
s ~ S a~ ) I x ~ l :~: l ~

O ' , ' n X X ~- 2 = X 3 ~ X ~ X X C.~ S X X 3~
~.
n ~;l ~ X 2 X ~ 3 C 3 X X X q rS X ~ 2 2 ~ I.r _ , :

1~ I S X 3: 2 ~ X ~: X X X X S X :r: X 2 X S ~
' I~
X X X O
C~ ~ H X X H H ~ X ~ ' ~5 X -- C C c.2,~ 3 ~ X :C C V ~ ~S~
O .,~ , .
O O O O O O ~ O V~ O ~ O O O O O O O ,1 ~
~q ~S~ S ~ ~ X X ~ S ~ X X ~ VS ~ I a ~ ~1) 0 , ; ~ . !

~ o 2 X ~a~ S ~
~ ~ . I I 11 11 11 ',.'.
O ~ O O O O O O O O O O O O O O O o O o ~ ~ a a: C~ ~S ~ S~ X c~ S~ S

~ .:;
. :

~-~` 133~798 Table 2 NH

H R

R Salt form M p(C) H3C0 x~j~ Cl 218-222 ~JN Cl Z 3 9 - 2 35 ; ::
':
~' : _ 3,5 _ 133~79~
Table 3 ~NH

H R

R Salt form Mp ( C ) H3CO ~N Cl 162-172 S 1~ N
Cl 237-239 -..,~

~ C~ 250-Z53 , ' , :`.`' :: 6 ~33079~
Table 4 . _ .. _ ' ., Q~ Structural type I

R'~ 3 R~l~N-H ~ -R~R~ Structural type II - ~ -, - , ~, BS- ~sse ~:

~- 133~79~
. .
. .

~ ~ ~ ~ ~, ~ V V ~ <~ ~ ~ ., ~ o S 2 ~ ' ~ T
~O ~ .
_1 ' `

a~ .
h ~ - ` ~ `
tl~ ~.~'' ' ~ : ,` :
~ _ ,, :` :~

er T ~ 2 S _ C 1T ~ 3 2 :~: S X S :~ I S ~ 3~

2 --I I = . S S -- T = ~: :
~` ~
~ S ~S T :~C2 3 S ~

VS ~ V - `~

- 2 3~ I3: ''S S S 3 -- 3.~ --- ~33~8 . . -o ~ ~_ ~
.
o ~o~ ~ , _ ~ ~

~U O I ~ l I CD Cl~ cn ID

_I

IJ a~

~ ' . " ' .

~ ~ , O
~ O ~X :' -r I I X O Z
~ ~ ~ V

X <`'1 ~ Il ~ <~ X 2 ~
e~ X -- X X V ~ - -- -- S S S
C~ Z X2 - O C:~Z 2 X ~ 2 ~
~';. ~ ' ~Y = X T -- X ~ 1 ' S

~ XX X -' X I X '' I I I
i l I ' ' ' tY I X: = = I X

--O O. O C:~ O O O O C~ O O O
X T X T 2 X X ~-- --' :

--O O C~ O O O O O O O O O :~
- S ~- XS :C S ~ I -r ~ S X
QC V ~ V ~- V ~ V

'~

~; ,:

` 133~7~
.. ..

V , o _ ~ ,~ ,5, o ~, ,~ , ~. ,~
~_ 0 ~ o ~ u~
o ~
o C~ ,xt o ,,.`-,, C~ ~ _ U'.t ot l~ ~t er _ _ _ _ ,.~
. .

~ o a~ CD t~ -r a~
0'~
:, _I
11~ `
S~
....

ca :

t.~l ~
.
X.~ ~ ~,,~ ,, ~r X S -r t~ ~ ~_) Z Z O ~ I I O ,~
,~ < ~ ,r~ ~ t.~ t~ ~t t.~l U~ X X X :C O -r S X T ~ .
~J tV t~) ~
I _ __ _ _ ~ ..
e~ O -- X X X ~ S X X. -r c~ O Z Z Z :Z Z Z Z Z Z 2 ~' '.' ' ' ' Cl~ X X X ~1: I X T T -r :~

~ ~r r T T :~ I T T = -r I :~

Cl~ T S 1 X ~ I T c I T
tt--O O O O O O O O O O O ~ , IX~ r -r X ~ -- -- X T ~ X ' ~', -- C~ O O O O O O O O O O ' ~' r-tl`'lt ~ 7 ~ ~rl ~1 ~ t.~ ~ t~: .
S X T T X X X = X ~

. ':

_ ,4p _ ~ .
133079~

~ ~er O ~O
o , ~r o ~ ~ c~

h :
U~ .
T
C~
~ ~ C S
T _ ~ . 1~
= O ~: ' Ss (~o -~3 S O
' ~ '~ ~
'~ ~,J~.J T
S ~ ~ I,~ O ~ . ' .
Z T ~ ~ _ f ~ _ l l ~' ~ ~ 7--J: ~ ~ J T
Z Z O Z. 2 Z Z Z ~:
' .
= _ _ ~.. T X

T ; ~ T T
:~' :' ~:

O ':
CC ' ' ' O ~ O O O O , O ' X S S X X ~ I T
O O O O O O O ~ ~
:.

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

~ _ ~ a~ er ~ ~ ~ ~ O
o ~
_ . .~ t~ O
_ _ o o o ~

~IS O ~ ~ L~ ~ a~ c~ I LO c~ CD I ~ ~
_I

c~ $~ H ~1 ~1 H ~

U~ :

. : - .

I I C~J
O O ,.

'~ ~ x~ ~ I I==~ ~ ~ ~ ~ Y
el- ~ I <`~ C~ O ~J t,~.l C~ l t~t L~ ~ ~J~ L~J t.~l~ L~J ~ :' S ~¦ t~ I ~ T T 1 X T
T ~ ~ X ~ ) l ~ ~ t~
~ _ t~ <,~ _) ~ ~ _ ~ _ _ _ _ e~ X 1 _t t_t J T X X T
CC X Z Z Z Z X 2 X ~ Z Z Z Z
~ :. .
T X X X:~:

C~J
T ~J T ~: 1:~ X _~. T T T

~ X ---- --r T 2:1: T T I - T T
C~ t_'t ~ -) t_) t-~ t-~ ~ ~ :, -- O O O O O O O O O O O O iO ' ' t.~'7 ~7 ~ ~ ~ ~t , ~ ~ t~t,~
-- ~ ~ T ~ ~, T ~ T T
' ~- O C~ O O O C~ O O L~ OC:~ O O
-- ~ t,'~7 ~ ~ <~ t~t t, ,t ~ t~') ~t ~J T T T X--~ IT~ T X T T T

3 ~ 7 9 ~

. .,, ~

o _ o~

: "
~ ~ .
m m m c~ m m m ~.
_I .

S~ ~

~

~ ~ ~ :
Cl O ~ ~~ , et :C S ~ q C~l S C~ "' ~r ~ s 3: s ~- s s s s 3~
~C = Z ;~ Z2 Z Z Z Z .. C
"' ~'' .

C~: 2 X S ~ 2 ~: S S ~ ; ~:
~ .
C~ X S X ~ !X X ~ S -r T

S ~ X I 3: T T ~ I ~r I

--O OC~ O O O O O O O O ~ :,.
T r- . X I S
,:
--O O ~ O O O O O O O O

S 3 ~ , T X S --1~ T S

' ' ' ~ ~' - i~l3~ --``: 13~79~
. . _ U~
o ~ o o o o c~ o ~ o o o r o~ ~ o O ~ a7 ~
o u cn O~ o ~ -- ~ ~ a ~ O
o _ o u a~ a~ 0 co 1-- .-- o 1-- o ~ o a~
`

~'d O ~ ~, T ~: T

_I ~
~ ..
, ` :' ' U

~ .
, ,_ _ ., t~ 1 I X ~`
O O O Z~

s x s ~ ~ o . .
X X ~ S T ~ O ~ Z Z
T e s S T 1~ J
c~:Z Z Z 2 ~: z 2 Z z z 2 z - z z Z z 0~ S ~ X S S ~ T S ~-- X 1: S

C~: S ~ S S ~- -. ~ T

S S ~ S ~ 1 T I S T
T ~ r S I S ~r ~ S :~ S

O O O O C~ O OO O O O O O O O O
S S 2 ~ ~ 2 ~r ,S S X I :1: ~ X _ T ~ .

O O O O O O O O O O O O O O O O O ~`~,' `
r --rj X X X ~ S :~~r T T T ~ --r T S ~ ~

ii~'~

-- 44i --- ~33a7~

o ~ , ~ o "~ ~ ~ ~ ~ _ _ ~; .

:

~7 :

:

Q ~
~

1'~ S ~ = S = = O L 1_1 L>

~i =, . ~ -r ~ . ~J 2 2 :~ 2 3 2 2 = -r ~ 5 2 2 S

:~: S S S T 2 S -e ~ S ~ I 2 2 :~

2 ~ 2 ~ = 2 ~ V

r 2 S = ~ ~ = S ~ S~

", ~:

~ li ; .. i; ~ ~ i ~ i i ' ~ i ,,;

- ~5~ 3 3 ~ 7 9 3 ~ , U3 "
s . . .
,~
o ~o ~ a ~ - -o .

_ h ~ v ~n- ~
1~ o = = C~

~.
J , :
i ~ ~ ~';:'`
U~ , ~,,.
.`'` ~'''' ~ ' S~ Z<~
c~: 0 2 Z :~:
....
-X

.~i .. :.

S S

-- X - S

- ~ ~ ,_) ~ ',;.,:-,, - e S S
<_~ ~ 1_) S ~ ~' ~' O C:~ ~ o o C ~
~ ~' T

::' :'~

-- 4116~ --~ 33~7~8 In ~n N 0~ ~O O ~ 0 S =

cn ~
~ ', ' - "
I

i --r ,, ~ ....
T

V ~ 1_~ T ~ X ~ X ~ ~
~ S X X ~ ~ 1 2 Z ~ 2 Z 2 Z X
~ ~ ' X 3~1 ~ T ~ 1 S I I ~ T

T ~ 3 r T S I ~ T I T

_ T X S -~ -r S

o o o ~ o o o o o o o o - X ~ I X~' S T ~ X S -- X S X ~ X Z X ~ S ~ I X I '~

' _ ,..
13307~8 Ga~
oa~ O
O
~ I I I I I I I

~ o c:l ~ m m mcn m m c~

:5 ~ Q~

Z` 2 2 Z _ Z Z Z 2 Z

S X . T ~ -r X

S S S ~ X ~ S S
' `, ~ .
~ _ _ _ _ _ _ _ _ ._ ,, ~ ~ S~1:'~ S

- _ O O~:7 0 0 0 0 O O O

-- O O O O O O O O O C:~ .``' X S T T

, .

- ~81- 133~79~

- ~ X :~ 2 ~ 3: X a: ~

n r O O O O O O ~ 0 ' ~ ~
~ ~ ~ ' ~ O O O O ~
~I; ~ X ~ O -~

~I ~ n C~; 2 ~ ~ x cX~ x x x s ~ _ 2 X X ~X ~ :5: = 2 "`~
X
~) V ` ;:
:~~Z ~ X ' S X X :~ = _ X X = ~
C~, X S ~, ~ O ' ~;.`
,. . X C ~ X ::: X C ~ C~ C~ 3 X C~

O O O O O ~ O O O O O O .
~ ~ I ~ X X X X ~ ~ X 2 :C X X X i; X

U~ , ~ ~ n n al c4 ~ ~ g ~ g ~

~ ' . ,~''' ' '' : '' ~ ,' ~' _ 49 _ 13 3 ~7 ~ 8 Table 6 </~

~ ICI -N-CH2-CH2~3( R 12 ) n ' V

, -'",, .

~( 12~n' ~-:

' ~5 Cl~3 '~', ~ .

- 50 - ~L33Q'~
~able 7 c-CH2 CH2~3 ' R12)n' Vl ~ ~ R 12 ) n ~ : ., r ~CH3 -:

,~

',' .~ Sl- 133~79~
E~am~les o~-E~armaceu~ic~ E~

a) Coated tablets 1 tablet core contains:
Active substance of general formula I ~0.0 mg Lactose 100.0 mg Corn starch 75.0 mg Gelatine 3.0 mg Magnesium stearate 2.0 mq 210.0 mg ~ ' A mix~ure of ~he active substance wi~h lactose and corn s~arch is granulated with a 10~ aqueous gelatine ~olution through a 1 mm mesh screen, dried at 40C and rubbed ~hrough a screen again. Tbe granule~ ~hus obtained are mixed wi~h magnesium stearate and compressed. The resulting cores are coat~d in the usual way with a coating applied -;
by ~eans o~ an aqueous 3uspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax. ;

b) Tablet Active ~ubstance o~ general ~ormula I 30.0 mg Lacto~e 100.0 mg Corn ~tarch 70.0 mg ~;
Soluble staroh 7.0 m~
Magne~ium stearate 3.0_mg ~ I '210. d mg Preparation ~ -The active subs~ance and magnesium s~earate are granulated with an aqueous solution o~ tbe soluble ~tarch, the granules are dried and intimately mixed with lactose and corn starch. ~he mixture is ~hen compressed to form tablets weighing 210 mg.

;~

- 52 ~ 133~

c) Capsules .

Active sub~tance according to claim 1 20.0 mg Lactose 230.0 mg 5. Corn starch 40.0 mg Talc 10.0 m~
300.0 mg PreParation The active substance, lac~ose and corn s~arch are first mixed together in a mixer and then in a grinding machine. The mixture is returned to the mixer, ~horoughly c~mbined with ~he talc and transferred by machine into hard gelatine capsules.

In these Examples, compound~ such as 1-(3,4-dihydroxy-6,7-dimethoxyisoquinolin-1-yl~
(3,4-dihydro-6,7-dimethoxyisoquinolin-1-ylidene)-ethane, ~-morpholinocarbonylmethyl-6,7-dimethoxy-3,4-dihydro~
iso~uinoline, 6,7-dimathoxy-3,4-dihydro-isoquinoline acetic acid methylamide, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid diethylamide or 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid phenylethylamide -or pharmaceutically accQptable salts thereof may ~ ~:
for example be used as active substance.

Claims (61)

1. A compound of formula I

I
[wherein A represents a benzo or thieno group;

R2 and R3 independently of each other each represent a hydrogen atom or a (C1-5)alkyl group, or together 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 (C1-4)alkyl, hydroxy, (C1-4)alkoxy, amino, thiomethyl, methane-sulphonyloxy or methanesulphonamido group, or two adjacent substituents R11 together represent -O-CH2-O-or -O-CH2-CH2-O-;

m represents 0, 1, 2 or 3 if A is a benzo group, or 0, 1 or 2 is A is a thieno group;

D represents a group of formula Ia or Ib Ia Ib (wherein in the group of formula Ia B represents a benzo or thieno group;

R1 represents a hydrogen atom, or a (C1-10)alkyl, phenyl, phenyl-(C1-5)alkyl, (C1-4)alkoxy or -NHCOX
(wherein X is (C1-5)alkyl) group;

R5 represents a hydrogen atom, or a (C1-4)alkyl or hydroxymethyl group;

R6 and R7 independently of one another each represent a hydrogen atom or a (C1-5)alkyl group, or together with the carbon atom to which they are bound R6 and R7 together represent a 5- or 6-membered carbocyclic ring;

R12 represents a halogen atom or a (C1-4)alkyl, hydroxy, (C1-4)alkoxy, amino, thiomethyl, methane-sulphonyloxy or methanesulphonamido group, or two adjacent substituents R12 together represent -O-CH2-O-or -O-CH2-CH2-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;

and in the group of formula Ib R1 is defined as for the group of formula Ia;

R'5 represents a hydrogen atom or a (C1-4)alkyl group;

R4 represents a (C1-4)alkoxy or an -NR9R10 group, wherein R9 and R10 independently of each other represent (a) hydrogen, (b) branched or unbranched (C1-12) alkyl, (C1-12)alkenyl or (C1-12)alkynyl (wherein the alkyl may be substituted by hydroxy, (C1-4)alkoxy, di(C1-4)alkylamino, furyl, pyrrolidinyl, morpholinyl, pyridinyl, indolyl, or the group , (wherein R12 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) (C3-7)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 R9 and R10 cannot simultaneously represent hydrogen, dimethylamino or di(C1-4)alkylaminomethyl;

or R9 and R10 together with the nitrogen atom to which they are bound together represent a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, the piparazinyl ring optionally being N-substituted by unsubstituted phenyl, mono- or di-(C1-4)alkoxyphenyl, pyrimidinyl or phenyl(C1-4)alkyl)]

or the pharmaceutically acceptable salts thereof;

with the exception of the compound of formula I
wherein D is the group of formula Ia and R1, R2, R3, R5, R6 and R7 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 Ib and R1, R2, R3 and R'5 represent a hydrogen atom, A represents the group and R4 represents the group .

2. A compound of formula I as claimed in claim 1, wherein D represents a group of formula Ia as defined in claim 1;

R1 represents a hydrogen atom, or a (C1-10)alkyl, phenyl(C1-5)alkyl or -NHCOX (wherein X is (C1-5)alkyl) group;

R11 and R12 independently of each other represent (C1-4)alkyl, hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R11 or R12 together represent -O-CH2-O- or -O-CH2-CH2-O-.

3. A compound of formula I as claimed in claim 1, wherein D represents a group of formula Ia;

R1 represents a hydrogen atom, or a (C1-10)alkyl or -NHCOX (wherein X represents (C1-5)alkyl) group;

R2, R3, R6 and R7 independently of one another represent a hydrogen atom or R2 together with R3 and/or R6 together with R7 together with the carbon atom to which they are bound represent a 5- or 6-membered carbocyclic ring;

R11 and R12 independently of each other represent hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methane-sulphonamido, or two adjacent substituents R11 or R12 together represent -O-CH2-O or -O-CH2-CR2-O-.

4. A compound of formula I as claimed in any one of claims 1 to 3, whereon D represents a group of formula It and R1 represents a hydrogen atom, or a (C1-6)alkyl or -NHCOCH3 group.

5. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and R5 represents a hydrogen atom, or a methyl or hydroxymethyl group.

6. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and R2, R3, R6 and R7 independently of each other represent a hydrogen atom or R2 together with R3 and/or R6 together with R7 and the carbon atom to which they are bound represent a 5-membered carbocyclic ring.

7. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and R11 and R12 independently of each other each represent hydroxy, methoxy, methanesul-phonyloxy or methanesulphonamldo, or two adjacent substituents R11 or R12 together represent -O-CH2-O-.

8. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and A and/or B
is a benzo group.

9. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and A and/or B
is a thieno group.

10. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia, m and/or n represents 2 and A and/or B is a benzo group.

11. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia, m and/or n represents 2 and A and/or B is a thieno group.

12. A compound of formula I as claimed in claim 10, wherein when A and/or B is a benzo group the two substituents R11 and/or R12 are in the meta- or para-position, respectively, to the fusion points of the group A or B.

13. A compound of formula I as claimed in any one of claims 1 to 3, wherein D represents a group of formula Ia and R11 and R12 are each methoxy.

14. A compound of formula I as claimed in claim 4 wherein R5 represents a hydrogen atom or a methyl or hydroxymethyl group, R2, R3, R6 and R7 independently of each other represent a hydrogen atom or R2 together with R3 and/or R6 together with R7 and the carbon atom to which they are bound represent a 5-membered carbocyclic ring and R11 and R12 independently of each other represent hydroxy, methoxy, methanesulphonyloxy or methane-sulphonamido, or two adjacent substituents R11 or R12 together represent -O-CH2-O-.

15. A compound of formula I as claimed in claim 1 being 1-(3,4-dihydroxy-6,7-dimethoxyisoquinolin-1-yl)-1-(3,4-dihydro-6,7-dimethoxyisoquinolin-1-ylidene)-ethane or a physiologically acceptable salt thereof.

16. A compound of formula I as claimed in claim 1 wherein D
represents a group of formula Ib and R4 is methoxy or ethoxy.

17. A compound of formula I as claimed in claim 1, wherein D
represents a group of formula Ib and R4 represents an -NR9R10 group, wherein R9 and R10 independently of each other represent (a) hydrogen, (h) (C1-8)alkyl, (C2-3)alkenyl or (C2-3)alkynyl (whilst the alkyl may be substituted by hydroxy, (C1-4)alkoxy, di(C1-4)alkylamlno, furyl, pyrrolidinyl, morpholinyl, pyridinyl or the group , wherein Ar, R12 and n' are defined as in claim 1), (d) dimethylamino, (f) phenyl, (g) morpholinyl, (h) pyridinyl, whilst R9 and R10 cannot simultaneously represent hydrogen, dimethylamino or di(C1-4)alkyl-aminomethyl; or R9 and R10 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(C1-4)alkoxy-phenyl, pyrimidinyl or phenyl (C1-4)alkyl.

18. A compound of formula I as claimed in claim 17, wherein R4 is an -NR9R10 group wherein R9 and/or R10 each represents unsubstituted phenyl, fluorophenyl, morpholino or 2- or 3-pyridinyl.

19. A compound of formula I as claimed in claim 17, wherein R4 is an -NR9R10 group wherein R9 and/or R10 each represents (C1-4)alkyl.

20. A compound of formula I as claimed in claim 17, wherein R4 is an -NR9R10 group wherein R9 and/or R10 each represents (C2 or C3)alkyl which may be substituted by hydroxy, methoxy, dimethylamlne, furyl, morpholino, pyrrolidinyl or pyridinyl.

21. A compound of formula I as claimed in any one of claims 17 to 20, wherein R4 is an -NR9R10 group wherein R9 is hydrogen.

22. A compound of formula I as claimed in claim 17, wherein R4 is an -NR9R10 group wherein R9 is hydrogen and R10 is a substituted alkyl of formula VII

VII

(wherein p is 0, 1 or 2, and R6, R7, Ar, R12 and n' are as defined in claim 17).

23. A compound of formula I as claimed in claim 22, wherein R12 represents (C1-4)alkyl, hydroxy, (C1-4)alkoxy, methane-sulphonyloxy or methanesulphonamido, or two adjacent substituents R12 together represent -O-CH2-O- or -O-CH2-CH2-O-.

24. A compound of formula I as claimed in claim 23, wherein R12 represents hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R12 together represent -O-CH2-O- or -O-CH2-CH2-O-.

25. A compound of formula I as claimed in claim 24, wherein R12 represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R12 together represent -O-CH2-O-.

26. A compound of formula I as claimed in claim 25, wherein R12 is methoxy.

27. A compound of formula I as claimed in any one of claims 22 to 26, wherein n' is zero.

28. A compound of formula I as claimed in any one of claims 22 to 26, wherein Ar is phenyl and n' is 2.

29. A compound of formula I as claimed in claim 28, wherein two substituents R12 are in positions 2- and 3-.

30. A compound of formula I as claimed in any one of claims 22 to 26 and 29, wherein p is 1.

31. A compound of formula I as claimed in any one of claims 22 to 26 and 29, wherein R6 and R7 are hydrogen.

32. A compound of formula I as claimed in claim 31 wherein n' is zero and p is 1.

33. A compound of formula I as claimed in claim 17, wherein R4 is an -NR9R10 group, wherein R9 and R10 together with the nitrogen atom to which they are bound represent morpholino, pyrrolidinyl or piperazinyl (which is N-substituted by methoxy-phenyl, phenethyl or 2-pyrimidinyl).

34. A compound of formula I as claimed in any one of claims 1, 16 to 20, 22 to 26, 29 and 32, wherein D represents a group of formula Ib, R1 represents hydrogen, (C1-10)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 two adjacent substituents R11 together represent -O-CH2-O- or -O-CH2-CH2-O-.

35. A compound of formula I as claimed in claim 34, wherein R1 represents hydrogen, (C1-10)alkyl or -NHCOX (wherein X is (C1-5)alkyl); R2 and R3 each represent a hydrogen atom or together with the carbon atom to which they are bound R2 and R3 together represent a 5- or 6-membered carbocyclic ring; R11 represents hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R11 together represent -O-CH2-O- or -O-CH2-CH2-O-.

36. A compound as claimed in claim 34 wherein R1 represents hydrogen, (C1-6)alkyl or -NHCOCH3.

37. A compound as claimed in claim 35 wherein R1 represents hydrogen, (C1-6)alkyl or -NHCOCH3.

38. A compound as claimed in any one of claims 35 to 37, wherein R'5 represents hydrogen, methyl or ethyl.

39. A compound as claimed in any one of claims 35 to 37, wherein R2 and R3 each represent hydrogen or together with the carbon atom to which they are bound represent a 5-membered carbocyclic ring.

40. A compound as claimed in any one of claims 35 to 37, wherein R11 represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R11 together represent -O-CH2-O-.

41. A compound of formula I as claimed in claim 38 wherein R2 and R3 each represent hydrogen or together with the carbon atom to which they are bound represent a 5-membered carbocyclic ring and R11 represents hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents R11 together represent -O-CH2-O-.

42. A compound as claimed in any one of claims 1, 16 to 20, 22 to 26, 29, 32, 33, 35 to 37 and 41, wherein A is a benzo group.

43. A compound as claimed in any one of claims 1, 16 to 20, 22 to 26, 29, 32, 33, 35 to 37 and 41, wherein A is a thieno group.

44. A compound as claimed in any one of claims 1, 16 to 20, 22 to 26, 29, 32, 33, 35 to 37 and 41, wherein m represents 2.

45. A compound as claimed in claim 44, wherein A is a benzo group and the two substituents R11 are in the meta- or para position relative to the fusion points of group A.

46. A compound as claimed in any one of claims 1, 16 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41 and 45, wherein R11 is methoxy.

47. A compound as claimed in claim 45 wherein m represents 2 and R11 is methoxy.

48. A compound as claimed in claim 1, wherein D represents a group of formula Ib, A represents benzo, R11 is methoxy, m is two, R1 is hydrogen or (C1-5)alkyl, R2, R3 and R'5 represent hydrogen and R4 represents morpholino, methylamino, diethylamino or phenethylamino.

49. A compound as claimed in claim 48, being morpholino-carbonylmethyl-6,7-dimethoxy-3,4-dihydroisoquinoline, 6,7-dimethoxy-3,4-dihydro-isoquinoline acetic acid methylamide, 6,7-dimethoxy-3,4-dihydro-isoquinol1ne acetic acid diethylamide, or 6,7-dimethoxy-3,4-dihydro-isoqulnoline acetic acid phenylethyl-amide, or a physiologically acceptable salt thereof.

50. The compound of the formula or a physiologically acceptable salt thereof.

51. The compound of the formula or a physiologically acceptable salt thereof.

52. The compound of the formula or a physiologically acceptable salt thereof.

53. The compound of the formula or a physiologically acceptable salt thereof.

54. A compound as claimed in any one of claims 1 to 3, 10 to 12, 15 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53 being in the form of physiologically acceptable salts with inorganic or organic acids.

55. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 3, 10 to 12, 15 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or explant.

56. A process for preparing a compound of formula I as claimed in any one of claims 1, 16 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53, comprising at least one of the following steps, (A) (to prepare a compound of formula I wherein D is a group of formula Ia) condensing a compound of formula II:

(II) (wherein A, R1, R2, R3, R6, R7, R11, R12 and m are defined as in any one of claims 1, 16 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53, 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 thienyl group, and R5 represents a hydrogen atom or a 66a (C1-4)alkyl group) in the presence of a condensing agent;
(B) (to prepare a compound of formula I wherein D is a group of formula Ia) condensing a compound of formula IIIa:

(IIIa) 66b (wherein R5 is hydrogen, R1, R2, R3, R6, R7, R11 and R12 are defined as in claim 1, Ar represents a phenyl or thienyl group and m' and n' independently of each other each represent 0, 1, 2 or 3 if the associated Ar is a phenyl group, or 0, 1 or 2 if the associated Ar is a thienyl group) in the presence of a condensing agent, without isolation of the intermediate product of formula (II); or C) (to prepare a compound of formula I wherein D is a group of formula Ib) condensing a compound of formula III:

(III) (wherein R5 is hydrogen, R1, R2, R3, R4 and R11 are defined as in claim 1, Ar represents a phenyl or thienyl group and m' represents 0, 1, 2 or 3 is Ar is phenyl, or 0, 1 or 2 if Ar is thienyl) in the presence of a condensing agent;
and, if desired, carrying out one or more of the following after-treatments:
alkylating a compound of formula I wherein R5 and R? is a hydrogen atom to form a compound of formula (I) wherein R5 or R? is a (C1-4)alkyl group;

hydroxymethylating a compound of formula I wherein D is a group of formula Ia and R5 is a hydrogen atom to yield a compound of formula I wherein R5 is hydroxymethylene; isolating the lndlvldual tautomers of compounds of formula I; isolating the free compound of formula I from its salt; reacting a compound of formula I to yield a pharmaceutically acceptable salt thereof.

57. A compound of formula II

(II) (wherein A, R1, R2, R3, R6, R7, R11, R12 and m are as defined in claim 1, 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 R5 represents a hydrogen atom or a (C1-4)alkyl group), or a physiologically acceptable salt thereof.

58. A process for the preparation of a compound of formula II as claimed in claim 57 which comprises cyclizing the corres-ponding malonic acid diamide of formula IIIa (III) (wherein R5 is hydrogen, R1, R2, R3, R6, R7, R11 and R12 are defined as in claim 57, 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.

59. The use of a compound of formula I as claimed in any one of claims 1 to 3, 10 to 12, 15 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53 or a compound of formula II as defined in claim 57, or a physiologically acceptable salt or salts thereof in the treatment of coronary heart disease and/or acute myocardial infarction, and/or in cardio- and/or cerebroproteation.

60. A commercial package containing as active pharmaceutical ingredient a compound of formula I (as defined in any one of claims 1 to 3, 10 to 12, 15 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53) or a compound of formula II (as defined in claim 57) or a physiologically acceptable salt thereof, together with insinuations for the use thereof for the treatment of coronary heart disease and/or acute myocardial infarction and/or for use in cardio- and/or cerebroprotection.

61. A process for the manufacture of a therapeutic agent for use in the treatment of coronary heart disease, and/or acute myocardial infarction and/or for use in cardio- and/or cerebro-protection, which process comprises admixing a compound of formula I as claimed in any one of claims 1 to 3, 10 to 12, 15 to 20, 22 to 26, 29, 32, 33, 35 to 37, 41, 45 and 47 to 53 or a compound of formula II as claimed in claim 57, or a physiologically acceptable salt thereof, with at least one pharmaceutical carrier or excipient.