CA1262545A - Imidazo-isoquinoline and imidazo-thienopyridine compounds - Google Patents

Abstract

Astract Compounds of general formula I
(A, R5 and R being described in detail in the specification) and acid addition salts thereof are suitable for use as pharmaceutical substances, particularly in cardioprotective pharmaceutical preparations.

Description

~ e and imidaz -thienopyridine comPounds The invention relates to new imidazo-isoquinoline and imidazo-thienopyridine compoundls, as well as to processes for their preparation and pharmaceutical compositions containing them.
GB-A-1594907 describes compounds o~ general formula (A) .
RO

RO ~ ~ Y (A) A B

wherein, for example, R represents hydrogen or Cl_4 alkyl, Y represents alkyl~
8 represents a lone pair of electrons and A is nitrile or carbamoyl.
According to the description in GB-A-1594907 these compounds are effective as strong broncho-; 15 dilating agents and may therefore be used ~as active ~ substances or antiasthmatic pharmaceutical prepara-- ~ tions. However compounds in which Y represents alkyl, A represents carbamoyl and B represents a lone pair of electrons are neither men~ioned nor exemplified.
It has now been found that cer~ain imidazo-,, ~- isoquinolines an~ imidazo-thienopyridines possess pharmacologically interesting cardioprotective ~properties.

~, :~ , 5~5 Thus according to one aspect of the invention we provide compounds of general formula (I3 ~ ~ ~ 5 (I) and the acid addition salts thereof, wherein A represents a group which, together wi~h the 2 carbon atoms of the pyridyl system to which it is bonded, forms-a mono- or polysubstituted phenyl group or a mono- or polysubstituted thieno group, the substituent or substituents being selected from Cl 3 alkoxy, hydroxy and methanesulphonyloxy groups;

R5 represents a Cl ~ alkyl group; and R represents (i) a hydroxy group;
: : 15 (ii) a saturated or unsaturated, branched or unbranched Cl 5 alkoxy group;
(iii) a group -NRlR2, wherein Rl and R2 in p dently of each other represent . a~ a hydrogen atom;
b) a saturated or unsaturated, branched or unbranched Cl 8 hydrocarbon moiety ~optionally mono- or polysubstituted : : by halogen atoms or by hydroxy, methoxy, amino, methylamino, anilino, dimethylamino, ~:~ : 25 ~ C3 7 cycloalkyl or phenyl groups (said phenyl groups optionally being mono-: : or polysubstituted by halogen atoms ~; or methoxy groups~ or ~y a heterocyclic ~: :: 5- to 7-membered ring which contains ~ :
~,:
, ~ ''"' ~ Z~25~5 one or two identical or different hetero-atoms selected from N~ S and O and which is optionally substituted by a ~Cl 3) alkyl group);
c) a C3 7 cycloalkyl group;
d) a phenyl group, optionally mono or polysubstituted by halogen atoms or methoxy groups;
e~ a heterocyclic 5-7 membered ring which contains one or two identical or different heteroatoms selected from N, S and O;
f) an amino group substituted by a heterocyclic 5-7 membered ring which contains one or two identical or different heteroatoms selected ~rom N, S and O, said ring optionally being mono-or polysubstituted by halogen atoms;
or Rl and R2 together with the nitrogen :~ 20 atom to which they are both attached ~: form a 5- or 6-membered ring which optionally contains an oxygen atom :~ or a further nitrogen atom as a ring heteroatom and which ring may be substi-tuted by a 5 or 6 membered homocyclic .
: or heterocyclic ring, which, when hetero-~: cyclic, contains one or two identical or different heteroatoms selected from N, S and O.
:
The term "halogen" indicates a fluorine, chlorine, bromine or iodine atom.
The preferred compounds are compounds of general formula (II) :
, , ~ '; , .
' :

,. - ,: .

'a45 R~ CH~ (II) wherein R3 and R4 independently of each other represent hydrogen atoms or hydroxy, methoxy or methanesul~honyl oxy groups and R-is as hereinbefore defined, and the acid addition salts thereof.
In the compounds of general formula (II) the following combinations of R3 and ~4 are preferred:

R3 = R4 = methoxy ~10 R3 = methoxy, R4 = hydroxy or vice versa, :~R3 = methoxy, R4 = methanesulphonyloxy or vice versa, R3 = methoxy, R4 = hydrogen or vice versa~

Particular mention should also be made of compounds of general formulae (III) and ~IV) S

~ ~ CH~ (IIIj :
: ~ R ~ L --N

CH3 (IV) R-~ N

~: :

, , and the acid addition salts thereof.
If R in formula (I) is a Cl_5 alkoxy group or a -~RlR2 group, this is preferably methoxy~
ethoxy or an -NR1R2 group wherein:

Rl = a hydrogen atom, and R2 = a Cl 5 alkyl, C3_s alkenyl~ C3_5 alkynYl~
C3 h cycloalkyl ~Cl 5) alkyl or C3 6 cycloalkyl group, e.g.: a methylS ethyl, n-propyl, n-butyl, n-pentyl, isopropyl~ isobutyl, isopentyl, allyl, propynyl, cyclopropyl, cyclohexyl or cyclohexylmethyl group;

or R1 and R2 éach represent a Cl 2 alkyl group;
or Rl = a hydrogen atom, and R2 = a C~ 5 alkyl group substituted by a) an unsaturated heterocyclic 5 or 6 membered ring containing at least one heteroatom selected from among N, S and O, e.g. thienyl, imidazoly], furyl or pyridinyl; or b) a saturated heterocyclic 5- or 6-membered ; ring having a nitrogen atom as a ring hetroatomr said nitrogen atom optionally being substituted by a methyl group, said ring also optionally containing an O atom as a further heteroatomt e.g. morpholinyl, pyrrolidinyl or N-methyl-pyrrolidin-2-yl;

or Rl = a hydrogen atom, R2 = a phenyl or halophenyl group, e.g.
4-fluorophenyl or 3-chlorophenyl, or Rl = a hydrogen atom, R2 = a Cl_5 alkyl group substituted by a halogen atom or a C1_2 alkoxy, hydroxy, di(Cl 2 alkyl) amino or anilino group, e.g. a methoxy (C2 or C3~ alkyl, 2-hydroxyethyl, 3-hydroxy-` .' . :

n-propyl, 2-chloroethyl, 3-chloro-n-propyl,

2-dimethylamino-ethyl, 2-anillno-ethyl or

3-dimethylamino-n-propyl group;

or Rl = a hydrogen atom R2 = an unsaturated heterocyclic 5 or 6 membered ring which contains one or two identical or different heteroatoms selected from N, S or O;

or Rl and R2 together with the nitrogen atom to which they are both attached form a piperazine group which is substituted by a heterocyclic 6-membered ring ccntaining one or two N atoms, e~g.

4-(2-pyridillyl)-piperazinyl, 4-(2-pyrazinyl)-piperazinyl or lS 4-(2-pyrimidinyl)-piperazinyl;
or ` Rl and R2 together with the nitrogen atom to which : they are both attached form a saturated heterocyclic

5 or 6 membered ring which optionally contains an N or O atom as further heteroatom.

Thus the class of compounds within formula (I) as defined above corresponding to formula (VIII) b (VIII) and the acid addition salts thereof, wherein R3' : 25 and ~4' independently of each other represent hydroxy , ,' , , , ~: .

~ _ 7 _ or methoxy groups and R5 is a Cl 4 alkyl group, Eall within general formula (A) above of GB-A-1594907 although no compounds of formula (VIII) are disclosed specifically by Gs A-1594907.
The compounds of formula (VIII) are effective in the treatment of the indications mentioned herein-below. There is no suggest-on in Gs-A-l5949o7 of any pharmacological activity for the compounds of formula (A) other than as bronch~lytics, and the cardioprotective and other properties of the compounds of the present invention are thus surprisinq~
The compounds according to the invention have a significant cardioprotective activity.
~s is well known; the myocardiac Ca2~ content is a measurement of hypoxic heart damage or heart damage caused by toxic catecholamine doses (Higgins et. al. Mol. Cell, Cardiol. 10, 427-438, 1984;
Nakanischi et. al. Am. J. Physiol. 242, 437-439, 1982, Fleckenstein A., Vortrage der Erlanger Physiol.
Tagung 1970, Edit. Keidel, Springer Verlag, Berlin, Heidelberg, New York, 1971). Conversely, the inhibition of hypoxic or isoprenalin-induced myocardiac calcium uptake is a measurement of the cardioprotective effectiveness of calcium antagonists (Fleckenstein, see above), of calmodulin inhibitors (Higgins loc.
cit~) and other drugs, e.g. ~-andrenolytics (Arndts, Arzneimittelforschung 25, 1279-1284, 1975).
The card;oprotective activity of the compounds according to the invention was tested on conscious rats after subcutaneous or oral administration of the active substance using the me~hod described by Arndts (loc. cit.) and the degree of activity of the test subs~ance was calculated as the H50 value; this value corresponds to the dosage which results in a 50~ inhibition in the m~ocardiac radio-calcium uptake induced by the administration of 30 mg/kg s.c. of isoprenalin.

, ' -~
.
:: : , . .

5'~

The new compounds tested proved to be upto five times more effective than the known commercial product propranolol.
In vitro tests on smooth muscle (strips of aorta) showed that the compounds according to the invention are calcium antagonists with a new mechanism of activity.
In view of these findings, the compounds of general formula ~I~ or the acid addition salts thereof should be effective as active substances in drugs to combat coronary diseases, particularly angina pectoris or to improve the ischaemia tolerance in the myocardium.
In addition, the substances according to the ;nvention promote blood flow through the tissues and aid the ox~gen supply to the tissues, particularly in the central ner~ous system. In tests ;n which the short-term memory is restricted by the admini~
stration of the muscarinic-cholinergic antagonist scopolamine (0.6 mg/kg i.p., Psychopharmacology 78, page 104 111 (1982)) the compounds are capable of counteracting or remedying this pharmacologically induced cerebral insufficiency.
Thus according to a further aspect of the invention we provide a me~hod of treatment of coronary disease or conditions of restricted cerebral perfor-mance, which comprises administering to a human or non-human animal subject an effeetive amount of a compound of general formula (I) as herein defined or a phys;ologically acceptable acid addition salt thereof.
In tests on the survival of animals in a sealed chamber (hypoxia tolerance test) through which a m;xture consisting of 96.5~ nitrogen and 3.5~ oxygen was passed, the animals which had been previously treated with the substances according to the invention sho~ed a statistieally highly . ~
.
-' ~2~ 5 g significant increase in survival compared withcontrol animals or animals which had been pretreated with diltiazem, verapamil or nifedipine.
The protective effect of these substances on the brain tested by this method was marked even at a dosage of 5 mg/kg p.o. Thus, the compounds according to the invention are clea~rly superior to the known substances mentioned both in terms of the effective dose and also in the improvement in performance achieved in animal experiments.
In view of these findinys, the compounds of general formula ~I) and the acid addition salts thereof are suitable as active substances for pharma-ceutical compositions to treat cerebral metabolic disorders or organic brain psychosyndromes as well as post-traumatic and alcoholic brain damage.
Thus according to a yet further aspect Oe the invention we provide a pharmaceutical composition containing as active substance at least one compound ~ 20 of general formula (I) as herein defined or a physio-i logically acceptable acid addition sàlt thereof.
The new compounds may be administered on their own or in conjunction with other active sub-stances according to the invention, optionally in combination with other pharmacologically active substances, e.g. other cerebroactivators. Suitable forms for admin;stration include tablets, capsules, suppositories, solutions, syrups, emulsions and dispersible powders. Tablets may be produced, for example, by mixing the active substance or substances with known excipients, e~g. inert diluents such as calc;um carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic -~ acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for obtaining delayed release such as carboxypoly-~ ' , .' ` ' , : ;
:: ' ~. .

s methylene, carboxymethylcellulose, cellulose acetate-phthalate or polyvinylacetate. The tablets may also consist of several layers.
Coated tablets may be produced accordingly by coating cores prepared analogously to the tablets with the agents conventionally used for tablet coatings, e.g. collidone or shellac, gum arabic, ; talc, titanium dioxide or sugar~ To obtain delayed release or avoid incompatibilities, the core may also consist of several layers. Similarly, the tablet coating may consist of several layers in order to obtain delayed release, using the active substances mentioned above for the tablets.
Syrups of the active substances or combinations of active substances according to the invention may additionally contain a sweetener such as saccharin, cyclamate, glycerol or sugar and a ~lavour-improving agent, e.g. flavourings such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents, e.g. condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxyben~oates.
In~ection solutions may be prepared in the usual way, e.g. by adding preservatives, such as p-hydroxybenzoa~es, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid and then transferred into injection vials or ampoules~
Capsules containing one or more active substances or combinations of active substances may be produced~
~ for example, by mixing the active substances with ;; inert vehicles such as lactose or sorbitol and encapsulating the mix~ure in ~elatine capsules.
Suitable suppos;tories may be produced by 3S mixing with the appropriate vehicles such as neutral fats or polyethylene glycol or derivatives thereof.
The compounds may be administered by both enteral and parenteral routes. The proposed dosage ~ `

for oral administration is from O.l to lO mg/kg, pre~erably from 0.2 to 0O5 mg/kg o active substance per dosage, whilst for parenteral administration it is from O.Ol to 0.5 mg/kg, preferably 0.05 to 0.2 mg/kg.
The compounds according to the invention may be prepared by various methods as described below, which form a yet still further aspect of the invention:
Process A
(to prepare compounds of general formula (I) wherein R does not represent -N~2~.
A compound of qeneral formula (V) O O
Il 11 Ar-CH2(~H2-NII-C-C~EI-C-R (V) F~N-~-R5 o (wherein ~r represents an unsubstitu~ed or a mono-or polysubstituted phenyl group or an unsubstituted or mono- or disubstituted thieno group, with the proviso that the phenyl or thieno group possesses a -CH= group adjacent to the point of attachment, i.e. possesses an ~ hydrogen atom, and the or each substituent is selected from Cl 3 alkoxy, hydroxy and methylsulphonyloxy groups, and R and R5 are as hereinbefore defined1, is cyclised, convenien-tly in the presence of a condensing agent.
Suitable condensing agents incIude Lewis acids such as phosphorus oxychloride, phosphorus pentachlorider tin tetrachloride and also inorqanic acids such as polyphosphoric acid, siloxane-polyphos-; phoric acid mixtures or solutions of p2Os in methane-sulphonic acid. They are generally used in excess.
Preferred condensing aqents are phosphorus oxychloride, :

'~. " -.

,, , ~ ~2~;~5 polyphosphoric acid and methanesulphonic acid/P2O5 mixtures containing about lO~ by weight of P2O5.
The cyclisation may be effected 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, e.g. benzene, alkyl benzenes, chloroform, methylene chloride and acetonitrile.
If desired, the condens;ng agent, e.g. phosphorus oxychloride, polyphosphoric acid or a methanesulphonic acid/P2O5 mixture, may be used as solvent.
The reaction may be carried out within a wide temperature ~ange, preferably with heating up to about the boiling point of the solvent.
].5 Process B
(to prepare compounds o general ormula (I) wherein R is -NRlR2).

A compound of general formula (VI) ~ ~ ~ (VI~

(wherein R5 and A are as hereinbefore defined) or a Cl 5 alkyl ester or an activated derivative thereof is reacted with a compound of general formula (VII) HNRlR2 (VII) ~' (wherein Rl and R~ are as hereinbefore defined).
Examples of suitable activated derivatives of the comPound of formula Vl include ncid halides, azides or mixed anhydrides (e.g~ with an aromatic or aliphatic carboxylic acid, alkyl carbonic acid or dialkylphosphoric acid, etc.~, also amides (for example with imidazole, 4~substituted im;dazole, dimethylpyrazole, triazole or tetrazole), or activated esters, e.g. cyanomethyl, methoxymethyl, vinyl, propargyl or p-nitrophenyl esters or esters with, for example, dimethylhydroxylamine, l-hydroxysuccin-imide or dicyclohexylurea. The active imidazolides and the Cl 5 alkyl esters are preferred.
The amide formation is generally carried out in an inert solvent such as dioxan, acetonitrile, dimethylformamide or a mixture of one or more solvents, optionall~ in the presence of an inorganic or organic base as acid acceptor. However, it is also possible to carry out the reaction without a solvent with an excess of the amine.
Depending on the starting materials used, the reaction temperature may vary within wide limits and may range between about 0C and the boiling temperature of the reaction mixture.
The end products of the reactions described ; above are generally bases and may be converted into acid addition salts, generally physiologically acceptable acid addition salts, in the usual way with inorganic or organic acids. If salts are obtained these can be converted into the free bases.
Acids suitable for salt formation include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, acetic, propionic, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic~ benzoic, cinnamic, ascorbic and methanesulphonic acids, etc.
~ome of the starting compounds of general ; 3~ formula (V) are new. They may be prepared by reacting a suitable reactive derivat;ve o~ an N-acylamino-malonic acid with a correspondinq amine or, on .

25~5 ~ 14 -the other hand, first a monoamide of the corresponding N-acylamino malonic acid is prepared and this is reacted with another amine to form a diamide of general formula (V) either as ;t is or after being converted into an active form.
The N-acyl-malon;c acid derivatives of general formula (V) may be prepared using the same methods as those described hereinbefore for preparing the carboxamides of ~eneral formula ~
Again, methods involving the use of active imidazolides are preferred.
The invention is further illustrated by the following non-limiting Examples in which percentages and ratios are by weight unless otherwise indicated:

, ~ .

;
., s~

_xample 1 Ethyl 5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-carboxylate 50 g of ethyl 2-(3,4-dimethoxyphenyl)-ethylamino carbonyl-N-acetyl-glycine are added with stirring to 100 g of a methanesulphonic acid/P2O5 mixture (100:10), previously heated to 100C, and left at about 120C for 30 minutes. After the reaction has ended the reaction mixture is successively poured onto ice, neutralised with sodium carbonate solution, extracted with CH2C12~ dried over Na2SO4, concentrated by evaporation to about 50 ml, mixed with ethanolic hydrochloric acid and the hydrochloride (m.p. 214C) is precipitated with the addition of diethylether.
Yield: 38.2 g (85% of theory) Example 2 5,6-Dihy~ro-8,9-dimethoxy-3-methyl-imidazo-~1,5-a~-isoquinoline l-carboxylic acid 25.9 ~ of ethyl S,6-dihydro-8,9-dimethoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-carboxylate are saponified in a solution of 5~0 g of KOH in ethanol at about 60C. After the reaction has ended the reaction mixture is successively neutralised with ethanolic HCl, cooled to 0C, suction filtered to remove precipitated KCl and the filtrate is ` evaporated. The resulting hydrochloride (m.p.
214C) is crystallised from ethanol.
Yield: 22.6 g (96~ of theory) -~2~

Example 3 5,6-Dihydro-8,9-dimethoxy-3-methyl-imidazo-~1,5-a~-isoquinoline-l-(N-methyl)-carboxamide : 5 V iant _ A mixture of 10 g of 2-(3,4-dimethoxyphenyll-ethylamino-carbonyl-N-acetyl-glycine N-methylamide, 100 g of acetonitrile and 30 ml of phosphorus oxychloride is refluxed for 1 to 2 hours. After the reaction has ended the reaction mixture is concentrated by evaporation in vacuo, made alkaline with saturated soda solution, the reaction product is isolated in the usual way, purified on silica gel (CH2C12:MeOH
100:5) and crystallised in the form of the hydrochloride (m.p. 208C) from ethanol.
Yield: 4.2 g (40% of theory) Variant B
A mixture of 16 g of 2-(3,4-dimethoxyphenyl)-ethylaminocarbonyl-N-acetylglycine-N-methylamide and 60 g of polyphosphoric acid is heated to 130C
for about half an hour. After the reaction has ended the reaction mixture is left to cool to ambient temperature, poured onto ice and made alkaline with concentrated NH3 solution. The reaction product is isolated by shaking with CH2C12, purified over silica gel (eluent: CH2C12/MeQH, 100:5~ and converted into the hydrochloride (m.p. 208-209C).
Yield: 7.2 g ~50% of theory) Variant C
5 g of 5,6-dihydro-8,9 dimethoxy-3~methyl-imidazo-~1,5-a]-isoquinoline-1-carboxylic acid : 35 hydrochloride are stirred in 40 ml of anhydrous dimethylformamide at ambient temperature with 3.1 g of N,N'-carbonyldiimidazole for 30 minutes and 5~5 then mixed with 10 ml of a saturated solution of methylamine in CHC13. The resulting solution is stirred for 1 hour, the solvent is drawn off in vacuo, the product is distributed b~etween CH2C12 and water and the organic phase is dried over Na2SO~
and concentrated by evaporation in vacuo. In order to form the hydrochloride, the residue is dissolved in a little anhydrous ethanol, mixed with ethanolic hydrochloric acid and then the hydrochloride (m.p.
209C) is crystallised by the addition of ether.
Yield 5.4 g (93% of theory~

Variant D
10 g of methyl 5,6-dihydro-8,9 dimethoxy-3 methyl-lmidazo-[1,5-a]-isoquinoline carboxylate are st;rred ;n 200 ml o~ a chloroform solution saturatecl with methylamine or 24 hours at ambient temperature. When the reaction has ended the reaction mixture is evaporated in vacuo and the reaction product is converted into the hydrochloride (m.p.
208C).
Yield: 8.0 g (81~ of theor~).

The following end products were also syntheslsed analogously to the methods given in Examples 1 to 3:

'' '' ;.. ;, 5~5 Table 1 ~ CH . HCl ; CH~ ~ ~ 3 R-C

Example R MpC Yield ~ of theory -NH2 215 ~ 85

6 -NHC2H5 . 180-183 79

7 -NH(CH2)2-CH3 219-222 6a ; -NH(CH2)3-CH3 212-214 70 9 -NH(CH2)4CH3 204 71 -NH-CH(C~3)2 >250 66 11 -NH-CH2-CH(CH3)2 : 228-229 64 12 -NH(cH2~2-ca(cH3)2 208-220 71 ,~ :

.
: ., - . .

S4~

Example R MpC Yield % of theory 14 -NHCH2C_C~ 189 57 -NH-CH2-~ 239-241 61 16 -NHCH2-O . 228-230 72 17 -NH-~ 208-210 69 18 -NH~ 237-238 61 19 -tlH~(CH2)20CH3 219-224 74 -N~- (CH2) 30C~3 Z03 67 21 ( 2) 2 155 68 ...
22 -NH(cH2)3-oH. 164-165 S4 ` 23 -NH~CH2)2C1 217 46 : 24 -NH~cH2)3cl 218 43 , ~ 25 -NH(CH2)Z-N(CH3)2 215 68 26 -NH(CHZ)2-NH-~ 214 63 :~ :
: 27 -NH(CHz)2-~ 239-240 70 Z8 -NH-CH2-~ 226 73 : ; 29 -N~-(CHz)2~ Z70-273 68 `

s~s Example R MpC Yield % of theory -NH-~C~2)2- ~ 244-246 ~3 31 -NH-(CH2)2- ~ 155 (Decomposed) 64 32~ -NH-(CH2)2-N ~ 96 67 33 -NH-CH2 ~ 221 63 34 -NH ~ 176-179 59 -NH ~ F 242-243 67 36 ~ Cl 212 ~eco~posecl) 70 37 -N(CH3)2 244-246 59 38 -N ~ 228-230 53 . 39 -N ~ 262-263 55 ; ~40 -NH(CH2~3-N(CH3)2 239-241 67 41 -N ~ ~ 175 63 42 -N ~ ~ 153-154 65 : 43 -N ~ ~ 210-212 r 67 44 -NH- ~ : Z60 56 -NH-~H- ~ -Cl 219-220 57 , N.N
* The compound of Example 32 ~was obtained as a ree base~ M.p. and yie~ld apply to the base.
: ~ -,: ~

~ ~ .

~ ~2~15 Table 2 __ 3 ~
H0 /~ CH~; . HCl Bxample R M pC Yield ~
of theory 46 -OC2~5 238-239 62 47 -~H-(CH2)2-OCH3 >250 59 48 -NH(CH2)2~3 >250 61 ' :

' :

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

5~5 _ 22 _ Table 3 CH30~ CH3 . HCI

.

Example R MpC Yield % of theory 49 -NK-(CH~) ~OCH3 l9q-199 56 ;
;
' :

:
:
'`

"

~ - 23 -Table 4 .

C~30 ~

H~C02S0 ~ ~ `I ~ _CH3 . HCl Example - R MpC Yield %
of theor~

-OC2~5 Z10-211 67 , .

Table S
::
' CH30 ~ H3 ~':

. . .
~ , ~

~ ~Z~i45 Example R MpC Yield ~
of theory 51 2 5 201-203 ~7 ~ -N~-(CH2)~- ~ 148-149 65 52(a) ~NHC~2CH(CH3)2 184-1~6 --__ Table 6 N ~ CH3 . HCl R~

~, .

Example R MpC Yield ~
of theory : : 54 -NH(cH2)2ocH3 156-15~ : 63 '' ~

~, :

.

.. . .. .....
; : .. ~ . -.

. ~

i2~

Table 7 R-Example E'~ M'p. C Y:ield 9~
o:E theory -OC2~5 20~-210 67 5 6 ( 2 ) 2 3 2 0 ~ 6 2 57 -NH(CH2 ) ;~3 >250 61 58 -NH(CH2)z~ 245-ZS0 58 59 -NM-CH2-CH=CH2 274 73 -NH-(CH2)2~7 226 229 75 ;;.. :.

.'~, ;

- , ~6;~5~5 Examples of pharmaceutical formulations a) Tablets per tablet Active substance 25 mg Lactose 140 mg 5 Corn starch 240 mg Polyvinylpyrrolidone 15 mg Magnesium stearate ~
425 mg The finely ground active substance, lactose and some of the corn starch are mixed together.
The mixture is screened then moistened with a solution of polyvinylpyrrolidone in water, kneaded, granulated whilst wet and drled. The granulate, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to form tablets o~E suitable size and shape.

b) Tablets per tablet Active substance 15 mg Corn starch 190 mg 20 Lactose 55 mg Microcrystalline cellulose 35 mg Polyvinylpyrrolidone 15 mg Sodium carboxymethyl starch 23 mg Magnesium stearate 3 mg 335 mg The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and combined with the remaining corn starch and water to form a granulate which is dried and screened. The sodium carboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form . ~ .

2~5 tablets of sui.table size.

c) Ampoules Active substance 10.0 mg 5 Sodium chloride lO.O mg Doubly distilled water q.s. acl 1.0 ml The active substance and sodium chloride are dissolved in doubly distilled water and the solution is transferred into ampoules under sterile 10 conditions.

d) Drops Active substance 1.0 mg Methyl p-hydroxybenzoate 0.1 mg Propyl p-hydroxybenzoate 0.1 m~
15 Demineralised water q.s. ad lOO.O ml The active substance and preservatives are ; dissolved in demineralised water and the solution is filtere~ and transferred into lOO ml vials.

.

' :
: :~

, :. :
. ~ . .

,

Claims (9)

Patent Claims

1. Compounds of general formula (I) (I) and the acid addition salts thereof, wherein A represents a group which, together with the 2 carbon atoms of the pyridyl system to which it is bonded, forms a mono- or polysubstituted phenyl group or a mono- or polysubstituted thieno group, the substituent or substituents being selected from C1-3 alkoxy, hydroxy and methanesulphonyloxy groups;

R5 represents a C1-4 alkyl group; and R represents (i) a hydroxy group;
(ii) a saturated or unsaturated, branched or unbranched C1-5 alkoxy group;
(iii) a group -NR1R2, wherein R1 and R2 indepen-dently of each other represent a) a hydrogen atom;
b) a saturated or unsaturated, branched or unbranched C1-8 hydrocarbon moiety (optionally mono- or polysubstituted by halogen atoms or by hydroxy, methoxy, amino, methylamino, anilino, dimethylamino, C3-7 cycloalkyl or phenyl groups (said phenyl groups optionally being mono-or polysubstituted by halogen atoms or methoxy groups) or by a heterocyclic 5- to 7-membered ring which contains one or two identical or different hetero-atoms selected from N, S and O and which is optionally substituted by a (C1-3) alkyl group);
c) a C3-7 cycloalkyl group;
d) a phenyl group, optionally mono or polysubstituted by halogen atoms or methoxy groups;
e) a heterocyclic 5-7 membered ring which contains one or two identical or different heteroatoms selected from N, S and O;
f) an amino group substituted by a heterocyclic 5-7 membered ring which contains one or two identical or different heteroatoms selected from N, S and O, said ring optionally being mono-or polysubstituted by halogen atoms;
or R1 and R2 together with the nitrogen atom to which they are both attached form a 5- or 6-membered ring which optionally contains an oxygen atom or a further nitrogen atom as a ring heteroatom and which ring may be substi-tuted by a 5 or 6 membered homocyclic or heterocyclic ring, which, when hetero-cyclic, contains one or two identical or different heteroatoms selected from N, S and O.

2. Compounds as claimed in claim 1 of general formula (II) (II) wherein R3 and R4 independently of each other represent hydrogen atoms or hydroxy, methoxy or methanesulphonyl-oxy groups and R is as defined in claim 1, and the acid addition salts thereof.

3. Compounds as claimed in claim 2 wherein one of R3 and R4 is a methoxy group, the other being (i) a methoxy group, or (ii) a hydroxy group, or (iii) a methanesulphonyloxy group, or (iv) a hydrogen atom; and the acid addition salts thereof.

4. Compounds as claimed in claim 1 of general formula (III) or (IV) (III) (IV) wherein R is as defined in claim 1, and the acid addition salts thereof.

5. Compounds as claimed in claim 1, 2 or 3, wherein R represents methoxy or ethoxy, or a group -NR1R2 wherein R1 = a hydrogen atom, and R2 = a C1-5 alkyl, C3-5 alkenyl, C3-5 alkynyl, C3-6 cycloalkyl (C1-5) alkyl or C3-6 cycloalkyl group;
or R1 and R2 each represent a C1-2 alkyl group;

or R1 = a hydrogen atom, and R2 = a C1-5 alkyl group substituted by a) an unsaturated heterocyclic 5 or 6 membered ring containing at least one heteroatom selected from among N, S and O; or b) a saturated heterocyclic 5- or 6-membered ring having a nitrogen atom as a ring hetroatom, said nitrogen atom optionally being substituted by a methyl group, said ring also optionally containing an O atom as a further heteroatom;

or R1 = a hydrogen atom, R2 = a phenyl or halophenyl group, or R1 = a hydrogen atom, R2 = a C1-5 alkyl group substituted by ahalogen atom or a C1-2 alkoxy, hydroxy, di(C1-2 alkyl) amino or anilino group, or R1 = a hydrogen atom, R2 = an unsaturated heterocyclic 5 or 6 membered ring which contains one or two identical or different heteroatoms selected from N, S or 0, or R1 and R2 together with the nitrogen atom to which they are both attached form a piperazine group which is substituted by a heterocyclic 6-membered ring containing one or two N atoms;
or R1 and R2 together with the nitrogen atom to which they are both attached form a saturated heterocyclic 5 or 6 membered ring which optionally contains an N or O atom as further heteroatorm.

6. Compounds of general formula (I) as claimed in claim 1 being 5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-l-(N-methyl)-carboxyamide;

5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-(N-ethyl)-carboxyamide;

5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-[N-n-pentyl]-carboxyamide;

5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo[1,5-a]-isoquinoline-1-[N-(2-methoxy-ethyl)]-carboxyamide;

5,6-dihydro-8,9-dimethoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-[N-2-(4-morpholinyl)ethyl]-carboxyamide;

5,6-dihydro-8-methoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-[N-isobutyl]-carboxyamide;

ethyl 5,6-dihydro-8-methoxy-3-methyl-imidazo-[1,5-a]-isoquinoline-1-carboxylate;

5,6-dihydro-3-methyl-imidazo[1,5-a]-thieno[3,2-c]-pyridine 1-[N-(2-methoxy-ethyl)]-carboxyamide; and the acid addition salts thereof.

7. A process for the preparation of compounds as claimed in claim 1, 2 or 3, wherein A) (to prepare compounds of general formula (I) wherein R does not represent -NH2) a compound of general formula (V) (V) (wherein Ar represents an unsubstituted or a mono-or polysubstituted phenyl group or an unsubstituted or mono- or disubstituted thieno group, with the proviso that the phenyl or thieno group possesses a -CH= group adjacent to the point of attachment, and the or each substituent is selected from C1-3 alkoxy, hydroxy and methylsulphonyloxy groups, and R and R5 are as hereinbefore defined) is cyclised, B) (to prepare compounds of general formula (I) wherein R is -NR1R2) a compound of general formula (VI) (VI) (wherein R5 and A are as defined in claim 1) or a C1-5 alkylester or an activated derivative thereof is reacted with a compound of general formula (VII) HNR1R2 (VII) and if desired, C) the free base obtained is converted into an acid addition salt or a salt obtained is converted into the free base.

8. A pharmaceutical composition containing as active substance at least one compound of general formula (I) as defined in claims 1, 2 or 3 or a physiologically acceptable acid addition salt thereof.

9. The use of a compound of general formula (I), as defined in claim 1, or a physiologically acceptable acid addition salt thereof, for treatment of coronary disease or conditions of restricted cerebral performance.