FI60566B - FOERFARANDE FOER FRAMSTAELLNING AV 2H, 4H-5,6-DIHYDRO-1,2-THIAZOLO / 3,2-A / ISOKINOLINDERIVAT MED HJAERTMUSKELNS KONTRAKTILITET FOERHOEJANDE VERKAN - Google Patents

Description

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C (45) Patent granted on 10 02 1982 Patent aeddelat V v ^ (51) K ».ik.3 / Im.ci.3 C 07 D 515 / 04- FINLAND — FINLAND W) Patent application— Pitantant & knlnf 791377 ( 22) Hakumlspllvl - AntBknlngfdag 27.0U.79

(23) Alkupiivt — GlMghetsdag 29.05.7U

(41) Tullut (ulklMksI - Bllvlt offumllg 27.0U. 79

Patent and Registration Office .... ....... . ,. .....

_ __, (44) Date of issue and date of publication. -

Patent · och registerstyrelsen Anaökan utlagd och utl.skrifMn publkarad 30.10.81 (32) (33) (31) Pjrydatty «tuolta» - Baglrd priorltet 30.05-73

Hungary-Hungary (HU) CI-1381 (71) Chinoin Pharmaceuticals and Chemicals Gyära Rt., To u. 1 to 5,

Budapest IV, Hungary-Hungary (HU) (72) Kalman Harsänyi, Budapest, Kalman Takacs, Budapest, Pal Kiss, Budapest, ^ aszlg ^ Sz ^ looking for, Szeged, Gyula Papp, Szeged, Eva Benedek, Gyor, Hungary- (7U ) Oy Kolster Ab (5U) Method for the preparation of new 2H, UH-5'-dihydro-1H-thiazolo / SjP-a / isoquinoline derivatives having a myocardial contractile-enhancing effect - Förfarande för framställning av 2H, UH- 5,6-Dihydro-1,2-thiazolo [3,2-a] isoquinoline derivatives with a solid state of the net (62) Divided by application I6UU / 7U (patent 57262) -Avdelad frän trap 16UU / 7U (patent 57262)

The invention relates to a process for the preparation of novel isothiazoloquinoline compounds of formula (I)

O f] O

R -C-C ""

% Y

2 R 60566 1 2 where R and R represent hydroxy or alkoxy containing 1-1 * carbon atoms, 3. . U. 1 * R is hydrogen, cyano, carboxyl, or carbamoyl, Y is a group = N-R, wherein R is a hydrogen atom or an alkyl or benzoyl group containing 1-U carbon atoms, and salts thereof.

As can be seen from the above formula, the new compounds consist of two fused heterocyclic rings.

2H, 1 + H- (1,2) -thiazolo [3,2-a] isoquinolines have a 1,2-thiazole ring fused to an isoquinoline ring. These compounds are hereinafter briefly referred to as 1,2-thiazoloisoquinolines (isothiazoloisoquinolines). The degree of oxidation of the .... 2 carbon atoms in the 2-position is +3, so they are C-formic acid derivatives.

The invention is characterized in that the compound of formula (n>

R -C-CCT

OF

12 3.. ·. . .

wherein R, R, R and Y have the same meaning as above for oxidation with bromine or iodine, and to obtain a compound of formula (i) in which the 8- and 9-positions have a lower alkoxy group, a compound of formula (i) in which 8- and The 9-position has a hydroxy group, optionally alkylated, and to obtain a compound of formula (i) having a hydroxy group at the 8- and 9-positions from a compound of formula (i) having a lower alkoxy group at the 8- and 9-positions, the alkyl group is cleaved off if desired, and to obtain a compound of formula (i) having a carbamoyl or carboxyl group in the 1-position, a compound of formula (I) having a cyano group in the 1-position is optionally hydrolyzed to give a compound of formula (i) to obtain a compound in the 2-position = N-benzoyl, acylating a compound of the formula I in which the 2-position has an imino group, if desired, and to obtain a compound of the formula (i) in which the 2-position has = N-alkyl, a compound of formula (I) wherein 2-a the compound of formula (I) is converted to a salt, if desired, or a salt of a compound of formula (I) is converted to the free base, if desired.

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In particular, the compounds of the general formula (i) of the invention can be used as medicaments. Of note is the beneficial effect of these compounds on myocardium, small blood circulation, and myocardial oxygen consumption. The toxicity of the compounds is low. Some members of the group of compounds of the invention may also be used as cardiac drugs. Other compounds of the invention may be used as respiratory enhancers.

The starting materials of the formula II are preferably prepared starting from the isoquinoline of the formula

2 I * 2 ^ L · N

R NH R

·? R-CH-halogen i.e. a compound having a halogen-substituted side chain in the 1-position of the isoquinoline ring. This compound is reacted with a corresponding sulfur-containing carbonic acid derivative.

As can be seen from the formula, the compounds III can exist in at least two tautomeric forms.

Suitable compounds of the formula (III) are, in particular, compounds having a bromine-substituted side chain which can be easily prepared by bromination of the correspondingly substituted 1-methylene-1,2,3,4-tetrahydroisoquinolines. In many cases, it is preferable to treat the resulting isoquinoline having a bromine-substituted side chain without isolating the compound from the reaction mixture.

Reaction of an isoquinoline of formula (III) with a sulfur-containing carbonic acid derivative gives isoquinolines of formula (II) in one or more steps.

It is also possible to start from isoquinoline of the formula trp - γγ'ϊ <··

R i / VyN

R “CH R ^ -CH ^ ** 6 O 5 6 6 k ...

wherein R is hydrogen, lower alkyl, aryl, cyano, carboxyl, carboxylic halide or carboxylic amide. When such a compound is reacted with a sulfur-containing carbonic acid derivative, sulfur-containing compounds of formula (II) are obtained, possibly in several steps.

For example, a compound of formula (IV) may be reacted with benzoyl isothiocyanate. In this case, an isoquinoline is formed which is substituted in the ring by an N-benzoylimino group, from which the benzoyl group can be removed by hydrolysis, if desired. From these intermediates, 1,2-thiazoloisoquinolines can be prepared which have an imino group or a = N-benzoyl group in the 2-position in the fused ring system.

The benzoyl isothiocyanate reaction is preferably carried out in acetone, a chlorinated solvent, a ketone, a nitrile having a low number of carbon atoms or an ether.

In one embodiment, the preparation of the starting materials of formula (II) .... The starting material is a compound of formula (IV) wherein R is a cyano group and which is reacted with hydrogen sulphide to give a thiocarbamoyl-substituted compound of formula (II) which is obtained by oxidation of the corresponding 1,2-thiazoloisoquinoline. The reaction is preferably carried out by introducing gaseous hydrogen sulfide into the system in the presence of a basic substance such as triethylamine, piperidine, but preferably pyridine, at a temperature of 0 to 50 ° C. The incorporation of hydrogen sulfide can be accelerated by performing the operation at high temperatures in a closed vessel.

When a compound of formula (IV) is reacted with ethylmagnesium bromide, trans-grignardization occurs. The reaction liberates ethane, which is removed from the reaction mixture by heating. The reaction is conveniently carried out in toluene containing a small amount of ether. If the obtained compound is reacted with hydrogen sulfide, a compound of formula (II) is also obtained, and in particular a compound whose side chain is substituted by a dithiocarboxy group.

Reaction of a compound of formula (IV) having a side chain substituted with carbonyl chloride with sodium hydrogen sulfide provides a compound of formula (II) 3 wherein R is hydrogen and Y is oxygen.

According to the invention, the isoquinolines of the formula (II) are prepared by oxidizing 1,2-thiazoloisoquinolines.

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The oxidation is conveniently carried out with bromine or iodine in the presence of an acid-receiving agent such as pyridine, quinoline, picoline, lutidine and the like. The reaction temperature is generally about 50 ° C.

It will be apparent to one skilled in the art that the carbonic acid derivatives used to prepare the starting materials will be selected so as to directly obtain the desired substituents on the resulting 1,2-thiazole ring.

The hydroxy group in the 8-position and the 9-position, respectively, can then be alkylated, respectively the alkoxy group can be converted into a hydroxy group. Hydrogen halide, pyridine hydrochloride or the like can be used to break the ether bond. The alkoxy group can be obtained in the presence of an acid-receiving agent by means of the corresponding alkyl halide or sulfate. The alkyl group then contains 1-1 »carbon atoms.

A thiazoloisoquinoline having a cyano, carbamoyl or carboalkoxy group in the 1-position can be converted to the corresponding derivative having a carboxyl group in the 1-position.

The nitrile group in the 1-position can be converted to an acid amide or carboxyl group by treatment with an acid. The nitrile group, in turn, can be converted to the acid amide with concentrated acids, for example sulfuric acid or polyphosphoric acid, as well as alkaline hydrogen peroxide. Sulfuric acid is used above all. The nitrile group in the 1-position can also be converted to a carboxyl group by treatment with a base. The nitrile group can be converted to a carbalkoxy group by acid catalyzed alcoholysis. The acid amide group can be converted to a nitrile group with phosphorus pentoxide, phosphorus oxychloride or thionyl chloride.

Oxidation with potassium permanganate of a compound having a methyl group in the 1-position can give the corresponding carboxyl-substituted compound. The carboxyl group at the 1-position of the fusion compound can be protonated catalytically with alcohol or decarboxylated by heating.

The imino-substituted compound in the 2-position of the fused ring system can be alkylated with conventional alkylating agents, conveniently by adding a strong base and forming a salt. For example, sodium alcoholate, amide, hydride can be used. The N-position can be acylated in pyridine, for example, with various acylating agents, such as carboxylic acid chlorides, aryl or alkylsulfonic acid chlorides. The acyl group having 1 to 7 carbon atoms can be cleaved from the acyl-substituted imino group in the 1-position of the isothiazoloisoquinoline by acid hydrolysis.

Reaction of the fusion compound contained in the imino group with an amine salt gives the corresponding N-substituted derivative. This reaction is preferably carried out in dimethylformamide at the boiling point of the solvent.

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The bases of formula (i) may be converted into their salts with acids, for example hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, rhodanoic acid, propionic acid, lactic acid, malic acid, citric acid, succinic acid, succinic acid, maleic acid, ethanolic acid, fumaric acid, fumaric acid, salts with polyhydric acids.

The compounds of general formula (i) can be prepared in a known manner and, if appropriate, after the addition of customary carriers and excipients, into tablets, granules, suppositories, capsules, solutions, powders or injectable solutions.

The invention is further illustrated by the following examples:

Example 1 1-Cyano-2-imino-2H, 1 + H-5,6-dihydro-8,9-dimethoxy-1,2-thiazolo [3,2-a] nitrooline hydrobromide

Dissolve 1 g of (0.005 mol) of 1- (c <-thiocarbamoyl) -cyanomethylene-1,2,3,4-tetrahydro-6, T-dimethoxyisoquinoline in 25 ml of anhydrous pyridine and add dropwise 30-1 + 0 ° At C 0.8 g (0.01 mol) of bromine as a solution in methanol. The reaction mixture is stirred for one hour and cooled to room temperature. The precipitate is filtered to give 1.1 g of 1-cyano-2-imino-2H, 1 + H-5,6-dihydro-8,9-dimethoxy-1,2-thiazolo [3,2-a] isoquinoline hydrobromide. Crystallized from 50- $ ethanol, m.p. 276-2770C, decomp.

Analysis C 1 H 2 N 2 O 2 BrS (molar weight = 368.26)

Calculated:% C 1 + 5.65 H 3.86 N 11.1 + 1 Br 21.97 S 8.71 Found:% C 1 + 5.88 H 3.78 N 11.66 Br 22.05 S 9 , 02.

Example 2 2-Imino-2H, 1 + H-5,6-dihydro-8,9-dimethoxy-1,2-thiazolo [3,2-a] isoquinoline hydrobromide

To a solution of 1.32 g (0.005 mol) of 1- (6,7-dimethoxy-3,1 + -dihydro-1-isoquinolyl) thioacetamide and 25 ml of pyridine at a temperature of 28-30 ° C is added dropwise a solution of 0 , 8 g (0.01 mol) of bromine and 5 ml of methanol. The reaction mixture is stirred for a further hour at this temperature, evaporated to dryness in vacuo and the residue is crystallized from anhydrous ethanol. 8.0 g of 2-imino-2H, 1 + H-5,6-dihydro-8,9-dimethoxy-1,2-thiazolo [3,4-b] isoquinoline hydrobromide are obtained. The product melts with decomposition at 191 + -195 ° C.

Analysis C 1 H 2 N 2 O 2 • BrS (molar weight = 31 + 2.23)

Calculated:% C 1 + 5.35 H 1+, 2 N 8.1 Br 23.1 + 5 S 9, 5 Found:% C 1 + 5.62 H 1 +, 12 N 8, 18 Br 23.31 + S 9.36.

The starting thioic acid amide is prepared as follows: 7 60566

To a solution of 11.5 g (0.05 moles) of 1-cyanomethylene-6,7-dimethoxy-1,2,3, H-tetrahydroisoquinoline and 5.05 g (0.05 moles) of triethylamine in 1 ml of pyridine, 3.75 g of hydrogen sulfide are passed, and the resulting reaction mixture is placed in a metal bomb tube. The bomb tube is heated in an oil bath at 100 ° C for six hours. The reaction mixture is poured into water with stirring and the separated yellowish-white crystals are filtered off. 11.2 g of oC- (6,7-dimethoxy-7, t-dihydro-1-inquinolyl) -thioacetamide are obtained, m.p. 205-206 ° C (recrystallized from nitromethane).

Analysis for C 13 H 15 N 2 O 2 S (mol * Weight = 26a, 35)

Calculated:% C 59.06 H 6.10 N 10.52 S 12.13 Found:% C 59.15 H 6.12 N 10.50 S 12.05.

Example 3 1-Cyano-2H, 1H-5,6-dihydro-2-N-benzoylamino-8,9-dimethoxy-1,2-thiazolo [3,2-b] isoquinoline hydrobromide 3.93 g (o, 01 moles) ° C-Cyano-3,1 + -dihydro-6,7-dimethoxy-isoquinolin-1-ylthio-N-benzoylamide acetamide is heated in a boiling water bath in 50 ml of acetic acid with stirring. After the mixture has cooled to 80 [deg.] C., 6.28 g (0.025 mol) of bromine dissolved in 25 ml of acetic acid are added dropwise.

A solution is obtained which, on stirring at 80-90 ° C, starts to precipitate a crystalline product after about 1 U. After stirring for 1 hour, the reaction mixture is cooled and filtered. 5. g of bromide are obtained, which decomposes on boiling in acetone. 3.5 g (72%) of 1-cyano-2H, 1 + H-5,6-dihydro-2-N-benzoylamino-8,9-dimethoxy-1,2-thiazolo [3,2-a] isoquinoline hydrobromide are obtained. , sp. 22 ° C (dec.) (Recrystallized from acetic acid).

Analysis for CH 2 Cl 2 N 2 O 2 S (molar weight = 1 + 72.36)

Calculated:% C 53.39 H 3.8t N 8.90 Br 16.92 Found:% C 53.59 H 3.57 N 8.98 Br 16.89.

The starting material can be prepared by reacting the corresponding 1-methyl-3,1 + -dihydroisoquinoline and benzoyl isothiocyanate.

Claims (1)

A process for the preparation of new 2H, UH-5,6-dihydro-1,2-thiazolo [3,2-a] isoquinoline derivatives having a myocardial contractile activity and having the formula k2XDC ^ a (i) r3-cc ^ 1.2 . wherein R and R represent a hydroxy group or an alkoxy -... containing 3-U carbon atoms. . a group, R is a hydrogen atom or a cyano, carboxyl or carbamoyl group and Y is a radical. . k. it. ..... a cabbage of the formula = NR, wherein R is a hydrogen atom or an alkyl group containing 1-U carbon atoms or a benzoyl group, and for the preparation of their salts, characterized in that the compound of formula (II) 3 Π R Wherein R, R, R and Y are as defined above, are oxidized with bromine or iodine, and to give a compound of formula (i) having a lower alkoxy group in the 8- and 9-positions, the formula (i) ) having a hydroxy group at the 8- and 9-positions, if desired, is alkylated, and to obtain a compound of formula (i) having a hydroxy group at the 8- and 9-positions from a compound of formula (I) wherein the 8- and 9-positions have a hydroxy group. The 9-position has a lower alkoxy group, the alkyl group is optionally cleaved off, and to obtain a compound of formula (I) having a carbamoyl or carboxyl group at the 1-position, a compound of formula (I) having a cyano group at the 1-position, if desired hydrolyzed, 9,60566 to give such a compound of formula (i) in which the 2-positionr a is = N-benzoyl, the compound of the formula I in which the imino group is in the 2-position is, if desired, acylated, and to obtain the compound of the formula (i) in which the 2-position is = N-alkyl , the compound of formula (I) having an imino group in the 2-position is alkylated if desired, and that the compound of formula (i) obtained is, if desired, converted into a salt or the salt of the obtained compound of formula (I) is, if desired, converted to the free base.