CS208741B2 - Method of making the new derivatives of the 6,7-dimetoxyisochinolinacetamide - Google Patents

Description

The present invention relates to a process for the preparation of the novel 6,7-dimethoxy-quinolone-naphthonamide derivatives of the formula I

( ₂ ) ch ₂ conh-r ²

Wherein ^R1 is hydrogen, ^b of non-benzyloxy radical arbonylový

O

R is a phenyl group optionally substituted by halogen, an alkyl group з. 1 to carbon atoms, alkoxy t 1 to 4 carbon atoms or a group alkylkerbonylovou t 1 to carbon atoms, preferably t pyridylovl or thiazolylovl or chinoxalylovl group, ^R is a methyl of ^{b to} yte and pharmaceutically upoořebitelrých Tooie.

The process for the preparation of these novel compounds of formula (I) is based on the fact that the 6,7- (6-methyl-1,2,3,3-tetrahydroisoquinoline acetic acid) of the formula (II) is:

2086 41 (II)

wherein * \ ^R3 hy ^d roxylovou group, a halogen atom, preferably chlorine or bromine, an acyloxy group, an alkyloxy group having 1 to 4 carbon atoms, aryloxy, e.g., phenoxy, phenyl is optionally substituted by alkyl having 1 to 4 carbon atoms or nitro or hydroxyl; and

R ⁴ as defined above is reacted with a benzyloxycarbonyl halide and the resulting 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinacetic acid of formula III

(III) where

R @ 1 and R @ 2 have the same meaning as above, or a reactive derivative thereof, which is preferably reacted with an isobutyloxycarbonynyl chloride, and optionally reacted directly with the amine of the general formula IV in dicyclohexyltatenediimide.

R ² -NH ₂ (IV) wherein

R 6 has the same meaning as above, whereupon the Oenzyl-N-oxaphthyl group is optionally removed and the compound obtained is optionally converted into its pharmaceutically acceptable salt.

The most structurally similar compounds: N-alkylacetemide and N-arylalkyleaamide derivatives are produced by the Lomiornihn method, J. G. et al. (J. Med. Chem. J, 506 (1961), U.S. Pat. No. 3,021,331 CA 57,778 d (1962)) and these compounds have been used as starting materials for the production of condensed cyclic compounds. No. 3,654 / 81, the above compounds have been described as starting materials, i.e. the biological activity of the compounds of the present invention could not be expected from these patents.

According to one embodiment of the present invention, the reactive derivative of 6,7-dimethoxy-1 _l / 3,4-1-tetrahydtn isochinnlinové acid of formula II is reacted with BE-zynxykarOonylchloridem. The reaction is carried out in the absence of solvent at a temperature of -10 to +100 ° C. Hydrochloric acid is formed during the reaction and is bound by an organic or inorganic base. Tertiary amines, such as treethyamine, diethylemine or pyridine, are used as organic bases, but an excess of the isoquinoline derivative may also serve as an acid binding agent. Organic bases which can be used are metal hydroxide, metal carbonate, alkaline earth hydroxide or carbonate earth carbonate. The reaction can also be carried out in a solvent. Water, low alkyl ketones or ether are preferred as a solvent. In carrying out the reaction, 6,7-diethoxy-1,2,3,3,4-tetrahydro-1-isoquinolinic acid or a reactive derivative thereof may be added dropwise to the equimolar propagation solution while stirring. base and benzyl chloride. The reaction is complete after stirring for 1-8 hours. The acid product is isolated by filtration after acidification of the reaction mixture

20374 'by filtration and optionally evaporation. The product thus obtained is optionally purified by crystallization or other physical methods.

The 6,7-dimethoxy-2-benzyloxycarbonyl-1,2,3-3-tetralydro-1-isoquinolinacetic acid obtained is reacted with amines of the general formula. IV in the presence of a tertiary amine, such as triethylamine, as well as. alkoxycarbonyl chloride such as isobutyloxycarbonyl chloride. The reaction is preferably carried out in a solvent. Ketone is the preferred solvent. an ether such as acetone, methyl ethyl ketone, tetrafluorophenol. The favorable reaction temperature is in the range of -15 to 30 ° C. The temperature is preferably maintained during the reaction. below 5 ° C and the reaction is terminated at 20 to 25 ° C; The product is preferably isolated by filtration. tertiary salt and evaporation of the filtrate. . The rest contains the product,. which is possibly cleaned by physical methods _? for example by crystallization. ...

Benzyloxycarbonyl obtained 2 "senza yloxylarbsnyll6 · _¢ 77diIietexy-1.2 _.3> 4 tttřlhydrr-1 · isochinolinacetamidu is optionally removed by Senzyloz: _yklr'b.on) LLOV derivative is dissolved in acetic acid solution, obsíaihjící Concentrated hydrogen bromide, from which a 6,7-dimethoxy-1,2,3,4-tetrahydro-4-trifluoromethyl chloride derivative is obtained in a short time, and the product is isolated by filtration. "

The benzyloxycarbonyl group can also be removed by catalytic hydrogenation. The procedure is as follows:. that. se. The benzyloxycarbonyl derivative is dissolved in a solvent and hydrogenated in the presence of a hydrogen transfer catalyst (e.g. palladium-activated carbon). After filtering the catalyst, the product is isolated by filtration or evaporation. »·

Compounds according to. The present invention exhibits high activity activity. This activity overcomes the effect of phthylsulfonyl and the compounds are even less toxic than the known phenylautaxone. Thus, for example, N- (4-quinoxyl) -6,7-dimethoxy-1,2,3,4-tetahydrate-1-quinolineclamide induces 44% braking of foot swelling in carrageenan test at a dose of 2. 5 mg per kilogram when administered, 30% braking in rats at a dose of 2.5 mg / kg and 47% braking at a dose of 10 mg / kg ip, dose Θθ mg / kg with myH, no concept yet.

N (p · meeoxylenyl) '6 _> 7-dimethoxy-1,2,3,4-tetrahydro-l-1-itoquinoline citrate exerts a braking rate of 25% in the carrageenan rat edema test at 10 mg / kg ip and braking

57% at 25 mg / kg. The myoicity of myH when administered i.p is 280 m / kg. ·

The known indomethacin (1- (p-chlorobenzyl) -2-methyl-5-methyl-2-indoleic acid) acts in the carrageenan leg swelling test at 10 mg / kg i, p. 50% braking. Nappoti this toxicity is 33 mg / kg FenylSutazon (4-n · » 'buSyl _{diftnllpyrlzolidin-1,2-d-3} 5-dione) causes at karageninovém test * foot swelling in rats at 30 mg / kg, 22% braking. TooicCtl u Si at. administration po is 660 mg / kg.

The preparations according to the invention. can be administered orally, parenterally or locally. Tablets, capsules or dragees, syringes, syringes, powders or sprays, etc. may be prepared. Pharmaceutical preparations may contain inorganic or organic, solid or liquid carriers such as water, polyethylene, talc, starches, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, calcium carbonate, magnesium, cocoa butter, petrolatum, etc.

Conventional auxiliaries such as stabilizing agents, spray-promoting agents, etc. can also be added. Preparations can be prepared in various ways.

Further details of the invention may be found in the following examples.

Example. 1

27.8 g (0.1 mol) of 6,7-dimethoxy-1,2,3,4-tetrottoydro-1-isoquinolineacetic acid are dissolved in 50 ml of an aqueous solution of 4 g of sodium hydroxide. The solution is cooled to -10 to -15 ° C and 17 g (0.1 mol) of benzyloxycarbonylchoride is added dropwise from the cooling over 30 minutes. The cooled reaction mixture was stirred for an additional 3 hours and washed with 40 mL of 20% hydrochloric acid.

The precipitated crystals are filtered off, dried and re-precipitated from a mixture of benzene and ether. It is obtained

32.5 g 2-b ^ i ^ Jzj ^] ^ i ^ 10 ^ yrbrb ^: ^] ^ * ^ 1,5,7-in ^ m ^ ooy-1,2,3,4-β ^ β 1d-1-isoquinolinoetic acid.

Mp 153-154 ° C.

For ^C ₂₁ H ₂₆ KO ₆ calculated: 65.44% C, 6.01% H, 3.63% N; Found:% C, 65.26;% H, 5.90;% N, 3.46.

Example 2

0.02 mol of 2-benzyloocarbonyl-6,7-dimethyl-o-1,2,4,4-tetratryl-1-oloclinolineacetic acid was dissolved in 80 ml of anhydrous tetratydrourane and cooled to -10 to -15 ° C with stirring. within 5 miniu! a solution of 0.02 mol of trimethylamino and 0.02 mol of isobutoxycarbonyl chloride is added dropwise. After stirring for a further 5 minutes, 0.02 mol of amine in 20 ml of tetratydrourane is added dropwise to the mixture, the mixture is stirred for a further 5 hours and allowed to stand overnight. . The precipitated trisyl mononitrile is filtered and washed with tetrilirofuran. The tetrahydrofuran solutions were evaporated. The residue was dissolved in 70 ml of ethyl acetate and washed to give a residue. to neutral reaction with 2.6 ml of water, 1% sodium hydroxide solution and 3.5 ml of water. The ethyl acetate is dried over sodium sulfate i. odpea! under vacuum. The residue crystallized. Data on the compounds obtained are shown in Table I.

Example 3

7.7 g (0.02 mol) of _{2-benzySoxχSkaronyl-6,7-1-1,2-dimitoxy>} 44ttera] lyldOo1-ieochinolinoctové rozpuutí acid in 30 ml chloroform and heated for one hour under reflux with 2.83 g (0.024 mol). The reaction mixture obtained is evaporated. in vacuo and the acid chloride obtained as a residue was dissolved in 10 ml of benzene.

2.9 g (0.02 mol) of 2-aminoquininoxaline are dissolved at 0 DEG C. with 10 ml of benzene and a solution of 2-benzyloxycarbonyl-1,7-iminooxyl-1-phthalenoyl hydrochloride prepared as described above is added dropwise to this solution. 15 ml of 2N sodium hydroxide. After adding. of the above solutions was allowed to warm and stirred at room temperature for 3 hours. Then the mixture is isolated and the benzene phase is washed with 2N sodium hydroxide and water. The benzene solution was dried and evaporated. 9.4 g of 2- (2-benzyloxycarbonyl-6, -dimethoxy) -2,3,4-tert-hydroxyquinolylcellinyl) -clinoxylin are obtained.

Melting point 166-167 ° C (mixture of ethanol and ether).

Example ^ d 4

10.12 g (0.02 mol) of p-nitrifenyl- (2-eenzyloxycarbonyl-6, toxyl-1,2,3,4-tetratidroocinolyl) acetate and 2.14 g (0.02 mol) of p-toluidine were added. 50 ml of toluene under reflux for 3 hours. The mixture is wetted, washed with 1N sodium hydroxide and water. The toluene solution is dried over anhydrous sodium sulphate and evaporated. There were obtained 9.2 g of N-pptolyl-22-benzs10-cyclopropyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isocylisyl) acetamide.

Melting point 167-169 ° C (ethanol).

Example 1 a d 5

7.7 <(0.02 mol) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinacetic acid and 1.86 g (0.02 mol) of aniline are dissolved in 80 A solution of 4.52 g (0.022 mol) of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran was added dropwise with stirring. The reaction mixture was stirred at 1 ° C for one hour and at room temperature for 2 hours. The precipitated dicyclohexylurea is filtered, washed with tetrahydrofuran and the filtrate is evaporated.

9.2 g of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl acetamide are obtained.

Melting point 104 to 106 ° C (benzene: ether)

Example 6

7.7 g (0.02 mol) of 2-benzyloxycarbonyl-6,7-diinethoxy-1,2,3,4-tetrahydro-1-isoquinolinacetic acid and 2.9 g (0.02 mol) of 2-aminoquininoxaline are well The mixture was stirred and heated under nitrogen at 170-180 ° C for 3 hours. After cooling, 8.2 g of 2- (2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolination of tamido) -quinoxaline are obtained.

Melting point 165-166 ° C (ethanol-ether).

Example 7

0.02 mol of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinoacetamide derivative is dissolved in 4-5 equivalents of a 30% solution of hydrogen bromide in glacial acetic acid. After 30 to 50 minutes, crystals precipitate from the solution, and the solution solidifies. Upon addition of ether, crystals are separated, filtered and washed with ether. The product is dried and recrystallized. Details of the substance so produced are given in Table II.

Table I

Physical and chemical constants of the compounds of formula I according to Example 2

R ² R ¹ = benzyloxycarbonyl melting point of crystals. solvent yield% analysis calculated / found C H N phenyl mp 104-106 ° C benzene / ether 86 70.41 69.91 6.13 6.05 6.08 6.17 p-tolyl mp 168-169 ° C benzene ether 65 70.86 70.81 6.37 6.41 5.90 6.16 4-fluorophenyl mp 142-144 ° C benzene ether 72 67.77 67.47 5.69 5.75 5.86 6.00 4-bromophenyl mp 152-154 ° C ethanol-ether 64 60.11 59.86 5.04 5.00 5.10 5.09

continuation of Table

R1 = benzyloxycarbonyl

R ² melting point yield analysis of crystals ·% calculated / found solvent _GH

4-methoxyphenyl melting point 145 ° C benzene-trole ter 86 68.55 68.87 6.16 6.55 6.71 5.85 3-chloro-4-methylphenyl melting point Mp 185-186 ° C benzene 82 69.30 69.64 6.02 6.63 5.58 6.02 2,4-dibromophenyl mp 125-126 ° C benzene ether 84 66.07 66.40 5.74 6.01 5,51 5.74 4-acetylphenyl melting point Mp 168-169 ° C benzene 76 52.44 52.55 4.24 4.46 4.53 4.41 3-pyridyl mp 113-115 ° C benzene ether 89 67.66 67.32 5.90 6.15 9, H 8.92 1,3-thiazol-2-yl oil 78 61.66 62.02 5.39 5,56 8.99 8.75 2-quinoxalyl melting point Mp 166-167 ° C ⁷⁰ 67.91 67.89 5.50 5.95 10.93 10.85

ethanol-ether ⁴ . -T and 'bu 1 к а II

Physical and chemical constants of the compounds of formula I according to Example 7 R ¹ = hydrogen

R ² melting point covers. solvent yield% analysis calculated / found C H N Br phenyl melting point 74 56.02 5.69 6.88 Mp 232-233 ° C 55.92 5.67 6.49 ethanol-water 3: 2 p-tolyl melting point 84 57.01 5.98 18.97 ion 253 DEG-254 DEG 57.25 6.10 18.67 ethanol-water 3: 2 4-fluorophenyl melting point 72 53.65 5.21 6.59 18.19 ion Mp 232-234 ° C 54.02 5.35 6.14 18.18 ethanol-water 4: 1 4-bromophenyl melting point 82 46.93 4,56 32.87 ion Mp 234-235 ° C 46.80 4.50 коvalent ethanol-water 3: 2 32.90

continuation of Table II

R ^{2 rI} = leads ^{to k} the temperature fills the solvent yield% analysis calculated / found C H N Br 4-me Соху- * спу2 temperature melts 90 54.92 5.76 6.40 Mp 238-239 ° C 55.12 5.69 6.63 2-ananol-water 2: 3 3-chloro-4- temperature melts 94 52.70 5.31 17; 53 ion -methylphenyl Mp 224-225 ° C 53.0) 1 5.48 17.40 4-anol-water 4: 1 2,4-dibromophenyl temperature melts 95 40.38 3.75 4.96 14.13 ion Mp 207-208 ° C 40.79 3.93 4.91 14.57 ethanol-water 9: 1 4-Cetylphn-1 temperature melts 86 56.13 5.61 6.24 Mp 206-208 ° C 55.98 5.85 6.17 7: 3 3-pyridyl temperature melts 88 41.61 4.96 8.28 31.51 224 DEG-226 DEG 42.36 5.12 8.66 30.98 eta-1-water 9: 1 t 1 mol crystalline water 1.3 - ^^ о1-2--1 temperature melts 72 46.39 4.87 19.19 ion 238 DEG-240 DEG 46.53 5.03 19.12 ethanol-water 1: 1 temperature melts 84 52.83 5.28 11.74 16.76 Mp 192-194 ° C 52.83 5.23 11.38 16.48 ttol1 · leader 7: 3

Claims (5)

SUBJECT OF THE INVENTION First Zfpsob vjřroby ndoých ddeivátii 6 _{I-7-dd.metooy} soohhnolinacttamidu formula I (I) wherein ^R1 is hydrogen meant no ^b of benzyl-p group kartonylovou R 6 is an optionally substituted halogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 alkoxy group or an alkoxyalkyl group C 1-4 alkyl, pyridyl, quiooxalyl or thiazolyl, and their pharmaceutically usable salts, characterized in that they have 6,7-di-m-toxin-1,2,2 3,4-Thiazolio-1-tsochioolone acetic acid or a reactive derivative thereof having the general formula II (II) wherein they are hydroxyl, acyloxy, C 1 -C 4 alkyloxy, halogen, preferably chlorine or bromine aryloxy, preferably phenoxy optionally substituted by hydroxyl, nitro or C 1 -C 4 alkylaluipine, reacted with benzyloxycarbonyl halide and the obtained .beta.-benzyloxycarbonyl-6,6-dimethoxy-1,2,3,4-tetrahydro-1,2,3,4-tetrahydro 1-Aminoquinoline acid or a reactive derivative thereof of formula III CH-R ³ (III) wherein R ^P is as defined above, the NEC ^hook with an amine of Formula IV ^ ecnéto R ² -NH ₂ (IV) wherein the R is as defined above, and optionally the benzyloxycarbonyl group is removed and the compound of formula I obtained is optionally converted. or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, characterized by: 2. A method according to claim 1, wherein the reactive derivative of formula (III) is a mixed arthydride with isobutylcarbonyl chloride and reacted with an amine of formula (IV) wherein R is as defined above. 3. A process according to claim 1, wherein 2-benzylcarbonylbore-7,7-dimethoxy-1,2,3,4-etrralydro-1-irochiarlaacetic acid is reacted with an amine of the formula IV in the presence of diclkylcarbodiimide. wherein R ² is as defined above. importance. 4. The process of claim 1, wherein the 2-benaylobarboxylic acid derivative is reacted with hydrogen bromide in glacial acetic acid to remove the benzyloxycarbonyl group first. 5. The process according to claim 1, wherein the 2-benzylcarbonyl-1,2,3,4-tetrazoloyl-11-irochaoolacetamide derivative is catalytically hydrogenated to remove the benzylcarbonyl group.