FI60561C - FOERFARANDE FOER FRAMSTAELLNING AV ANTIINFLAMMATORISKA 6,7-DIMETOXI-1,2,3,4-TETRAHYDRO-1-ISOKINOLINACETAMIDDERIVAT - Google Patents

Description

ΓβΊ mi ANNOUNCEMENT / nr ,, * | 3Γλ W (11) UTLÄCGNINGSSKRIFT 6Ub6 '+ C ^ gPatent granted 10 02 1932

Patent meddelat ^ (51) Ky.ik.3 / I «.a.3 C 07 D 217/12, 401/12, 417/12 FINLAND —FINLAND (M) Plt« nttlh> k * mui - Ptt «nt« ns6knlng 773951 (22) H * k * ml * pllvl - AfM0knlngtd «g 28.12.77

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Patent and Registration Board. .

_,. . (44) Date of issue] · Month of publication. -

Patent-och registrstyrelsen v 'An $ ak »n uttagd oeh utl.tkrifun public · ™ * 30.10.81 (32) (33) (31) Requested privilege — Begird prloritet 30.12.76

Hungary-Hungary (HU) CI-17H

(71) Chinoin Pharmaceuticals and Chemical Products Factory RT, l-5, to utca, Budapest IV, Hungary-Hungary (HU) (72) Gabor Bernäth, Szeged, JenoKobor, Szeged, Zoltan Ecsery, Budapest,

Emil Minker, Szeged, Matyäs Koltai, Szeged, Hungary-Ungem (HU) (7 * 0 Oy Kolster Ab (5 * +) Method of anti-inflammatory 6,7-dimethoxy-1,2,3, ** - tetrahydro-1-iso The present invention relates to a process for the preparation of new anti-inflammatory 6-quinoline-acetamide derivatives. To the preparation of anti-inflammatory 6,7-dimethoxy-1,2,3,3 * + "tetrahydro-1-isoquinolineacetamide derivatives For the preparation of 7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide derivatives of general formula (I) O 1

MeQ_. y! N-R

'2

C0NH-CH 2 R

2 60 5 61 and salts thereof, wherein R 1 is hydrogen or benzyloxycarbonyl, and 1 * 2 is a pyridyl, thiazolyl or quinoxalyl group or a phenyl group optionally substituted by a C 1-4 alkoxy, C 2-4 alkanoyl or C 1-4 alkyl group and / or one or two halogens.

The novel compounds of formula I can be prepared by reacting 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline acetic acid of formula

MeO ^ \ / Ό I (II)

! NH

MeCr ^

CH 2-COOH

is reacted with a benzyloxycarbonyl halide, and the resulting 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolineacetic acid of the general formula

MeQ ^ _ lOj j n f l! i (III> I 'N-C-O-CH- 2

CH2 ~ COOH

or its general formula

We ° ',. \, Loj (IV) O l? r N-C-O-CHo / 'V .. ^ y' 2

MeO

a derivative of ch2cor3 3 6 O 5 61 wherein the R1-4 alkoxy or optionally NC4-substituted phenoxy group is reacted with an amine of the general formula R2 to NH2 (V), and if desired, the benzyloxycarbonyl group is removed by heating the resulting compound with hydrogen bromide and ice. and, if desired, converting the resulting compound of general formula I into a pharmaceutically acceptable salt, or liberating a base from the resulting salt.

1- (2-Benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylacetamides of formula I are novel compounds, Lombardino JG et al., J. Med. Chem. 3, 505 (1961). ), U.S. Patent No. 3,021,331, CA 57,786 d (1962) have prepared N-alkyl and N-aralkylacetamide derivatives closest to the compounds of formula I and used them as starting materials in the preparation of fused cyclic compounds.

The above compounds were also used as starting materials according to the following reference: U.S. Patent No. 3,654,281, CA 77, 19688a (1972). The biological activity of the compounds prepared according to the present invention could not be predicted from the above references.

The process according to the invention is carried out by reacting 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineacetic acid of the formula II with benzyloxycarbonyl chloride in a solvent or without a solvent at a reaction temperature of -10 to + 100 ° C. The hydrochloric acid released during the reaction is bound with an organic or inorganic base. Preferred organic bases are tertiary amines, such as triethylamine, dimethylamine or pyridine, but an excess of an isoquinoline derivative can also be used as acid scavengers. Suitable inorganic bases include alkali metal hydroxides and carbonates and alkaline earth metal hydroxides and carbonates. The reaction can be carried out in a solvent. Suitable solvents include water, lower alkyl alcohols, ketones and ethers. The reaction can be carried out by first adding 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetic acid to a solution of an equimolar amount of base, and then adding benzyloxycarbonyl chloride dropwise with stirring and cooling.

60561

The reaction is allowed to proceed to completion when stirring is continued for 1-8 hours. The reaction mixture is then acidified and the product is recovered by filtration or, if desired, by evaporation. If desired, the product thus obtained can be purified by crystallization or other physical methods.

The resulting 6,7-dimethoxy-2-benzyloxycarbonyl-1,2,3,4-tetrahydro-1-isoquinolineacetic acid is reacted with an amine of general formula V in the presence of a tertiary amine such as triethylamine and an alkoxycarbonyl chloride such as isobutyloxycarbonyl chloride. . If desired, the reaction can be carried out in a solvent. Preferred solvents are ketones and ethers such as acetone, methyl ethyl ketone or tetrahydrofuran. The reaction can be carried out at a temperature between -15 and + 30 ° C. It is preferred to keep the temperature below + 5 ° C during the reaction and in the final range in the range of 20-25 ° C. It is preferred to separate the product from the reaction mixture by filtering off the tertiary amine salt formed and evaporating the filtrate. The residue contains the desired product which can be purified by a physical method such as crystallization.

In another embodiment of this invention, the acid chloride is prepared from 6,7-dimethoxy-2-benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline acetic acid of general formula III and an inorganic acid chloride such as phosphorus oxychloride or thionyl chloride, and the acid chloride thus obtained is obtained by reacting the acid chloride with the amine according to The acid chloride may be prepared in a solvent such as benzene or in a chlorinated solvent such as chloroform, but the chlorinating reagent itself may also act as a solvent. The acid chloride is prepared at 20-100 ° C, preferably at the boiling point of the solvent or chlorination reagent, and the hydrogen chloride gas or sulfur dioxide gas formed is removed from the reaction mixture. After the acid chloride is formed, the excess chlorination reagent and solvent are distilled off, and the remaining crude acid chloride is used crude to prepare the amide. The amide is preferably prepared in the presence of an acid scavenger. Organic or inorganic bases can be used as acid scavengers.

The acid chloride or its benzene solution and the aqueous sodium hydroxide or sodium carbonate solution are simultaneously added dropwise to the amine or amine benzene solution. Alternatively, the acid chloride may be added to a mixture or solution of an amine and an organic base such as triethylamine. In this case, it is preferable to carry out the reaction under anhydrous conditions. The reaction takes place in 1 to 5 hours at a temperature between -10 and + 100 ° C. The product is isolated by filtration or evaporation of the reaction mixture. If desired, the product can be purified by crystallization or some other physical method.

In another embodiment of this invention, an alkyl or aryl ester of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid of general formula IV (prepared from an acid or acid chloride of general formula III by a method known per se) method) is reacted with an amine of general formula V. The reaction can be carried out in a solvent or by heating the reactants without a solvent.

Aromatic or aliphatic hydrocarbons, alcohols or ethers can be used as solvents. It is preferable to distill off the alcohol formed in the reaction. The reaction can be carried out using a so-called active esters such as p-nitrophenyl ester or N-hydroxyphthalic acid imide ester or 3-hydroxy-4 (3H) -quinazolinone ester. The reaction temperature depends on the substituent R, i.e. the nature of the ester used in the reaction. Alkyl esters require a higher temperature (50-150 °) and a longer reaction time (2-10 hours) than aryl esters, especially active esters. After completion of the reaction, the product is isolated by filtration or evaporation. If desired, the product can be purified by physical methods such as crystallization.

In another embodiment of this invention, 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid is reacted with an amine of general formula V in a carbodiimide such as dicyclohexylcarbodiimide. acid. The reaction is preferably carried out in a solvent. Preferred solvents are aromatic or aliphatic hydrocarbons such as benzene and its homologues, gasoline, etc., ketones such as acetone and acetophenone and ethers such as ethyl ether, dioxane and tetrahydrofuran. The reaction takes place easily, so it is preferable to carry it out at a low temperature such as -20 to + 30 ° C. During the reaction, the carbodiimide forms a urea derivative which forms an insoluble precipitate. Upon completion of the reaction, the urea derivative is filtered off and the filtrate is evaporated to give a residue which is the desired product which can be purified by crystallization or some other physical method.

In another alternative embodiment of this invention, 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acid of general formula III is reacted with an amine of general formula V, preferably using heating. The reaction can be carried out with or without a solvent.

It is preferable to use a water-insoluble solvent, and the water formed in the reaction is removed by azeotropic distillation. Thus the equilibrium shifts to the formation of the acid amides of the formula I. When operated without a solvent, the acid of general formula III is heated with an amine of general formula V at a temperature between 100 and 200 ° C. Dewatering is also advantageous in this case. This is achieved if the reaction is carried out in an open vessel or nitrogen or some other inert gas is poured onto the reaction mixture. The reaction can be performed in vacuo. If a solvent is used, it is removed by distillation after completion of the reaction and the product obtained is purified, if desired, by crystallization.

The resulting 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide derivative can then, if desired, be deprotected by dissolving the benzyloxycarbonyl derivative in concentrated acetic acid containing hydrogen bromide, and The 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide derivative crystallizes and can be isolated by filtration.

The benzyloxycarbonyl group can also be removed by catalytic hydrogenation. The benzyloxycarbonyl derivative is dissolved in a solvent and hydrogenated in the presence of a hydrogen transfer catalyst such as palladium on carbon. The catalyst is filtered off and the product can be recovered by filtration or evaporation.

The compounds prepared by the method of this invention are effective anti-inflammatory agents. The anti-inflammatory effect is greater than the known anti-inflammatory effect of phenylbutazone 7 60561 and the toxicity of the compounds of the invention is lower than that of phenylbutazone. Thus, N- (2-quinoxalyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide inhibited carrageenan-induced foot swelling test by 44% at a dose of 25 mg / kg i.p. in mice, 30% at 2.5 mg / kg in rats and 47% at 10 mg / kg in rats. At a dose of 80 mg / kg i.p. not a single mouse died.

N- (p-methoxyphenyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide inhibited carrageenan foot edema in rats by 25% at a dose of 10 mg / kg i.p. and 57% at a dose of 25 mg / kg i.p. Toxicity is observed in mice at a dose of 280 mg / kg i.p.

1- (p-chlorobenzoyl) -2-methyl-5-methoxy-2-indolylacetic acid, a known indomethacin, inhibited carrageenan-induced foot edema in rats by 50% at a dose of 10 mg / kg i.p. and toxicity is observed at a dose of 33 mg / kg orally.

Phenylbutazone (4-n-butyl-1,2-diphenylpyrazolidine-3,5-dione) inhibited carrageenan-induced foot swelling in rats by 22% at a dose of 30 mg / kg and the toxicity was observed in mice at a dose of 660 mg / kg p.o.

The invention is illustrated by the following examples.

Example 1 28.7 g (0.1 mol) of 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetic acid are dissolved in 50 ml of an aqueous solution containing 4 g of sodium hydroxide. The solution is cooled to -10 to -15 ° C and then 17 g (0.1 mol) of benzyloxycarbonyl chloride are added over 30 minutes under cooling. The cooled reaction mixture is stirred for a further 3 hours and then acidified with 40 ml of 20% hydrochloric acid. The precipitated crystals are filtered off, washed with water, dried and recrystallized. 32.5 g of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetic acid are thus obtained. Sp. 153-154 ° C. Analysis: C 21 H 26 NO 6 calculated: C 65.44% H 6.01% N 3.63% Found: C 65.26% H 5.90% N 3.46%

Example 2 0.02 moles of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-60561 8 tetrahydro-1-isoquinolineacetic acid are dissolved in 80 ml of anhydrous tetrahydrofuran, the solution is cooled to -10 to -15 ° C and 0.02 mol of triethylamine and 0.02 mol of isobutyloxycarbonyl chloride in 5 ml of tetrahydrofuran are added simultaneously dropwise over 5 minutes with stirring. Stirring is continued for a further 5 minutes, then 0.02 mol of the corresponding amine in 20 ml of tetrahydrofuran are added dropwise to the reaction mixture, the resulting mixture is stirred for 5 hours and then allowed to stand overnight. The precipitated triethylammonium chloride is filtered off and washed with tetrahydrofuran. The tetrahydrofuran solutions are evaporated. The residue is dissolved in 70 ml of ethyl acetate and washed first with 2.6 ml of water, then with 1% sodium hydroxide solution and finally with water until neutral. The ethyl acetate solution is dried over sodium sulfate and evaporated in vacuo. The residue is crystallized. Table I shows the data for these prepared compounds.

Example 3 7.7 g (0.02 mol) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetic acid are dissolved in 30 ml of chloroform, 2.83 g (0.024 mol) are added. ) thionyl chloride and the mixture thus obtained are refluxed for 1 hour. The reaction mixture is then evaporated in vacuo and the residual acid chloride is dissolved in 10 ml of benzene.

2.9 g (0.02 mol) of 2-aminoquinoxaline are dissolved in 10 ml of benzene, and to the solution thus obtained are added dropwise at 0 ° C simultaneously the above-prepared 2-benzyloxycarbonyl-6,7-dimethoxy-1-isoquinolylacetyl chloride solution and 15 ml. 2N sodium hydroxide solution. The mixture is allowed to warm after the addition and then stirred at room temperature for 3 hours. The benzene layer is separated and washed first with 2N sodium hydroxide solution and then with water. The benzene solution is dried and evaporated. 9.4 g of 2- (2-benzyloxycarbonyl) -6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylacetamidoquinoxaline are thus obtained. Sp. 166-167 ° C (from ethanol and ether).

Example 4

A mixture of 10.12 g (0.02 moles) of p-nitrophenyl (2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline) acetate, 2.14 g (0.02 mol) of p-toluidine and 50 ml of toluene are refluxed for 3 hours. The reaction mixture is cooled and washed first with 1N sodium hydroxide solution and then with water. The toluene solution is dried over anhydrous sodium sulfate and evaporated. 9.2 g of N-tolyl- (2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl) acetamide are thus obtained. Sp. 167-169 ° C (ethanol).

Example 5 7.7 g (0.02 moles) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineacetic acid and 1.86 g (0.02 moles) of aniline are dissolved in 80 ml of tetrahydrofuran and then a solution of 4.52 g (0.022 mol) of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran is added dropwise at 0 [deg.] C. with stirring. The mixture is stirred for 1 hour at 0 ° C and then for 2 hours at room temperature. The precipitated dicyclohexylurea is filtered off and washed with tetrahydrofuran, and the filtrate is evaporated. 9.2 g of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylacetamide are thus obtained. Sp. 104-106 ° C (benzene-ether mixture).

Example 6 7.7 g (0.02 moles) of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineacetic acid and 2.9 g (0.02 moles) of 2-aminoquinoxaline are mixed together at 170-180 ° C at 3 hours under nitrogen. After cooling, 8.2 g of 2- (2-benzyloxycarbonyl-6,7-dimethoxy-1-, 2,3,4-tetrahydro-1-isoquinolylacetamido) quinoxaline are obtained. Sp. 165-166 ° C (ethanol-ether mixture).

Example 7 0.02 moles of 2-benzyloxycarbonyl-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide are dissolved in a solution of 4-5 equivalents of a 30% solution of hydrogen bromide in glacial acetic acid. After 30-50 minutes, crystals begin to form and the solution solidifies. Ether is added to complete the crystallization, the solid is filtered and washed with ether. It is then dried and recrystallized. Table II shows the information on the products thus obtained.

10 605 61

Table I

Physical and chemical properties of the compounds of formula I prepared according to Example 2.

R 1 = benzyloxycarbonyl R 2 Sp. Crystallization Yield Analysis calculated / found solvent

C H N

Phenyl Sp. 4 ° 4 ° i06 ° C 86 70.41 6.13 6.08 benzene ether 69.91 6.06 6.17 p-tolyl M.p. 168-169 ° C 66 70.86 6.37 5.90 ethanol 70.81 6.41 6.16 4-fluoro-M.p. 142-144 ° C 72 67.77 5.69 5.86 phenyl benzene ether 67-47 5.75 6.00 4-brommi-M.p. 152-154 ° C 64 60.11 5.04 5.10 phenyl ethanol ether 59.86 5 # 00 5> 4-methoxy-m.p. 45 ° C 86 68.55 6.16 5.71 phenyl benzene-petroleum-68.87 6.55 5.85 ether 3-chloro-4-m.p. 185-186 C 82 69.30 6.02 5.58 methylphenylbenzene 69.64 6.63 6.02 methyl 2,4-dibromide M.p. 125-126 ° 0 84 66.07 5.74 5.51 phenyl benzene ether 56 # 40 6 <01 5 #? 4 4- acetyl M.p. 168-169 C 76 52.44 4.24 4.53 phenyl benzene 52.55 4.46 4.41 3-pyridyl M.p. H3-115 ° C 89 61.66 5.90 9.11 benzene ether 67.32 6.15 8.92 1,3-thiazole oil 78 61.66 5.39 8.99 2- yl 62.02 5.56 8.75 2-quinoxa- M.p. 167 ° C. 70 67.91 5.50 10.93 iyyii ethanol ether 67.89 5.95 10.85 6 O 5 61

Table II

Physical and chemical properties of the compounds of formula I prepared according to Example 7. r1 = hydrogen _ Analysis I <Sp. crystallization Yield calculated / found solvent C H N Br

Phenyl Sp. 232-233 ° C 74 5G .02 5.69 6.88 ethanol-water 3: 2 55.92 5.67 6.49 o ion p-tolyl M.p. 253-254 C 84 57.01 5.98 18.97 ethanol-water 3: 2 57.25 6.10 18.67 ions 4-fluoro-M.p. 232-234 C 72 53.65 5.21 6.59 18.19 phenyl ethanol-water 4: 1 54.02 5.35 6.14 18.18 ion 4-brcmi-M.p. 234-236 ° C 82 48.82! * Κη 22 # 87 ...

phenyl eolinol water 3: 2 46 * 80 4.50 covalent 32.90 4-methoxy-M.p. 238-239 ° C 90 54.92 5.76 6.40 phenyl ethanol-water 2: 3 55.12 5.69 6.63 ion 3-chloro-M.p. 224-225 ° C 94 52.70 5.31 17.53 4-methylethanol-water 4: 1 53.01 5.48 17 * 40 lifenyl ion 2,4-di-M.p. 207-208 ° C 95 40.38 3.75 4.96 14.13 Bromomethanol-water 9: 1 40.79 3.93 4.91 14.57 phenyl 4-ace M.p. 206-208 ° C 86 56.13 5.61 6.24 ethyl ethanol-water 7: 3 55.98 5.85 6.17 phenyl 3-pyrr.-m.p. 224-226 ° C B8 42-61 4.g6 B.29 31.51

dyyU ethanol-water 9: 1 42.36 5-1z B <66 30.gB

+1 mole of water S? 2 2 8-240 ° C 72 46.39 4.87 19.29 azole-2-ethanol-water 1: 1 46 192-194 ° C 84 52.83 5.28 11.74 16.76 salyl ethanol-water 7: 3 52.83 5.23 11.38 16.48

Claims (2)

A process for the preparation of new anti-inflammatory 6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline acetamide derivatives of the general formula MeO_ ^ \ Λ '"- 1 I ί.Π J R1 (I) MeO— 5 "R CH2-CONH-R2 and salts thereof, wherein 1 R is hydrogen or benzyloxycarbonyl, and 2 R is a pyridyl, thiazolyl or quinoxalyl group or a phenyl group optionally substituted by a C 1-4 alkoxy, C 2-4 alkanoyl or C 1-4 alkyl group and / or by one or two halogens, characterized in that 6.7 -dimethoxy-1,2,3,4-tetrahydroisoquinolineacetic acid of formula Me 0 .. ^ Γπ: 1 (ii): \ nh Me V 'CH 2 -COOH is reacted with benzyloxycarbonyl halide to give 2-benzyloxycarbonyl-6,7 -dimethoxy-1,2,3,4-tetrahydroisoquinoline acetic acid of general formula 13 60561! O Me Cl. ^ 1 I '1' Ί ° ^ I i n-c-o-ch2 (in) Me ^ ^ CH2-C00H or the general formula Me ° \. * ·. \ l o j v! 1 0. - a derivative of I n i -co-ch2 (iv) MeO.- "\ CH2COR1, in which R1-4 alkoxy or an optionally NO2-substituted phenoxy group, is reacted with an amine of the general formula R2 - NH2 (V), and if desired the benzyloxycarbonyl group is removed by heating the compound obtained with hydrogen bromide and glacial acetic acid, and, if desired, the compound of general formula I obtained is converted into a pharmaceutically acceptable salt, or the base is liberated from the salt obtained. 3,4-Tetrahydro-1-isoquinolineacetamide derivatives of the formula te, -Κ1 ID CH2-CONH-R och salter därav, i vilken formulel R is a substance or benzyloxy-2 carbonyl, and R is en pyridyl, thiazolyl - with a quinoxalyl group or a phenyl group, optionally substituted with C 1-4 alkoxy, C 2-4 alkanoyl- or _ ^ -alkyl and / or halogen, with the addition of 6, 7-di- methoxy-1,2,3,4-tetrahydroisoquinoline nättiksyra med den allmänna formeln i ^ eO. (ii) MeO 2 - (CH 2 -COOH) affords benzyloxycarbonyl halides and 2-benzyloxycarbonyl-6,7-dimethyl-1,2,3,4-tetrahydroisoquinol nitrate with the formula ~ -: CV i '-j J NCO-CH- MeO- ^ "^ * T CH2-COOH