CS203179B2 - Process for preparing derivatives of n-/benzothiazol-2-yl/oxamidic acid - Google Patents

Description

The invention relates to a process for the preparation of N- (benzthiazol-2-yl) oxamic acid derivatives having the general formula I,

wherein the substituents

R 1, R 2, R 3 and R d are hydrogen, halogen, hydroxyl, phenyl, straight or branched C 1 -C 6, preferably C 1 -C 6 -alkyl or C 1 -C 6, preferably C 1 -C 4 -alkoxy, nitro or trifluoromethyl or substituents

R a and R 3 together denote methylenedioxy a

X represents a hydrogen atom, a C 1 -C 6, preferably a C 1 -C 6 -acyl group, and when X represents an ethyl group, the substituents

R 1, R 2, R 5 and R 1 must not simultaneously represent a hydrogen atom and their pharmacologically acceptable salts.

The term halogen means fluorine, chlorine or bromine, preferably chlorine.

The straight or branched alkyl groups of R @ 1, R @ 2, R @ 3 and R @ 4 preferably denote methyl, ethyl, n-propyl, isopropyl or tert-butyl.

It has been found that the novel N- (benzthiazol-2-yl) oxamic acid derivatives of the general formula I have a marked antiallergic effect, both parenterally and orally, which can be demonstrated by a pharmacological test passive cutaneous anaphylaxis (PCA test) in vivo rats. The inhibitory effect of this class of substances can also be conclusively demonstrated in vitro by mast cell-induced degranulation.

An unsubstituted representative of a group of substances according to the invention of the formula I is known from the literature, namely ethyl ester of N- (benzthiazol-2-yl) oxamide (see PA Petjunin, W. Ob. Chim. 34 [1], 28-32 [1964] ]). This ethyl ester, however, does not disclose its therapeutic usefulness or efficacy, only its use as an intermediate in the preparation of N- [benzthiazol-2-yl] oxamide hydrazide, an antituberculous drug.

The novel compounds of the formula I are therefore also valuable intermediates in the synthesis of pharmaceutically usable substances, for example novel N- (benz203179 thiazol-2-yl) oxamic acid hydrazides with antituberculous activity.

The process for the preparation of the compounds of the above formula I and their pharmacologically acceptable salts is carried out by reacting a 2-aminobenzothiazole derivative of the formula I in an aprotic solvent at room temperature or under solvent-free conditions at temperatures up to 150 ° C. II,

wherein the substituents

R 1, R 2, R 3 and R 4 are as defined above, dehydrated by bromination in a suitable solvent, for example chloroform, or

b) according to the Kaufmann method, an aniline derivative of the general formula V in which the substituents

R1, R2, Из and R4 are as defined above, with a oxalic acid derivative of the formula III,

Y — C — C — OX

II o o (III) in which

X is as defined above for (I) and

Y denotes a C 1 -C 6, preferably a C 1 -C 4 -alkoxy group or a halogen atom, or a salt thereof, whereby optionally the substituents R 1, R 2, R 3, R 4 and X are subsequently converted to other substituents R 1, R 2, R 3 R 4 and X and the acids obtained are optionally converted into pharmacologically acceptable salts.

The oxamic acid derivatives of the formula (I) in which X is an atom, a hydrogen or an alkyl group, or salts thereof as intermediates, can be converted into one another by known methods of esterification or saponification, whereas the free carboxylic acids of the formula (I) in which X represents a hydrogen atom, can be obtained by a special variant of the method of preparation thermolytically from the tertiary butyl ester.

It is further possible to convert oxamates of the formula I in which the substituents R1, R2, R3 or R4 denote hydroxyl or alkoxy groups with each other by etherification or cleavage of the ether bond, and at the same time transesterification or saponification can take place.

The 2-aminobenzthiazoles of general formula (II) used as starting compounds are partially novel and are prepared by cyclization reactions known from the literature, so that preferably

a) by the Hugershoff reaction, a thiourea derivative of the general formula IV,

wherein the substituents

R 1, R 2, R 3 and R 4 are as defined above, rhodanate in the ortho position and optionally without isolation of the thiocyanate of formula VI,

fy (VI) wherein the substituents

R 1, R 2, R 3 and R 4 are as defined above, cyclizes to the 2-aminobenzthiazole of formula II.

The thioureas of formula (IV) required as intermediates are in part also novel and can be prepared by methods known in the literature from the above anilines of formula (V) as described in the Examples (Org. Synth. Coll. Vol. III, 735 (1955)). ).

The reaction of the compounds of the formula II with oxalic acid derivatives of the formula III takes place with oxalic acid ester halides, in particular with oxalic acid ethyl ester, in aprotic solvents such as methylene chloride, pyridine, chloroform and carbon tetrachloride at room temperature (method A). The reaction of the 2-amino compound of formula II with dialkyl oxalic esters such as diethyl oxalic acid and ethyl tert-butyl oxalic acid ester is preferably carried out without solvent, under reflux, optionally at temperatures up to about 150 ° C (method

B). The use of ethyl tert-butyl oxalic acid directly produces the free oxamidic acid derivatives, since 2-methyl-1-propene is cleaved thermolytically under the reaction conditions under Method B.

The necessary conversion of the substituents R 1, R 2, R 3, Rd or 'X', optionally subsequent to the condensation, can be carried out by methods known per se. Thus, for example, a compound of formula (II) in which R @ 1 is, for example, hydroxy can be converted into an alkoxy group by treatment with appropriate alkylating agents. Conversely, alkoxy groups can be converted into hydroxy groups by conventional methods. Further, the carboxylic acid esters of formula I (X = alkoxy) in the corresponding carboxylic acid (X-hydrogen atom) can be saponified with mineral acids or alkali metal hydroxides in a polar solvent (such as water, methanol, ethanol, dioxane or acetone). Preferably, the saponification is carried out with a strong base (such as sodium or potassium hydroxide) in a mixture of methanol and water at room temperature or at slightly elevated temperatures. Conversely, however, it is also possible to esterify the carboxylic acids in the usual manner or to convert esters with a certain radical X into an ester with another radical X by esterification. The esterification of the carboxylic acids is expediently carried out in the presence of an acid catalyst such as hydrogen chloride, sulfuric acid, p- toluenesulfonic or strongly acidic ion exchanger. Reconditioning, on the other hand, requires the addition of a small amount of a base such as an alkali metal or alkaline earth metal hydroxide or an alkali metal alcoholate.

To prepare salts with pharmacologically acceptable inorganic or inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, methylglucamine, morpholine or ethanolamine, the carboxylic acids are reacted with the corresponding bases. Mixtures of carboxylic acids with a suitable alkali metal carbonate or bicarbonate are also contemplated.

In the preparation of dosage forms, the compounds of the formula I - in a manner known per se - are mixed with suitable pharmaceutical carriers, flavorings and coloring agents and are formed, for example, as tablets or dragees or are - suspended or dissolved with water in oil, for example in olive oil.

The compounds of formula I may be administered in liquid or solid form orally or parenterally. Water for injection is preferably used, which contains stabilizing agents, solubilizers and / or buffers customary for injection solutions. Such additives are, for example, tartrate or borate buffer, ethanol, dimethylsulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) to control viscosity, or polyethylene derivatives of sorbitan hydrides.

Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal or vegetable fats, or solid high molecular weight. polymers (such as polyethylene glycols). Formulations suitable for oral administration may contain flavoring or sweetening agents, if desired. For external application, the compounds of formula I may be used in the form of powders or ointments; for this purpose they are mixed, for example, with powdered physiologically acceptable diluents or with grease bases.

The following examples illustrate the invention in more detail, but do not limit it.

The structure of the following examples is provided by elemental analysis, infrared, ultraviolet, NMR and mass spectra. From the overall analytical evaluation are given in individual examples - characteristic determination of physical data.

Example 1

N- (4-methoxybenzthiazol-2-yl) -oxamic acid ethyl ester

Method A

18.02 g of 2-amino-4-methoxybenzthiazole (0.1 mol) is dissolved in 250 ml of methylene chloride with the addition of 16.1 ml of pyridine and a solution of 15.01 g is added at 8-10 ° C over 15 minutes. oxalic acid ethyl ester chloride (12.3 mL) (0.11 mol) in 30 mL of methylene chloride. It is then stirred for a further 20 minutes at 10 DEG C., the precipitate formed is filtered off and the filtrate is evaporated in vacuo. The residue was then stirred with dilute hydrochloric acid (about 0.5 N) and the solid collected by suction filtration. It is washed with dilute hydrochloric acid and water, dried (crude product yield 27.8 g, m.p. 173-174 ° C) and recrystallized from nitromethane.

24.8 g of the expected product are obtained, m.p. 174-175 ° C. Yield: 88.47% of theory.

The structure is confirmed by elemental analysis, IR, UV, NMR and mass spectra (MW 280).

Method B

18.02 g 2-A: 4-amino ^^ ^ ^^ t ^] ^ 'o ^{^,} ^ YBI] ^^ ^ 1] hiazo glycol (0.1 mol) was - heated to reflux condenser for 4 hours in 135 ml of di-oxalic acid ethyl ester (1 mol). The reaction mixture is filtered while hot, after cooling the precipitate is filtered off with suction, washed with cold ethanol. and recrystallized from nitromethane. Gets. 18.1 g (64.6% of theory) of the desired product with a melting point of 175 ° C.

The IR spectrum shows identity with the substance obtained by Method A (inter alia carbonyl bands at 1705 cm ⁴ (5.87 µη / a 1740 cm ^-1 (5.75 µm)).

Example 2

N- (4-methoxybenzthiazol-2-yl) oxamic acid (sodium salt)

Method A

a) 5 g of the ethyl ester described in Example 1 (0.0178 mol) was suspended in 150 ml. water and 17.8 ml of 1N sodium hydroxide are added at room temperature over 45 minutes. After stirring for a further 2 hours, the reaction mixture was filtered and the sodium salt of oxamide acid was isolated by lyophilization. The material is then taken up in 100 ml of water, filtered again and the desired acid is liberated after addition of 2N hydrochloric acid. After drying, 3.05 g (68% of theory) of the title compound of melting point 223 DEG -255 DEG C. is obtained.

(b) 1.2 g of acid are suspended in 100 ml of water and neutralized with 4.75 ml of 1N sodium hydroxide. The clear solution is then lyophilized. 1.21 g of N- (4-methoxybenzthiazol-2-yl) -oxamic acid sodium salt (water content 8 ° / o) with a melting point of 255 to 256 ° C (decomposition) is obtained.

Method B g of 2-amino-4-methoxybenzthiazole (0.0277 mol) was heated at 150 ° C for 2 hours with 24.13 g of ethyl tert-butyl ester. oxalic acid. After cooling, the contents of the flask were diluted with ether and filtered off with suction. It is washed with ether to give 6.17 g of compound, m.p. 221-223 ° C. which, how. It was determined, inter alia, by IR, identical to N- (4-methoxybenzthiazole-2-yl) oxamic acid, prepared according to Example 2, by Method A. Yield: 88.3% of theory.

Mass spectrum: mol. weight 252.

Example 3

N- (6-methoxybenzthiazol-2-yl) oxamic acid ethyl ester

As described in Example 1, Method A, 18.02 g of 2-amino-6-methoxybenzthiazole (0.1 mol) is reacted with 15.01 g of oxalic acid ethyl ester chloride (0.11 mol) in

280 ml of methylene chloride in the presence of ml of pyridine. The precipitate is collected by suction and washed. with dilute hydrochloric acid and water. Recrystallization from ethyl acetate yielded 9.1 g of the product, m.p. 193-194 ° C. The first filtrate was evaporated in vacuo, the residue was stirred with ether and the solid product collected by suction filtration. Wash with dilute hydrochloric acid. and water and then crystallized from ethyl acetate with the addition of activated carbon. An additional 11.7 g of a melting point of 192 is obtained. Deň: 32 ° C. The total yield of the desired oxamide acid ethyl ester is thus 20.8 g (74.20% of theory).

IR spectrum: 1730 cm ⁴ (5.78 µη), 1710 cm 1 (5.84 µη) for carbonyl bands; 3270 cm-1 (3.06 μη) for NH bands. Mass. spectrum: mol. weight 280.

Example .4

N- (6-methoxybenzthiazol-2-yl) -oxamic acid

According to Example 2, Method A, 5 g of the oxamic acid ester (0.0178 mol) mentioned in Example 3 are suspended in 150 ml of water and, after addition of 17.8 ml of 1N sodium hydroxide, are saponified for two hours at room temperature. The reaction mixture is filtered and the sodium salt of the desired oxamide. acid. is isolated by lyophilization (m.p. > 300 ° C).

Yield: 4.1 g (84.01% of theory).

Dissolve g of sodium salt in 50 ml of water and acidify the clear solution with 2N hydrochloric acid until pH. 2. The yellow precipitate is filtered off with suction, washed with water and. dried. under vacuum at 50 ° C. 1.4 g of the free oxamide acid with melting point is isolated. Mp 227-228 ° C. Analytically, the structure has been demonstrated, inter alia, by the nuclear magnetic resonance spectrum.

Mass spectrum: mol. weight 252.

Example 1 a d 5

N- (6-ethoxybenzthiazol-2-yl) oxamic acid ethyl ester

According to Example 1,. Method A, 5.8 g of 2-amino-6-ethoxybenzthiazole (0.03 mol) and 4.5 g of oxalic acid ethyl ester chloride (0.033 mol) were reacted within one hour. 85 ml of methylene chloride with addition of 4.83 ml of pyridine. Gets. with 6.7 g of the desired oxamide ester (76% of theory), m.p. 184 ° C (nitromethane).

Mass spectrum: mol. mass: 294. Thin layer chromatography: chloroform: methanol = 9: 1.

Example

N- (6-ethoxybenzthithiazol-2-yl) -oxamic acid ethyl ester

Analogously to Example 1, Method A, 18.02 g of 2-amino-5-methoxybenzthiazole (0.1 mol) was reacted with 15.01 g of oxalic acid ethyl ester chloride (0.11 mol) with the addition of 16.1 ml. pyridine in 280 mL methylene chloride over a total reaction time of 35 minutes at 10 ° C. It is then filtered off with suction, washed with hydrochloric acid (2N) and water and the crude product is crystallized from nitromethane (26.4 g; 94.2% yield; m.p. 165-166 ° C).

22.9 g of the title compound are obtained (yield: 81.7% of theory), m.p. 168-169 ° C. Found mol. Weight: 280

IR spectrum: 1738 cm ^-1 (5.77 µu), 1698 cm ^-1 (5.89 µπι), for carbonyl bands, 3265 cm ^-1 (3.06 µΐη) for NH bands.

Example 7

The N- (5-methoxybenzthiazol-2-yl) oxamide (sodium salt) g ester (0.0178 mol) described in Example 6 was suspended according to Example 2a, b, method A in 150 ml of water and saponified by the addition of 17, 8 ml of sodium hydroxide solution over 2 hours at room temperature. After filtration, the aqueous solution is lyophilized. 3.4 g of the desired sodium salt are obtained (69.7% of theory), melting point: 329 DEG C .; water content: 5%.

A sample of the sodium salt was dissolved in water and 1 N hydrochloric acid was added. The acid thus isolated is analytically pure and has a melting point of 228-229 ° C.

Example 8

N- (7-Isopropyl-4-methoxy-benzthiazol-2-yl) -oxamic acid ethyl ester

a) 7.03 g of benzoyl chloride (0.05 mol) was dissolved in 25 ml of acetone and a solution of 3.8 g (0.05 ml) of ammonium rhodanide in 25 ml of acetone was added at 15-20 ° C. To this solution was added dropwise a solution of 8.26 g of 2-amino-4-isopropylanisole (0.05 mol) in 25 ml of acetone over 10 minutes, heated for

4.5 hours under reflux, poured onto ice and suctioned off to give 1- (5-isopropyl-2-methoxyphenyl) -3-benzoylthiourea as an intermediate which is sufficiently pure for further work-up according to thin layer chromatography.

b) The N-benzoylthiourea prepared in Example 8a was suspended in 150 ml of methanol and 4 g of sodium methylate were added. Immediately a solution is formed, then stirred at room temperature for one hour, 2N hydrochloric acid is added until the pH is 4.0 to 4.5, evaporated in vacuo and the oily residue is triturated with ligroin. The solid product is filtered off with suction, washed with water and dried under vacuum at 70 ° C. There was thus obtained 1- (5-isopropyl-2-methoxyphenyl) thiourea, m.p. 109-111 ° C. Yield: 8.1 g (72.25% of theory, based on 2-amino-4-isopropylanisole).

(c) The thiourea is cyclized to the substituted 2-aminobenzthiazole by the Hugershoff method:

7.85 g of the substituted phenylthiourea (0.035 mol) prepared according to Example 8b are dissolved in 70 ml of chloroform and a solution of 5.7 g of bromine (0.0357 mol) in 10 ml is added at 20-30 ° C over 5 minutes. ml of chloroform. The reaction mixture was heated to reflux for 45 minutes under vigorous hydrogen bromide evolution. The mixture was then allowed to cool, the precipitate was filtered off with suction and stirred first with sodium bisulfite solution and then with 2N sodium hydroxide. The recovered precipitate was washed with water and dried in vacuo.

6.4 g (82.66% of theory) of 2-amino-7-isopropyl-4-methoxybenzthiazole of melting point 198 DEG-191 DEG C. are obtained.

d) To prepare the oxamate, 4.45 g of 2-aminobenzthiazole (0.02 ml), prepared according to Example 8c, according to the method of Example 1, Method A, was reacted with 2.99 g of oxalic acid ethyl ester chloride (0.022 mol) in 60 ml methylene chloride with addition

3.2 ml pyridine. After analogous work-up, the crude product is obtained after crystallization from ethanol with the addition of activated carbon

4.6 g (71.31%) of N- (7-isopropyl-4-methoxybenzthiazol-2-yl) -oxamic acid ethyl ester, m.p. 180-181 ° C.

Mass spectrum: mol. weight 322.

Example 9

N- (4-Methoxy-7-phenyl-benzothiazol-2-yl) -oxamic acid ethyl ester

a) According to Example 8a, 9.96 g (0.05 mol) of 2-amino-4-phenylanisole, 3.8 g (0.05 mol) of ammonium rhodanide and 5.8 ml of benzoyl chloride (0.05 mol) are obtained. in 50 ml of acetone as a crude product in practically quantitative yield of 1 - [(2-methoxy-5-phenyl) phenyl] -3-benzoylthiourea, m.p. 138-142 ° C.

b) Analogously to Example 8b, 10.68 g (82.79% of theory, based on the starting anisole derivative) of 1 - [(2-methoxy-5-phenyl) are obtained from the N-benzoyl compound of Example 9a by adding sodium methylate to a methanolic suspension. phenyl] thiourea, m.p. 190-192 ° C.

c) Analogously to Example 8c, the thiourea described in Example 9b with 1.98 ml (0.0388 mol) of bromine in 75 ml of chlo203179 isoform 7.17 g of solid, m.p. to 190 ° C. It is a 2-amino-4-methoxy-7-phenylbenzthiazole hydrobromide addition compound with 1 mole of free base. After treatment with an aqueous potassium hydrogen carbonate solution, 5.82 g of the desired substituted 2-aminobenzothiazole of melting point 202 DEG-204 DEG C. remained. Yield: 73%.

d] The conversion to the oxamate is carried out according to Example 8d. Starting from 5.8 g (0.0226 mol) of the 2-aminobenzthiazole prepared according to Example 9c was obtained with 3.95 ml of oxalic acid chloride in 90 ml of methylene chloride and 5 ml of pyridine. 38% (theory) of N- (4-methoxy-7-phenylbenzthiazol-2-yl) oxamide, ethyl ester, m.p. 183-185 ° C.

Found mol. Mass 356. Other analytical evaluations, including the nuclear magnetic resonance spectrum, confirm the structure.

He did

N- (7-tert-butyl-4-methoxybenzthiazol-2-yl) oxamide, ethyl ester

The preparation is carried out according to the regulations described in Examples 8a to d:

a) 1- (5-tert-Butyl-2-methoxyphenyl) -3-benzbylthiourea is obtained from 2-amino-4-tert-butylanisole, ammonium rhodanide and benzoyl chloride in almost quantitative yield of the crude product, m.p. C.

b) 1- (5-tert-butyl-2-methoxyphenyl) thiourea was obtained by alkaline debenzoylation of the benzoylthiourea described in Example 10a with dilute sodium hydroxide solution or methanolic sodium methylate solution in 75% yield based on the starting anisole derivative. Melting point: 166-167 ° C.

c) The Hugershoff reaction yielded, according to Example 8c, from 4.76 g (0.02 mol) of the phenylthiourea prepared according to Example 9b;

3.27 g of bromine (0.0204 mol) in 40 ml of chloroform 4.1 g (86.86% of theory) of 2-amino-7-tert-butyl-4-methoxybenzthiazole, m.p. 225 DEG-226 DEG.

d) Analogously to Example 1, Method A, 3.54 g (0.015 mol) of the 2-aminobenzthiazole prepared according to Example 10c are reacted with 2.25 g of oxalic acid chloride · ester in 45 ml of methylene chloride and 2.5 ml of pyridine. . Recrystallization of the crude product from ethanol gave 3.5 g (69.44% of theory) of N- (7-tert-butyl-4-methoxybenzthiazol-2-yl) oxamide, ethyl ester, m.p. 181-182 ° C.

Mass spectrum: mol. mass 336. UV spectrum (MeOH): 308 nm · log ε 4.04.

Example 11

Ethyl ester · · N- (4,7-dimethoxybenzthiazol-2-yl) oxamic acid

The preparation is carried out according to the regulations given in Examples 8a to d:

a) 1- (2,5-dimethoxyphenyl) -3-benzoylthiourea is obtained from 2,5-dimethoxyaniline, benzoyl chloride and ammonium rhodanide (molar ratio 1: 1: 1) in acetone. The crude product, obtained practically in quantitative yield, has a melting point of 140-144 ° C.

b) 1- (2,5-dimethoxyphenyl) thiourea Prepared from the crude product described in Example 11a by treatment with methanolic sodium methylate solution. 13.12 g (61.9% of theory) of the desired thiourea are isolated from 15.1 g of 2,5-dimethoxyaniline (0.1 mol), m.p. 160-162 ° C.

c) Hugershoff cyclization yielded from 12 g (0.056 mol) of the thiourea described in Example 11b with bromine in chloroform 9.41 g (79.54% of theory) of 2-amino-4,7-dimethoxybenzthiazole with temperature mp 210-213 ° C.

(d) 7 g of aminobenzthiazole from Example 11c (0.03 mol) were treated with 4.78 ml of oxalic acid chloride in 100 ml of methylene chloride and 6.3 ml of pyridine. 7.55 g (81.1% of theory) of N- (4,7-dimethoxybenzthiazol-2-yl) oxamic acid ethyl ester of melting point 223 DEG-225 DEG C. are obtained.

Mass spectrum: mol. mass 310. UV spectrum (MeOH), λmax: 308 nm loge 4.01.

Example 12 .....

N- (5,6-Dimethoxybenzthiazol-2-yl) oxamic acid ethyl ester

a) According to Examples 8a and 8b, 113.6 g of ammonium rhodanide in 620 ml of acetone were obtained from 100 g of 3,4-dimethoxyaniline (0.65 mol), 94.2 g of benzoyl chloride (0.67 mol) and 620 g of acetone. (83.31% of theory) of 1- (3,4-dimethoxyphenyl) thiourea (after recrystallization from ethanol). Melting point: 228-230 ° C.

b) According to the Hugershoff method described in Example 8c, the cyclization of 106.13 g (0.5 mol) of the thiourea prepared according to Example 12a was carried out in 89.1% yield (93.7 g after recrystallization from ethanol) with formation of 2-amino-5,6-dimethoxybenzthiazole. Melting point: 220-221 ° C.

c) Following the procedure of Example 1, Method A, 6.3 g (0.03 mol) of the aminobenzthiazole prepared according to Example 12b were reacted with 4.3 ml of oxalic acid chloride in 100 ml of methylene chloride. and

5.6 ml of pyridine to give 7.14 g (76.7% of theory) of N- (5,6-dimethoxybenzthiazol-2-yl) oxamide, ethyl ester, m.p. 190-191 ° C (from ethanol).

Mass spectrum: mol. mass 310 / UF-spectrum (MeOH): λ max 331 nm λ log 4.09.

Example 13

N- (4,6-dimethoxybenzthiazol-2-yl) oxamic acid ethyl ester

In analogy to Example 11 for 4,7-dimethoxy-, in Example 12 for 5,6-dimethoxy derivative, 2-amino-4,6-dimethoxybenzthiazole oxamic acid ester is obtained from 2,4-dimethoxyaniline.

Example 14

N- (6-methoxy-5,7-dimethylbenzthiazol-2-yl) oxamic acid ethyl ester

The working conditions given in Examples 8a to d are followed:

a) 1- (4-Methoxy-3,5-dimethylthio) -3-benzoylthiourea in virtually quantitative yield from 4-amino-ino-2,1,1-c-ii (4-methoxy) -4-ylanisole ammonium rhodanide and benzyl chloride Melting point: 118 to 120 ° C (crude product containing acetone).

b) 1- (4-Methoxy-3,5-l-thiazole) thiourea by debenzoylation of the compound obtained in Example 14a.

Yield: 81.35% of theory. M.p .: 216-217 ° C.

c) -2-Amino-6-methoxy-5,7-dimethylbenzthiazole - was obtained by Hugershoff cyclization of the thiourea obtained according to Example 14b (batch size e.g. 8 g = 0.038 mol) in 65% yield. Melting point: 191-193 ° C.

d) From 4.7 g (0.0225 mol) of aminobenzthiazole prepared according to Example 14c, 3.2 ml of oxalic acid chloride (0.0286 mol) in 75 ml of methylene chloride and 4.1 ml of pyridine 6 are obtained. 45 g (93% of theory) of N- (6-methoxy-5,7-dimethyl-benzenesothiazol-2-yl) -oxamic acid ethyl ester. Melting point: 159-160 ° C.

Mass spectrum: mol. mass 308. UV spectrum: λ max 327 nm loge 4'09.

Example 15

N- (4-Methoxy-5,7-dimethylbenzthiazol-2-yl) oxamic acid ethyl ester

(a) Analogously to the procedure of Examples 8a, b, 7.56 g of 2-amino-4,6-dimethylanisole (0.05 mol), benzoyl chloride and ammonium rhodanide are obtained, without characterization of the N-benzoyl intermediate 8, 1 g of 1- (2-methoxy-3,5-dimethyl) thiourea. Yield: 77%. M.p .: 141-142 ° C.

b) The substituted thiourea of Example 15a was reacted in an amount of 7.36 g - (0.035 mol) analogously to Example 8c with bromine in chloroform to give 2-amino-4-methoxy-5,7-dimethylbenzthiazole. Yield: 97.3% of theory 77.1 g) (m.p.) 164-166 ° C.

c) 4.16 g (0.02 mol) of the aminobenzthiazole described in Ex. 15b, according to Ex. Method A, was reacted with 2.99 g of oxalic acid ester chloride (0.022 mol) in 60 ml of methylene chloride and 3.2 ml of pyridine. Recrystallization from ethanol gave 5.0 g (81.16% of theory) of N- (4-methoxy-5,7-dimethyl-benzothiazol-2-yl) -oxamic acid ethyl ester, m.p. 143-144 ° C.

Mass spectrum: mol. mass 308. UF-spectrum: Amax 308 nm loge

4.10. The NMR spectrum (DDMSO) confirms the structure.

Example 16

N- (Benzothiazol-2-yl) -2-oxamic acid ethyl ester

4.5 g (0.03 mol) of commercial 2-aminobenzthiazole were reacted as described in Example 1, Method A, with 4.5 g of oxalic acid ester chloride. 6.6 g of the title compound (88% of theory), m.p. 187 DEG-188 DEG C. (from ethanol), were obtained.

P. A. Petjuni, describe this chemical chemistry (S. Obsc. Chim. 34, 28-34 (1964)), with a melting point of 183-38.

184.5 ° C.

Example 17

N- (4-Methylbenzimidazol-2-yl) oxamic acid ethyl ester

a) Analogously to Examples 8a, b, 1- (β-β-ω-β-1) -thiourea is prepared from ammonium rhodanide and benzoyl chloride. M.p .: 158-159 ° C.

b) According to Example 8c, the 2-amino-4-methylbenzimidazole was prepared from the thiourea of Example 17a (16.6 g / 0.1 mol) by the Hugerehoff reaction. Yield: 12.5 g (76.21% of theory). M.p .: 136-137 ° C.

(c) Method A of Example 1 yielded from 4.9 g (0.03 mol) of aminobenzothiazole according to Example 17b and 4.5 g of oxalic acid ester chloride (0.033 mol) in 90 ml of methylene chloride and 4.8 ml of pyridine after the usual procedure. work-up 7.4 g (93.7% of theory) of N- (4-methyl-benzothiazol-2-yl) -oxamic acid ethyl ester, m.p. 191-192 ° C. After overlapping the ethyl acetate with ethyl acetate, the melting point no longer increases.

IR: 5.74 .mu.m and 5.86 .mu.m (carbonyl). Mass spectrum: mol. mass 264. UV spectrum (MeOH): λ max 309 nm logs

4.10.

Example 18

N- (5,6-Dimethyl-benzthiazol-2-yl) -oxamic acid ethyl ester

The commercially available 2-amino-5,6-dimethylbenzthiazole (17.8 g / 0.1 mol) was reacted according to Example 1, Method A, with 15 g oxalic acid chloride chloride (0.11 mol) in 250 ml methylene chloride and 16.1 ml of pyridine. 23.3 g (54.6% of theory) of the title compound of melting point 155 DEG-157 DEG C. are obtained. After recrystallization from ethanol, the melting point is between 156.5 and 157 ° C.

Mass spectrum: mol. mass 278. UV spectrum: λ max (MeOH) 316 nm log ,12 4.12. IR spectrum: 1740 cm ^-1 (5.57 / g), 1705 cm ^-1 (5.87 / g).

Example 19

N- (4-chlorobenzthiazol-2-yl) oxamic acid ethyl ester

The commercially available 2-amino-4-chlorobenzthlazole (0.1 mol / 18.4 g) was treated as described in Example 1, Method A, with 15 g of oxalic acid ester chloride (0.11 µl) in 280 ml of methylene chloride and 16 ml. 1 ml pyridine. 23.3 g (82.04% of theory) of an analytically pure title compound of melting point 238 DEG-239 DEG C. are obtained.

Recrystallization from ethoxyethanol did not change the melting point.

Mass spectrum: mol. mass 284. IR spectrum: ester carbonyl 1732 cm ^-1 (5.77 µmη) amide carbonyl 1710 cm ¹ (5.85 / лп).

Example 20

N- (7-chloro-4-methoxybenzthiazol-2-yl) oxamic acid ethyl ether

a) According to Example 8a, it is reacted

157.6 g of 2-methoxy-5-chloroaniline (1 mol) with 145.1 g of benzoyl chloride and 78.3 g of ammonium rhodanide in 1000 ml of acetone. 1- (2-Methoxy-5-chlorophenyl) -3-benzoylthiourea is obtained, which is further processed as a crude product.

b) All of the N-benzoyl compound still wet with acetone was stirred in 2.8 liters of 2N sodium hydroxide, heated to reflux for 10 minutes and filtered while hot. Then, the filtrate was cooled to 5 ° C, the precipitate was filtered off with suction, stirred with sodium bicarbonate solution and the filtered solid was washed with water. 1- (2-methoxy-5-chlorophenyl) thiourea, m.p. 125-130 ° C. Yield:

182.5 g (84.23% of theory, based on the starting chloranisidine).

c) According to Example 8c, 108.4 g of the thiourea obtained in Example 20b were cyclized by the Hugershoff method. 46.4 g (43.2% of theory) of 2-amino-7-chloro-4-methoxybenzthlazole of melting point 200 DEG-203 DEG C. are obtained as the first precipitate. A further 30-40% of the desired compound can be isolated from the mother liquors.

d) The 2-aminobenzthiazole obtained according to Example 20c is charged in the batch with 0.03 moles, analogously to the procedure of Example 8d and III, respectively. of Example 1, Method A, is allowed to react. There was thus obtained N- (7-chloro-4-methoxybenzthiazol-2-yl) oxamic acid ethyl ester of melting point 233 DEG-235 DEG C. in 70 to 80% yield.

Mass spectrum: mol. weight 314. UV spectrum: λ max (MeOH) 305 nm loge 4.08.

Example 21

N- (5-chloro-4-methoxybenzthiazol-2-yl) oxamic acid ethyl ester

a) 1- (3-chloro-2-methoxyphenyl) thiourea was prepared analogously to Examples 8a and 8b via the N-benzoyl compound.

Melting point: 116-119 ° C. Total yield: 90.53% of theory.

b) 2-Amino-5-chloro-4-methoxybenzthiazole was obtained in 83% yield from the thiourea of Example 21a by the Hugershoff method of Example 8c. Melting point: 185-187 ° C.

c) 10.73 g (0.05 mol) of 2-aminobenzthiazole from Example 21b is reacted with 7.5 g of oxalic acid chloride chloride (0.55 mol) in 150 ml of methylene chloride and 8 ml of pyridine analogously to Example 8d to formation of N- (5-chloro-4-methoxybenzthiazol-2-yl) oxamic acid ethyl ester. After recrystallization from ethanol, 13 g (82.8% of theory) of the desired product are isolated. Melting point: 186-187 ° C.

Mass spectrum: mol. mass 314. IR: 1694 cm ^"1 / 5.90 pm amide carbonyl.

Example 22

N- (4-Chloro-7-methoxy-benzothiazol-2-yl) -oxamic acid ethyl ester

(a) The following intermediates are synthesized in analogy to the working procedures given in Examples 8a to 8c:

1- (2-Chloro-5-methoxyphenyl) -3-benzoylthio203179 urea, m.p. 159-161 ° C. Practically quantitative yield.

1- (2-Chloro-5-methoxyphenyl) thiourea, m.p. 168-170 ° C. Yield: 80.97% of theory.

2-Amino-4-chloro-7-methoxybenzthiazole, m.p. 266-267 ° C. Yield: 92.16% of theory.

b) According to the synthesis of Example 1, Method A, 6.44 g of 2-amino-4-chloro-7-methoxybenzthiazole (0.03 mol) was reacted with 4.5 g of oxalic acid ethyl ester chloride (0.033 mol) in 85 ml of methylene chloride and 4.8 ml of pyridine. 8.7 g (92.16% of theory) of N- (4-chloro-7-methoxy-benzothiazol-2-yl) -oxamic acid ethyl ester of melting point 266 DEG-267 DEG C. are isolated.

Mass spectrum: mol. mass 314. UV spectrum: Amax (MeOH) 300 nm loge 4.07. IR: 5.78 μη; 5.85 µm ester, respectively. amide carbonyl.

Example 23

N- (4-Trifluoromethylbenzthiazol-2-yl) oxamic acid ethyl ester

a) 2- (Trifluoromethyl) phenylthiourea was obtained according to Examples 8a and 8b from 2-trifluoromethylaniline in 81% yield. M.p .: 158-160 ° C.

b) From the thiourea of Example 23a, 2-amino-4-trifluoromethylbenzthiazole, m.p. 149-151 ° C, was obtained by oxidative cyclization according to Example 8c.

c) 4.36 g (0.02 mol) of 2-amino-4-trifluoromethylbenzthiazole was reacted according to Example 1, Method A, with 2.99 g (0.22 mol) of oxalic acid ethyl ester chloride. Recrystallization from ethyl acetate gave 5.0 g (78.6% of theory) of N- (4-trifluoromethyl-benzothiazol-2-yl) -oxamic acid ethyl ester, m.p. 219-220 ° C.

Mass spectrum: mol. mass 318. UV spectrum: 317 nm (MeOH) logo 4.16. IR spectrum: 3246 cm @ ^-1 (3.08 .mu.m) NH bands; 1742 cm ^-1 (5.74 μπι), 1700 cm ^-1 (5.88 μΐη) ester and amide carbonyl.

Example 24

N- (6-nitrobenzthiazol-2-yl) oxamic acid ethyl ester

5.85 g (0.03 mol) of commercially available 2-amino-6-nitrobenzthiazole were reacted as described in Example 1, Method A, with 4.5 g of oxalic acid ethyl ester chloride (0.033 mol) in 85 ml of methylene chloride. and 4.8 ml of pyridine for 45 minutes. 7.7 g (87% of theory) of the title compound of melting point 253 DEG-254 DEG C. are obtained.

Mass spectrum: mol. weight 295.

Example 25

N- (4-Nitrobenzthiazol-2-yl) -oxamic acid ethyl ester

a) 2-Amino-4-nitrobenzthiazole was prepared analogously to the literature data of H. Erlenmayer and H. Ueberwasser (Helv. Chim. Acta 23, 328, (1940)) in 88% yield from 2-nitrophenylthiourea. Melting point: 263-265 ° C.

b) 5.85 g (0.03 mol) of 2-amino-4-nitrobenzthiazole are reacted according to Example 1, Method A, with 4.5 g of oxalic acid ethyl ester chloride (0.033 mol) in 85 ml of methylene chloride and 4, 8 ml of pyridine over 1.5 hours. The crude product was freed from impurities by boiling in nitro methane. 6.7 g (75.7% of theory) of N- (4-nitrobenzthiazol-2-yl) -oxamic acid ethyl ester of melting point 269 DEG-270 DEG C. are obtained.

Mass spectrum: mol. mass 295. IR spectrum: 3290 cm ^-1 (3.94 µm) NH bands; 1728 cm @ ^-1 (5.79 дт), 1710 cm @ ^-1 (5.85 μπι) ester, respectively. amide carbonyl.

Example 26

N- (4-methoxy-6-nitrobenzthiazol-2-yl) oxamic acid ethyl ester

(a) 2-Amino-4-methoxy-6-nitrobenzthiazole is prepared by Kaufmann rhodanation as follows:

250 g (1.49 mol) of 2-methoxy-4-nitroaniline are suspended in 440 ml of glacial acetic acid and 300 g of potassium rhodanide (3.1 mol) are added. A solution of 237 g of bromine in 440 ml of glacial acetic acid is then added dropwise at room temperature with vigorous stirring and stirred at room temperature for 72 hours. It is then diluted with 2.5 liters of water, the precipitate is filtered off with suction, stirred with dilute aqueous ammonia solution and filtered off with suction again. The precipitate is washed with plenty of water, a small amount of ethanol and a little ether, and dried. The desired product is isolated in a yield of 282.6 g (84.4 percent of theory), m.p. 260 DEG-265 DEG. It is clean enough for further processing.

b) According to Method A in Example 1, 6.75 g (0.03 ml) of 2-aminobenzthiazole prepared according to Example 26a was reacted with

4.5 g of oxalic acid ethyl ester chloride (0.033 mol) in 85 ml of methylene chloride and 4.83 ml of pyridine over 30 minutes. The isolated crude product is boiled with 300 ml of ethanol and filtered while hot. Isolate

6.5 g (64.94% of theory) of N- (4-methoxy-6-nitrobenzthiazol-2-yl) -oxamic acid ethyl ester, m.p. 270-271 ° C.

IR: 3270 cm @ ^-1 (3.06 .mu.m / NH bands).

1700 cm ^-1 (5.88 μη) 1710 cm ^-1 (5.85 μη) double bands and 1728 cm ^-1 (5.79 μη) for amide respectively. ester carbonyls.

UV spectrum:? 364 nm log? 4.10. The mass spectrum was confirmed by mol. weight 325.

Example 27

N- (1,3-dioxolo [4,5-f] benzthiazol-6-yl) oxamide, ethyl ester

a) 1- (3,4-Methylenedioxyphenyl) -3-benzoylthiourea was prepared in 91.7% yield analogously to Example 8 and from 3,4-methylenedioxyaniline, ammonium rhodanide and benzoyl chloride. Melting point: 160-161 ° C (from methanol).

b) 1- (3,4-Methylenedioxyphenyl) thiourea was prepared from the N-benzoyl compound with sodium methylate in methanol according to Example 8b in a total yield of 76.53% (based on the starting analine). Mp .: 205-206 ° C.

c) From the thiourea of Example 27b (14.7 g / 0.075 mol), the Hugershoff reaction was analogously to Example 8c prepared by oxidation cyclization with bromine 6-amino-1,3-dioxolo [4,5- f] benzthiazole. Yield: 12.4 g (85.1% of theory). Melting point: 228-229 ° C.

d) Analogously to Example 1, Method A, 5.8 g (0.03 mol) of the 2-aminobenzothiazole methylenedioxy derivative (Example 27c) is reacted with 4.5 g of oxalic acid chloride in 85 ml of methylene chloride and 4.84 ml. pyridine, over 1 hour. The crude product is recrystallized from nitromethane.

The yield of pure N (1,3-dloxolo [4,5- f] benzthiazol-6-yl) oxamic acid ethyl ester was 7.1 g (80.5% of theory). Melting point: 241-242 ° C.

Example 28

N- (4-Hydroxybenzothiazol-2-yl) -oxamic acid ester (methyl and ethyl ester)

5.6 g (0.02 mol) of N- (4-methoxybenzthiazol-2-yl) oxamide-ethyl ester, prepared according to EXAMPLE 4 1, Method A, was dissolved in 200 ml of chloroform, cooled to -20 [deg.] C., and a solution of 10 g of boron tribromide (0.04 mol) in 50 ml of chloroform was added over 15 minutes. The reaction mixture was then allowed to warm to room temperature, an equal amount (3.78 mL) of boron tribromide was added at -10 ° C and stirred for 2 hours at room temperature. Further boron tribromide (0.01 mol) was complete. Methanol was then added and the resulting precipitate was filtered off with suction. 5 g of precipitate are obtained, m.p. 205 DEG-212 DEG C., which is a mixture of the methyl ester and the ethyl ester of the desired oxamide acid, which is formed by demethylation and simultaneous partial transesterification.

Mass spectrum: Found

252 (methyl ester)

266 (ethyl ester).

EXAMPLE 29 N- (6-Methoxybenzthiazol-2-yl) oxamide g-tert-butyl oxalic acid ester (0.15 mol) prepared according to L. A. Carpino, J. Chem. 82, 2725; 1960) in 100 ml of xylene was heated to 100 ° C and 18 g of 2-amino-6-methoxybenzthiazole (0.1 mol) was added. After stirring the reaction mixture at 100 ° C for 8 hours, it is cooled and filtered off with suction. The residue is boiled with ethyl acetate and filtered while hot. The precipitate formed is stirred with 2N hydrochloric acid and then with potassium carbonate solution and filtered off with suction. This residue was dissolved in methylene chloride, filtered and evaporated. The residue is triturated with ether and the crystals formed are filtered off with suction.

Yield: 8.1 g of N- (6-methoxybenzthiazol-2-yl) oxamide tert-butyl ester, m.p. 230-232 ° C.

Example 30

N- (6-Propoxybenzthiazol-2-yl) oxamic acid ethyl ester

As described in Example 1, Method A, 5 g of 2-amino-6-propoxybenzthiazole is reacted with ethyl oxalate chloride in pyridine and methylene chloride. 5.8 g of the desired oxamic acid ethyl ester (78% of theory), m.p. 143 DEG-145 DEG C., is obtained.

Results of pharmacological tests

With appropriate dosage and methods of using the compounds of the invention are comparable to commercially known compound "Fragivix", i.e. 2-ethyl-3- ^{(4-hydroxybenzoyl)} benzofuran. They can also be administered orally. The compounds of the invention allow extensive therapy for both acute and chronic phlebological and capillary affections, as well as vasicosis syndromes. The compounds of the invention slow down reactions leading to edema, including those of allergic origin.

A typical daily dose of 10 to 300 mg usually results in a reduction or elimination of the above-mentioned affections within a few days. The preferred dose is 30 to 100 mg.

Higher efficacy of the novel agents is demonstrated by comparing inhibition of passive cutaneous anaphylactic reactions in rats induced by injection of serum containing antibodies reactive to egg albumin. Diethylcarbamazine, i.e. 1-diethylcarbamoyl-4-methylpiperazine, was used as reference.

In particular, the following tests were carried out:

IgE containing egg albumin-reactive antibody (IgE type) was obtained by intramuscular injection in rats of 0.1 ml of an antigen solution (10 mg / kg) in sodium chloride solution together with 0.5 ml of Bordetell's cough vaccine (Behring; 2 X). 10 10 microbes / ml). After 9 to 14 days, animals were bled from the abdominal aorta, the serum was mixed and stored at -20 ° C until use. Serum titer, ie the highest dilution inducing passive cutaneous anaphylaxis (PCA) in the rat after a 48 hour latency period was between 1: 8: 32. The serum for use in these experiments was diluted 1: 24. The reactive character of the antibody was demonstrated by its ability to induce PCA after seven days of latent period as well as destruction of PCA activity by heating for 1 hour at 56 ° C.

Animals were anesthetized with 2,2-dlchloro-1,1,1-difluoroethyl methyl ether, marketed under the name Penthran, and sensitized by injecting 0.1 ml of antiserum into shaved abdo22 min flanks. After 48 hours for reactive PCA, the animals were injected intravenously with 1 ml of sodium chloride solution containing 0.5% by weight, egg albumin and 0.25% by weight. Evans blue.

After killing and bleeding the animals, the extent in square millimeters and the intensity of the resulting blue spot in the arbitrary grooves were evaluated.

The result of these two parameters was used to evaluate the degree of reaction, and the degree of reaction without using the active material served as a standard against the rate of inhibition of the anaphylactic reaction.

Six animals were used for the determination and control.

The test material was in some cases administered intravenously (i. V.) Immediately before the antigen using an aqueous solution containing 0.5% hydrochloric acid and 2% dimethylformamide and in other cases orally 10 or 40 minutes before the antigen. The application volume was varied to provide the indicated dose of active material. The following results were achieved:

Table

PCA reaction induced by reactive counter- (2 X crystallized ovalbumin and Bord. Vaccinia tin cough 2 X 10 ¹⁰ )

Administration of substances: oral 40 minutes before antigen (* or 10 minutes before antigen) (i. V. Immediately before antigen o-

rally) orally Active material i. v. dose mg / kg inhibition of PCA% dose mg / kg inhibition of PCA% diethylcarbamazine 60.0 58 60.0 10 Example 1 - - 1.5 75 Example 2 0.015 74 1.5 34 Example 3 - - 3.0 35 Example 6 - - 3.0 48 Example 7 0.15 71 1.5 30 Example 8 - - 3.0 29 * Example 12 - - 3.0 30 Example 14 - - 3.0 25 Example 15 -. - 3.0 40 Example 20 - -. 3.0 38 Example 22 - - 3.0 30 Example 25 - - 3.0 25 *

These pharmacological data show that the new compounds administered intravenously or orally have far more potent anti-anaphylactoid activity than diethylcarbamazine.

It is to be understood that the application and examples illustrate and not limit the invention, and that various modifications and changes may be made without departing from the scope thereof. it is clear from the spirit and scope of the invention.

Claims (1)

A process for the preparation of N- (benzthiazol-2-yl) oxamic acid derivatives of the general formula I, in which the substituents R 1, R 2, R 3 and R 1 are hydrogen, halogen, hydroxyl, phenyl, straight or branched C 1 -C 6, preferably C 1 -C 6 -alkyl or C 1 -C 6, preferably C 1 -C 1 -alkoxy, nitro or trifluoromethyl, or substituents R2 and R3 taken together are methylenedioxy and X represents a hydrogen atom, a C 1 -C 6, preferably a C 1 -C 6 -alkyl group, and when X represents an ethyl group, the substituents R1, R2, R3 and R1 must not simultaneously represent a hydrogen atom or a pharmacologically acceptable salt thereof, characterized in that a 2-aminobenzothiazole derivative is reacted in an aprotic solvent at room temperature or under solvent-free conditions at temperatures up to 150 ° C of the general formula II in which the substituents R1, R2, R3 and R4 are as defined above, with a oxalic acid derivative of formula III, Y — C — C — OX II o o (III) in which X is as defined above and Y represents a C 1 -C 6, preferably a C 1 -C 6 -alkoxy or halogen atom, or a salt thereof, whereby optionally the substituents R 1, R 2, R 3, R 1 and X are additionally converted into other R 1 substituents after coupling in a manner known per se R 2, R 3, R d and X and the optionally obtained acids are converted into pharmacologically acceptable salts.