DE1926558A1 - 2-arenesulphonamido-tetrahydro-benzoxaz- - oles with hypoglycaemic activity - Google Patents

Abstract

2-Arenesulphonamido-tetrahydro-benzoxazoles with hypoglycaemic activity. New cpds. of formula (I) (where R1 is phenyl, 4-Cl-phenyl, 2-carboxyphenyl or 2-OMe-5-Cl-phenyl, R2 is H or R1-CONR2- is phthalimido or homohthalimido, R3 is H or Me and A is a C2 divalent aliphatic hydrocarbon gp) and their alkali salts are prepd. by reacting p-(R1'CO-NR2-A-) benzenesulphonyl chloride (where R'1 is R1 or is lower alkyl) with a 2-amino-6-R3-tetrahydrobenzoxazole and, when R'1 is lower alkyl, hydrolysing the reaction product with dilute alkali and reacting the hydrolysis product with a reactive deriv. of R1COOH to give (I) or, when R1CO-NR2- is phthalimido, opt. hydrolysing with dilute alkali to give (I) in which R1 is 2-carboxyphenyl.

Description

New sulfonamides and processes for their preparation The invention relates to new sulfonamides of the general formula I. and a method for their production.

In the above formula 1, R1 denotes a phenyl, 4-chlorophenyl, 2-carboxyphenyl or a 2-methoxy-5-chlorophenyl radical, R2 is a hydrogen atom or together with the radical R1-OO- and the nitrogen atom a phthalamido or Homophthalimido groups, a hydrogen atom or the methyl group and A a divalent group aliphatic hydrocarbon radical with 2 carbon atoms.

The new compounds are characterized by a very good blood sugar lowering effect in low doses, their toxicity is greater.

The compounds are produced by reacting a sulfochloride of the formula II in which @ R1 'is any lower alkyl radical and R21 is a hydrogen atom or R1 and R21 have the meanings given above for R1 and R2, and A is as defined above, with a 2-amino-benzoxazole of the formula III in which R3 has the meanings mentioned at the beginning.

The reaction takes place in the presence of a hydrogen chloride binding agent Means, for example an inorganic or tertiary organic base, expedient in the presence of an inert organic solvent at elevated temperatures, preferably at temperatures up to 100 ° C. Used as an agent that binds hydrogen chloride a tertiary organic base is used, this can be in a corresponding excess serve as a solvent at the same time; the preferred solvent is pyridine used.

If one starts out from a compound of formula II in which the radicals R1 and R2 have the meanings given for R1 and R2, the desired end products are obtained directly. If, however, a compound of the formula II is used in which Rj is any lower alkyl radical, the reaction product obtained is first saponified using dilute alkyls and the compound of the formula IV obtained in which A and R have the meanings defined at the outset, with a reactive derivative of a carboxylic acid of the formula V R1-COOH V in which R1 has the meanings defined in formula 1, in particular an ester, an acid halide, a symmetrical anhydride or a mixed anhydride acylated with an eohlic acid ester.

The production of the sulfochlorides used as starting materials Formula II is carried out by known methods, for example by sulfochlorination of the corresponding phenylethylamides analogous to that of E. Miller J. M. Sprague, L. W. Kissinger and L. F. Mc.

Budney, J. Am. Chem. Soc. 62, 2100 (1940).

The 2-amino-benzoxazoles of the formula III are from Bull.Soc.Chin.

Prance 1967 (6) 204 - 43 known, or can be analogous to that described there Process are produced.

If compounds are obtained by the method described, in which the radical R1 is a 2-carboxyphenyl radical, these can, if desired subsequently by splitting off water in the melt at 180 - 200 ° C or by heating in a high-boiling inert solvent, for example Xylene, the water formed is expediently distilled off azeotropically into such compounds be transferred, in which the radical R1-CO- together with R2 and the nitrogen atom means a phthalimido radical. On the other hand, phthalimido compounds formed can if desired, subsequently by treatment with dilute alkalis at room temperature or moderately elevated temperature can be converted into compounds in which R1 denotes the 2-carboxyphenyl radical.

The compounds of the formula I obtained can, if desired, according to known methods are converted into their alkali salts.

The examples given below describe the production process of the new sulfonamides of the formula I: 1) 2- [4- (2-benzamido-ethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole 9.75 g (30mM) 4- (2-benzamido-ethyl) -benzenesulfochloride, B. = 127 - 129 ° C to a solution of 4.15 g (30 mM) 2-amino-4,5,6,7-tetrahydro-benzoxazole in 40 ml Pyridine was added and the mixture was heated on a water bath for 30 minutes. The solvent is in Vacuum largely distilled off, from the distillation residue is diluted with Hydrochloric acid precipitated the crude product. The crude product is cleaned in sodium hydroxide solution dissolved and precipitated with dilute hydrochloric acid and the precipitation recrystallized from acetone. Yield 5.4 g = 42.4% of theory.

B. = 216 - 21800 C22H23N3O4S C calc. 62.10 H calc. 5.45% N calc. 9.87 % C found 62.00% H found. 5.66% N found. 9.71% 2) 2- [4- (2-benzamido-ethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole Manufactured from 4- (1-benzamido-ethyl) -benzenesulphochloride, mp = 141 ° C, and 2-amino-4,5,6,7-tetrahydro-benzoxazole according to Example 1.

Yield: 43.7% of theory; B. = 205 ° C (acetone) C22H23N3O4S C calcd. 62.10 % H calc. 5.45% N calc. 9.87% C found. 62.20 H found. 5.54% N found. 9.50% 3) 2- {4- [2- (4-chlorobenzamido) ethyl] benzenesulfonamido} -4,5,6,7-tetrahydro-6-methyl-benzoxazole Manufactured from 4- [2- (4-chlorobenzamido) ethyl] benzene sulfochloride, mp = 128 ° C, and 2-Amino-4,5,6,7-tetrahydro-6-methylbenzoxazole, mp = 104-105 ° C, according to the example 1.

Yield: 30% of theory; B. = 16200 (acetone: ethanol 8: 2) C23H24N3ClO4S # H2O C calc. 56.10% H calc. 5.43 C, 3 # N N calc. 8.55% C found. 56.10% H found. 5.48% N found 8.18% 4) 2- {4- [2- (4-chlorobenzamido) ethyl] benzosulfonamido} -4,5,6,7-tetrahydrobenzoxazole Manufactured from 4- [2- (4-chlorobenzamido) ethyl] benzene sulfochloride, B. = 12800, and 2-Amino-tetrahydro-benzoxazole according to Example 1.

Yield: 15.5% of theory Th .; F. = 165 ° C 22H22ClN3O4S C calc. 57.45% H calc. 4.82% N calc. 9.15% C found. 57.30? H found. 5.02% N found. 8.87% 5) 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole Made from 4- [2- (5-chloro-2-metoxy-benzamido) -ethyl] -benzenesulfochloride, F. = 105 ° C, and 2-amino-4,5,6,7-tetrahydro-benzoxazole according to Example 1.

Yield: 38% of theory Th .; M.p. = 148 ° C (acetone) C23H24N3ClO5S C calcd. 56.5 % H calc. 4.95% g calc. 8.57% C found. 56.3% H found. 5.11 N found. 8.44% 6) 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-6-methyl-benzoxazole Manufactured from 4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfochloride, F. = 105 ° C and 2-amino-4,5,6,7-tetrahydro-6-methyl-benzoxanol, m.p. = 105 ° C, b.p. 0.35 = 126 ° C, according to Example 1.

Yield: 22% of theory Th .; M.p. = 171 ° C (acetone) C24H26ClN3O5S C calcd. 57.20 % H calc. 5.21% H calc. 8.35% C found. 57.10% H found. 5.29% g found 8.14% 7) 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole Made from 4- [1- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfochloride, F. = 134 ° C, and 2-amino-4,5,6,7-tetrahydro-benzoxazole according to Example 1.

Yield: 34% of theory Th .; F. = 125 ° C C23H24N3ClO5S # H2O C calc. 54.40% H calc. 5.16% N calc. 8.26% G found. 54.40% H found. 4.95% N found 8.10% 8) 2- [4- (2-phthalimido-ethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole Manufactured from 4- (2-phthalimido-ethyl) -benzenesulfochloride, f. = 171 ° C, and 2-amino-4,5,6,7-tetrahydro-benzoxazole according to Example 1-, but without reprecipitation of the reaction product from sodium hydroxide solution-hydrochloric acid.

Yield: 30% of theory Th .; F. = 20500 (acetone) C23H21N3O5S C calc. 61.2 % H calc. 4.68% N calc. 9.3% C found. 61.2% H found. 4.82% N found. 9.43% 9) 2- {4- [2- (2-Carboxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole Manufactured from 4- (2-phthalimido-ethyl) -benzenesulfochloride, B. = 17100 and 2-amino-4,5,6,7-tetrahydro-benzoxazole in Pyridine. After the pyridine has been distilled off, the reaction product becomes dissolved with sodium hydroxide solution at room temperature to 40 ° C, while at the same time hydrolytic Splitting of the phthalimide ring occurs. The desired reaction product is with precipitated dilute hydrochloric acid and recrystallized from acetone.

Yield: 24.7% of theory Th .; F. = 195 - 197 ° C (acetone) C23H23N3O6S C calc. 58.6% H calc. 4.92% N 8.93% C found. 58.7% H found. 4.91 ;; N found. 8.63% 10) 2 [4- (2-phthalimido-ethyl) -benzosulfonamido) -tetrahydrobenzoxazole Prepared from 2- {4- [2- (2-Carboxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole by splitting off water in the melt at 180-20,000 or by heating in xylene and azeotropically distilling off water.

Yield: 70% of theory Th .; M.p. = 205 ° C.

11) 2- {4- [2- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolyl- (2)) -ethyl] -benzosulfonamido} -4,5,6,7-tetrahydro- benzoxazole Made from 4- [2- (1,2,3,4-tetrahydro-1,3-dioxo-isoquinolyl- (2)) -ethyl] -benzosulfochlorid, F. = 155 ° C, and 2-amino-4,5,6,7-tetrahydro-benzoxazole according to Example 1.

Yield: 30% of theory; F. = 1800C (acetone) C24H23N3O5S # H2O C calc. 59.7% H calc. 5.17% N calc. 8.72% o found. 59.5% H found. 5.14 ß N found. 8.46% 12) 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzosulfonamido} -4,5,6,7-tetrahydro-benzoxazole 3.2 g (10mM) 2- [4- (2-amino-ethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole, F. = 168 ° C, for example by eight-hour hydrolysis of 2- [4- (2-acetaxidoethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole or the compound of Example 1 in 2N sodium hydroxide solution will, evaluate in a solution of 0.9 g (22.5 mM) sodium hydroxide solution in 10 ml H2O and with 2.9 g (12.4 mM) 5-chloro-2-methoxy-benzoyl chloride, dissolved in 3 ml acetone, at Room temperature implemented. When acidifying with dilute hydrochloric acid, the reaction product falls and is recrystallized from acetone.

Yield: 2.3 g = 42 9'3 of theory; F. - 109 - 110 ° C According to the Example 12 can also be used by reaction with the corresponding acid chloride Make the connections described in Examples 1, 4, 8 and 9.

13) 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole Prepared from 2- [4- (2-amino-ethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole and 5-chloro-2-methoxy-benzyl chloride in chloroform and triethylamine.

Yield: 38 3 of theory; B. = 109-110 ° C.

14) 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole Prepared from 2- [4- (2-amino-ethyl) -benzenesulfonamido] -4,5,6,7-tetrahydro-benzoxazole and methyl 5-chloro-2-methoxy-benzoate in chloroform.

Yield: 17% of theory Th .; M.p. = 109-110 ° C.

The compounds prepared according to the invention can be prepared according to known methods Incorporate methods into the usual pharmaceutical preparation forms; with regard to The indication of the compounds comes mainly from tablets and gelatine capsules in question. The mean single dose for therapeutic use on humans is 1-10 mg, preferably 5 mg.

A) Tablets with 5 mg of 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole Composition: 1 tablet contains: 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole 5.0 mg lactose 85.0 mg corn starch 26.0 mg polyvinylpyrrolidone 3.9 m magnesium stearate 1.0 mg 120.0 mg Manufacturing process: The active substance is made with milk sugar and Corn starch mixed intensively and with a 12.5% (w / w) solution of polyvinylpyrrolidone evenly moistened in ethanol. The mass is passed through a sieve with the mesh size Beat 1.5 mm, dried at 450C and sieved again through a 1.0 mm sieve. That Granules obtained in this way are mixed with magnesium stearate and compressed into tablets.

Tablet weight: 120 mg Punch: 7 mm, flat, with bevel and dividing notch B) Push-fit gelatin capsules with 5 mg of 244-Z2- (5-chloro-2-methoxybenzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-6-methyl-benzoxazole Composition: 1 capsule contains: 2- {4- [2-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamidci4, 5, 6, 7-tetrahydro-6-methyl-benzoxazole 5 mg corn starch, dried 95.0 mg 100.0 mg Manufacturing process: The intensive mixture of substances is sieved through a sieve with a mesh size of 0.75 mm and placed in hard gelatin capsules Bottled of suitable size.

Capsule filling: 100 mg

Claims (8)

Claims 1. New sulfonamides of the general formula I. in which R1 is a phenyl, 4-chlorophenyl-2-carboxyphenyl or a 2-methoxy-5-chlorophenyl radical, R2 is a hydrogen atom or, together with the radical R1-CO- and the nitrogen atom, is a phthalimido or homoph, nalimido group, R3 denotes a hydrogen atom or the methyl group and A denotes a divalent aliphatic hydrocarbon radical with 2 carbon atoms, as well as their alkali salts. 2. 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-benzoxazole and its alkali salts. 3. 2- {4- [2- (5-chloro-2-methoxy-benzamido) -ethyl] -benzenesulfonamido} -4,5,6,7-tetrahydro-6-methyl-benzoxazole. 4. A process for the preparation of new sulfonamides of the general formula I, in which the radicals R1, R, R3 and A have the meanings defined in Anas Claim 1, characterized in that a sulfochloride of the formula II in which R1 'is any lower alkyl radical and R2 is a hydrogen atom or R1 and R2 have the meanings given for R1 and R2, and A is as defined above, with a 2-amino-benzoxazole of the formula III in which R3 has the meanings mentioned in claim 1, reacted in the presence of a hydrogen chloride-binding one and, if R1 'is any lower alkyl radical, the reaction product obtained is converted into a compound of the formula IV by means of dilute alkalis in which h and R have the meanings defined in claim 1, saponified and this is acylated with a reactive derivative of a carboxylic acid of the formula 7 R1-COOH V in which R1 has the meanings defined for formula I and, if a compound is obtained , in which the radical R1 is a 2-carboxyphenyl radical, this is, if desired, subsequently converted by dehydration into a compound in which the radical R, -CO- together with R2 and the nitrogen atom is a phthalimido radical, or if a phthalimido compound is obtained If desired, this is subsequently converted into a compound by treatment with dilute alkalis in which R1 is the 2-carboxyphenyl radical and / or the compound of formula I obtained is converted into an alkali salt. 5. The method according to claim 7, characterized in that the implementation the compound of the formula II with a 2-aminobenzoxazole of the formula III in the presence an inert organic solvent at elevated temperatures, preferably at temperatures up to 100 ° C. 6. The method according to claims 7 and 8, characterized in that that used as a hydrogen chloride binding agent and as a solvent pyridine will. 7. New preparations with a blood sugar lowering effect marked by the content of a sulfonamide of the formula I and an inert carrier. 8. New blood sugar lowering preparations according to claim 10, thereby characterized in that they contain 1 to 10 mg, preferably 5 mg of a compound of the formula I included.