CH628039A5 - Process for the preparation of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide 1,1-dioxides - Google Patents

Description

The invention relates to a process for the preparation of new 4-hydroxy-2H-naphtho [2, l-e] -l, 2-thiazine-3-carboxamide-1,1-dioxydes as defined in claim 1.

The new compounds of formula I are distinguished by excellent anti-inflammatory properties and / or exert an extremely strong inhibitory effect on platelet adhesion and aggregation. With regard to their absolute antithrombotic activity and their wide therapeutic range, they are known 4-hydroxy-2-methyl-N- (2-thiazolyl) -2'Hl, 2-benzothiazine-3-carboxamide-l, 2- dioxide [cf. J.W. Constantine and J.M. Purcell, J. Pharmacol. Exp. Ther. 187 (1973) 653] significantly superior.

The compounds of formula I are prepared using the method defined in claim 1.

When carrying out the process according to the invention, the procedure is generally such that the 3-oxo-naphth- [2, ld] -isothiazoline-2-acetic acid-arylamide-l, l-dioxide of the formula II with a base in a suitable anhydrous organic solvents, e.g. Ethanol, tert-butanol, dimethylformamide or dimethyl sulfoxide, heated. Particularly suitable bases are alkali and alkaline earth alcoholates, such as sodium methylate, sodium ethylate, potassium methylate or potassium tert-butoxide. In general, at least 2, preferably 3, equivalents of the base in question are used. The rearrangement is carried out at a temperature in the range from 30 to 120 ° C. After the reaction has ended, the compound of the formula I can be isolated by stirring in ice water and acidifying.

To the compounds of formula I ', i.e. Compounds of the formula I in which the ring nitrogen atom is substituted by methyl or ethyl can be obtained by reacting a compound of the formula I with a methyl or ethyl halide in the presence of a base.

Alkali or alkaline earth metal hydroxides or carbonates, for example sodium, potassium or barium hydroxide or sodium or potassium carbonate, and also alkali or alkaline earth metal alcoholates, for example sodium methylate, potassium ethylate, potassium tert-butoxide, or tertiary amines, for example triethylamine, can be used as bases, if you are in an aqueous medium, in an alcoholic medium, such as in methanol, ethanol, n-propanol, iso-propanol or

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works in mixtures of the solvents mentioned. Other possible solvents are: dimethylformamide, dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoric triamide.

If alkali or alkaline earth carbonates are used as the base, aliphatic ketones, such as acetone, are suitable as further solvents.

The methyl or ethyl halide, preferably the bromide or iodide, is expediently added in alcoholic solution directly to the other components in the reaction mixture, with methyl bromide being used in a closed apparatus. On the other hand, if the reaction is carried out in inert organic solvents, e.g. carried out in benzene or another aromatic hydrocarbon, in tetrahydrofuran or another open-chain or cyclic ether, alkali metal hydrides or alkaline earth metal hydrides, e.g. Use sodium hydride or potassium hydride. The methyl or ethyl iodide is not added until the alkali metal or alkaline earth metal hydride has reacted completely with the compound of the formula I. The reaction temperature is in the range from 0 to 80 ° C.

If desired, the compounds of the formula I can be converted into their physiologically tolerable salts with inorganic or organic bases by methods known per se. Suitable bases are, for example, aluminum potassium alcoholates, alkali metal hydroxides, alkaline earth metal hydroxides, tri-alkylammonium hydroxides and alkylamines.

The starting compounds of formula II can be prepared by using an alkali salt of 3-oxonaphth- [2, l-d] -isothiazoline-l, l-dioxide [H. P. Kaufmann and H. Zobel, Chem. Ber. 55 (B) (1922) 1499] in an inert solvent, such as dimethyl sulfoxide or dimethylformamide, with a compound of the formula III

CICH2CONH-Ar (III)

implemented under heating.

As mentioned at the beginning, the compounds of the formula I have valuable pharmacological properties; they have an anti-inflammatory and / or strong inhibitory effect on platelet adhesion and aggregation and, moreover, have a favorable effect on rheumatic diseases of all kinds, e.g. on arthritis.

For example, the substances N- (3-chlorophenyl) -4-hydroxy-2-methyl-2H-naphtho [2, l-e] -l, 2-thiazine-3-carboxamide-l, l-dioxide = A

and

4-Hydroxy-2-methyl-N- (3-tolyl) -2H-naphtho- [2, l-e] -l, 2-thiazine-3-carboxamide-l, l-dioxide = B

compared to acetylsalicylic acid = C

examined for their inhibitory effect on platelet aggregation (Born test, collagen aggregation).

Platelet aggregation according to the method of Born and Cross [J. Physiol. 170 (1964) 397] measured on platelet-rich plasma from healthy subjects.

The decrease in the optical density of platelet suspensions after the addition of collagen is measured and recorded photometrically. The rate of aggregation is inferred from the angle of inclination of the density curve. The point on the curve at which the greatest light transmittance is present is used to calculate the “optical density”. The amount of collagen is chosen so that an irreversible control curve is obtained.

The figures given relate to the “optical density” and mean percentage change in the light transmittance (=% attenuation of the aggregation) under the influence of the substance compared to the control.

5 The commercial collagen from Hormon-Chemie, Munich, was used.

The following table contains the results obtained:

10 substance

Concentration [mol / liter]

Born test percentage change in light transmission

A

15

io-4 io-5 io-6

96% 81% 35%

B

io-4 io-5 io-6

97% 78% 65%

20th

Comparative

substance

C.

3.10-5

io-5

45% 13%

While the comparative substance C (acetylsalicylic acid) achieves a 50% weakening of the aggregation only at a concentration of 4.10 ~ 5 mol / liter, the substances A and B bring about such a weakening at a concentration reduced by a factor of 20.

The following examples are intended to explain the invention in more detail.

example 1

35 4-Hydroxy-N-phenyl-2H-naphtho [2, l-e] -l, 2-thiazine-3-carboxamide-1,1-dioxide

1.6 g (0.03 mol) of sodium methylate is mixed with 3.66 g (0.01 mol) of 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid-40 acid anilide-l, l-dioxide (F 238 to 240 ° C), adds 50 ml of anhydrous tert-butanol, introduces nitrogen and heats with stirring in an oil bath preheated to 100 ° C for 15 minutes. The mixture is cooled rapidly, then stirred into 200 ml of ice water and suctioned off from the precipitate, which is washed with a little 45 water. The cold filtrate is shaken out twice with 100 ml ether. The ether extracts are discarded. The aqueous phase is brought to pH 4 with dilute hydrochloric acid and the separated product is taken up in 15 ml of ethyl acetate / ether (1: 1). This organic phase 50 is extracted with water, then with sodium bicarbonate solution and again with water, then dried over sodium sulfate and concentrated. The remaining residue is recrystallized from ethylene chloride.

0.2 g of crystals of the abovementioned compound with a melting point of 262 to 263 ° C. are obtained.

a) 3-oxo-tiaphth [2, l-d] isothiazoline-2-acetic anilide-l, 1-

-dioxide

To 5.4 g (0.1 mol) of sodium methylate in 30 ml of anhydrous dimethyl sulfoxide are added 22.0 g (0.094 mol) of 60 3-oxo-naphth- [2, ld] isothiazoline-l, l-dioxide, then one is added dropwise Solution of 18.7 g (0.11 mol) of chloroacetic anilide in 30 ml of anhydrous dimethyl sulfoxide and stirred for 2 hours at 120 to 130 ° C. Then poured into 150 ml of water containing] 1 g of sodium acetate and suction filtered. The Nutschen 65 residue is washed with water and recrystallized from ethyl acetate. 19 g (55.3% of theory) of 3-oxo-naphth [2,1-d] isothiazoline-2-acetic anilide-1,1-dioxide of melting point 238 to 240 ° C. are obtained.

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Example 2

N- (3-chlorophenyl) -4-hydroxy-2H-naphtho [2, l-e] -l, 2-thia-zinc carboxamide-1,1-dioxide

Prepared analogously to Example 1 from 8.0 g (0.02 mol) of 3-oxonaphth [2, ld] isothiazoline-2-acetic acid- (3-chloroanilide) -l, l-dioxide (F. 214 ° C.) and 3.2 g (0.06 mol) of sodium methylate in 75 ml of tert-butanol. 0.5 g of crystals (from ethylene chloride) with a melting point of 263 ° C. is obtained.

The 3-oxo-naphth [2, l-d] isothiazoline-2-acetic acid (3 - chloroanilide) -1,1-dioxide is prepared analogously to Example la from chloroacetic acid (3-chloroanilide).

Yield: 66% of theory

Melting point: 214 ° C (from ethyl acetate).

Example 3

4-Hydroxy-N- (3-tolyl) -2H-naptho [2, l-e] -l, 2-thiazine-carboxamide-lyl-dioxide

Prepared analogously to Example 1 from 7.60 g (0.02 mol) of 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid (3-toluidide) -l, l-di-oxide (mp 175 ° C) and 3.2 g of sodium methylate.

0.52 g of crystals of melting point 245 ° C. (decomposition) (from ethylene chloride) is obtained.

The following are produced in an analogous manner:

a) N- (2-FluorophenyI) -4-hydroxy-2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide-1,1-dioxide from 3-oxo-naphth [2, id ] isothiazoline-2-acetic acid (2-fluoro-anilide) -1,1-dioxide;

b) N- (3-fluorophenyl) -4-hydroxy-2H-naptho [2,1-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from 3-oxo-naphth [2 , 1-d] isothiazoline-2-acetic acid- (3-fluoro-anilide) -1,1-dioxide;

c) N- (4-fluorophenyl) -4-hydroxy-2H-naptho [2, le] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from 3-oxo-napth [2.1 -d] isothiazoline-2-acetic acid- (4-fluorous anilide) -l, l-dioxide;

d) N- (3-bromophenyl) -4-hydroxy-2H-naphtho [2, le] -l, 2 - thiazine-3-carboxamide-l, 1-dioxide from 3-oxo-naphth [2,1- d] isothiazoline-2-acetic acid- (3-bromoanilide) -l, l-dioxide;

e) 4-hydroxy-N- (2-methoxyphenyl) -2H-naphtho [2, le] -l, 2 - thiazine-3-carboxamide-l, 1-dioxide from 3-oxo-naphth [2, ld] isothiazolin-2-acetic acid- (2-meth-oxyanilide) -1,1-dioxide and f) 4-hydroxy-N- (3-methoxyphenyl) -2H-naptho [2, le] -l, 2 - thiazine 3-carboxamide-l, l-dioxide from 3-oxonaphth [2,1-d] isothiazoline-2-acetic acid- (3-meth-oxyanilide) -1,1-dioxide.

The starting compounds are prepared analogously to Example la:

g) 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid- (3-toluidide) - 1,1-dioxide from 3-oxo-naphth [2, ld] isothiazoline-l, l-dioxide and

Chloroacetic acid (3-toluidide);

Melting point: 175 ° C;

h) 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid- (2-fluorani-lid) -l, 1-dioxide from 3-oxo-naphth [2, ld] isothiazoline-l, l-dioxide and chlorine acetic acid- (2-fluoroanilide);

Melting point: 217 ° C;

i) 3-oxo-naphth [2, l-d] isothiazoline-2-acetic acid- (3-fluorani-lid) -l, 1-dioxide from 3-oxo-naphth [2, l-d] isothiazoline-l, l-dioxide and

Chloroacetic acid- (3-fluoroanilide);

Melting point: 222 to 224 ° C;

j) 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid- (4-flu.orani-lid) -l, l-dioxide from 3-oxo-naphth [2, ld] isothiazoline-l, l- dioxide and chloroacetic acid- (4-fluoroanilide);

Melting point: 222 ° C; k) 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid- (3-bromani-lid) -l, l-dioxide from 3-oxo-naphth [2, ld] isothiazoline-l, l-dioxide and Chloroacetic acid (3-bromoanilide);

Melting point: 218 to 220 ° C; 1) 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid- (2-methoxy-anilide) -l, l-dioxide from 3-oxo-naphth [2, ld] isothiazoline-l, l-dioxide and Chloroacetic acid- (2-methoxyanilide);

Melting point: 214 to 216 ° C; m) 3-oxo-naphth [2, ld] isothiazoline-2-acetic acid- (3-methoxy-anilide) -l, l-dioxide from 3-oxo-napth [2,1-d] isothiazoline-1,1- dioxide and chlorine

acetic acid- (3-methoxyanilide);

Melting point: 153 to 155 ° C.

Example 4

N- (3-chlorophenyl) -4-hydroxy-2-methyl-2H-naphtho [2,1-eJ - 1,2-thiazine-3-carboxamide-1,1-dioxide

To a suspension of 1.2 g (3 mmol) of N- (3-chlorophenyl) -4-hydroxy-2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide - 1,1- Dioxide, 100 ml of methanol and 1.7 g (12 mmol) of methyl iodide are added dropwise 3.15 ml in sodium hydroxide solution (3.15 mmol). The reaction mixture is stirred for 72 hours at room temperature and then concentrated to dryness in vacuo, washed with a little water, the remaining solid portion is recrystallized from ethylene chloride and 0.8 g (64% of theory) of N- (3-chlorophenyl) is obtained ) -4-hydroxy-2-methyl-2H-naphtho [2,1 -e] -1,2-thiazine-3-carboxamide-1,1-dioxide. Melting point: 248 to 249 ° C (decomp.).

The following were produced analogously:

a) 4-Hydroxy-2-methyl-N-phenyl-2H-naphtho [2,1-e] -l, 2-thiazine-3-carboxamide-l, l-dioxide from 4-hydroxy-N-phenyl- 2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 273 to 274 ° C (dec.);

b) N- (3-bromophenyl) -4-hydroxy-2-methyl-2H-naphtho- [2, le] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from N- (3-bromophenyl ) -4-hydroxy-2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 268 to 269 ° C (dec.);

c) N- (2-fluorophenyl) -4-hydroxy-2-methyl-2H-naphtho- [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide from N- (2-fluorophenyl ) -4-hydroxy-2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 240 to 243 ° C (dec.);

d) N- (3-fluorophenyl) -4-hydroxy-2-methyl-2H-naphtho- [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide from N- (3-fluorophenyl ) -4-hydroxy-2H-naphtho [2, le] -1, 2-thiazm-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 278 to 279 ° C (dec.);

e) N- (4-fluorophenyl) -4-hydroxy-2-methyl-2H-naphtho- [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide from N- (4-fluorophenyl ) -4-hydroxy-2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 284 to 285 ° C (dec.);

f) 4-hydroxy-2-methyl-N- (3-tolyl) -2H-naphtho [2,1 -e] -l, 2-thiazine-3-carboxamide-l, l-dioxide from 4-hydroxy- N- (3-tolyl) -2H-naphtho [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 240 to 242 ° C (dec.);

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g) 4-Hydroxy-N- (2-methoxyphenyl) -2-methyl-2H-naphtho- [2,1-e] -l, 2-thiazine-3-carboxamide-l, 1-dioxide from 4-hydroxy -N- (2-methoxyphenyl) -2H-naphtho [2,1-e] -1, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 198 to 200 ° C;

h) 4-Hydroxy-N- (3-methoxyphenyl) ~ 2-methyl-2H-naphtho- [2, le] -l, 2-thiazine-3-carboxamide-l, l-dioxide from 4-hydroxy-N- (3-methoxyphenyl) -2H-naphtho [2, le] -1, 2-thiazine-3-carboxamide-l, l-dioxide and methyl iodide; Melting point: 242 to 244 ° C (decomp.).

Example 5

2-ethyl-4-hydroxy-N-phenyl-2H-naphtho [2, l-e] -l, 2-thiazine - 3-carboxamide-l, 1-dioxide

Prepared analogously to Example 4 from 4-hydroxy-N-phe-

nyl-2H-naphtho [2,1 -e] -1,2-thiazine-3-carboxamide-1,1-dioxide and ethyl iodide in a yield of 52% of theory.

Melting point: 245 to 247 ° C.

5 Example 6

Cyclohexylamine salt of 4-hydroxy-2-methyl-N- (3-tolyl) -2H-naphtho [2, l-e] -l, 2-thiazine-3-carboxamide-l, l-dioxyds

0.5 g of 4-hydro-2-methyl-N- (3-tolyl) -2H-naphtho [2, le] -lo -l, 2-thiazine-3-carboxamide-1,1-dioxide are in 10 ml Suspended methanol and mixed with 0.14 g of cyclohexylamine. The resulting solution is largely concentrated in vacuo and the residue is triturated with acetone. The crystals obtained are filtered off with suction and washed with a little acetone 15 and with ether;

Yield: 0.54 g;

Melting point> 200 ° C (decomposition).

v

Claims (8)

628039 2. The method according to claim 1, characterized in that an alkali or alkaline earth metal alkoxide is used as the base. 2nd PATENT CLAIMS 1. Process for the preparation of new 4-hydroxy-2H-naphtho [2,1 -e] -1,2-thiazine-3-carboxamide-1,1-dioxides of the formula I , CO-NH-Ar -H wherein Ar represents a phenyl, 3-chlorophenyl, 3-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-tolyl, 2-methoxyphenyl or 3-methoxyphenyl group, as well as theirs physiologically tolerable salts with inorganic or organic bases, characterized in that a 3-oxo-napth [2, ld] isothiazoline - 2-acetic acid arylamide-l, l-dioxide of the formula II -CH "-CO-NH-Ar in a water-free organic solvent at a temperature in the range from 30 to 120 ° C. is subjected to a base-catalyzed rearrangement and the process products are then optionally converted into their physiologically tolerable salts with inorganic or organic bases. 3. Process for the preparation of compounds of formula I ' OH CO-NH-Ar NO 'SO. wherein Ar has the meaning given; and Rj is methyl or ethyl, characterized in that a compound of the formula I is prepared by the process according to claim 1 and this is prepared using a methyl or ethyl halides in the presence of a base at a temperature of 0 to 80 ° C in the corresponding compound, wherein Rx is methyl or ethyl. 4. The method according to claim 3, characterized in that an alkali or alkaline earth metal hydroxide, an alkali or alkaline earth metal carbonate, an alkali or alkaline earth metal alkoxide or a tertiary amine is used as the base. 5. The method according to claim 4, characterized in that one works in a solvent and water or an alcohol or a mixture of the two is used as the solvent. 6. The method according to claim 3, characterized in that an alkali or alkaline earth carbonate is used as the base. 7. The method according to claim 6, characterized in that one works in a solvent and uses an aliphatic ketone as solvent. 8. The method according to claim 3, characterized in that an alkali metal or alkaline earth metal hydride is used as the base and this in an aromatic hydrocarbon or an open-chain or cyclic ether as solvent first with the compound of formula I and then with the methyl or ethyl halogen -nid implemented.