DE2314929A1 - NEW BIPHENYLYL-4-HYDROXY-CROTONIC ACID LACTONE - Google Patents

Description

Case 5/585
Dr.Pl/wt

DR. KARL THOMAE GMBH., BIBERACH AM DER RISS

New BiphenyIy1-4-hydroxy-crotonic acid lactones

The present invention relates to new biphenylyl - ^ - hy
droxy-crotonic acid lactones of the general formula I,

(D

in the

X represents a hydrogen or halogen atom.

The compounds of the above general formula I have valuable pharmacological properties, in particular anti-inflammatory properties Effect, and can be produced using the following methods

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Dehydration of a compound of the general formula II,

OH

CH - CH = CH - COOH

(ID

in the

X as defined at the beginning i.; T, or their salts with inorganic ones or organic bases.

The reaction is conveniently carried out in a solvent such as glacial acetic acid in the presence of a dehydrating agent such as acetic anhydride, concentrated sulfuric acid, phosphorus pentoxide or thionyl chloride or in the presence of a Lewis acid such as boron trifluoride or aluminum chloride and preferably at temperatures between 0 and 100 ^° C. The reaction can also be carried out without a solvent.

The compounds of general formula II used as starting materials are described in Belgian patent 759.053 and can be produced by reducing the corresponding oxocarboxylic acids with sodium borohydride.

As already mentioned at the beginning, the new compounds have the above general formula I valuable pharmacological properties on, in particular an anti-inflammatory effect.

For example, the connections were

A = ^ - (^ - BiphenylyD - ^ - hydroxy-c-rotonic acid lactone and B = ^J l- (2'-fluoro ^ 4-biphenylyl) -4-hydroxy-crotonic acid lactone

examined for their biological effects:

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1. Anti-inflammatory effect:

The anti-inflammatory effect was determined as an antiexudative effect against the carrageeinin edema of the rat hind paw by the method of Winter et al. (Proc. Soc. Exp. Biol. Med. 111 , 544 (1962)) after oral administration of at least three doses to at least 10 animals per dose. The measurement was carried out according to the method of Döpfner and Cerletti (Int. Arch, of Allergy and Immunol. JL2, 89-97 (1958)); Causes swelling.

2. Ulcerogenic effect:

The test for an ulcerogenic effect was carried out on rats of both sexes weighing between 130 and 150 g. The animals were given the substances to be tested for an ulcerogenic effect on three consecutive days once a day as a trituration in Tylose by gavage. The animals were sacrificed four hours after the last application; the gastric and duodenal mucosa were examined for ulcers. _{The ED 50 was} calculated according to Litchfield and Wilcoxon (J. Pharmacol, exp. Therap. 96 , 99 (1949)) from the percentage of the animals exhibiting at least one ulcer after the various doses.

3. Acute toxicity:

The acute toxicity of the substances was determined in groups of 10 rats. The substances were administered as a trituration in Tylose. The calculation of the LDc ₀ carried out according to Litchfield and Wilcoxon (J. Pharmacol, exp. Therap. 9_6, 99 (19 ^ 9)) from the percentage of animals which died after different doses [I ¹ I within days. I.

The following table contains the values found:

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Substance carrageein edema Ulcer effect Acute toxicity ED ^ mg / kg po ED ^ _Q mg / kg po LD ^ ing / kg po

22.5
18th

85

ko

1250 550

The new compounds of the above general formula I can be used for pharmaceutical use, if appropriate in combination with other active substances, incorporate into the usual pharmaceutical preparation forms. The single dose is 50 to 400 mg, preferably 100 to 300 mg, the daily dose 100 to 1000 mg, preferably 150 to 600 mg.

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

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Example 1 4- ^(2-fluoro-t 4-biphenylyl) -4-hydroxy-crotonsäurelakton

A suspension of 16.0 g of 4- ~ 4-hydroxycrotonic acid (melting point: 108 - HO ⁰ C) ^(2'-fluoro-1 -biphenyIyI!) In 50 ml of acetic anhydride is added under stirring with ml of conc. 1 Sulfuric acid. The substance quickly dissolved with an exothermic reaction (45 ° C.) and a red color. After 15 minutes, it is poured onto ice water, the crystalline reaction product is filtered off with suction, washed with water, dried and recrystallized twice from cyclohexane. Yield: 3.8 g (25 % of theory)
Melting point: 115 - H7 ° C
C ₁₆ H ₁₁ FO ₂ (254.27)

Calc .: C 75.58 H 4.36
Found i 75.60 4.35

UV spectrum (in ethanol) neutral: % max. = 245 nm

alkaline: % max. = 280 nm

IR spectrum: CO absorption at 1800 and 1760 cm "" ¹ NMR spectrum (in CDCI-): 8 aromatic and 1 olefinic H at 712 - 7.7 ppm, 1 olefinic H at 6.2 ppm, 1 aliphatic H at 6.1 ppm.

Example 2 4- (4-biphenylyl) -4-hydroxy-crotonic acid lactone

Prepared analogously to Example 1 from 4- (4-biphenylyl) -4-hydroxycrotonic acid (Melting point: 162 ° C).

Yield: 67 % of theory

Melting point: 115 - 118 ° C (from glacial acetic acid / water = 2.5 / 1) C ₁₆ H ₁₂ O ₂ (236.27)

Calc .: C 81.34 H 5.12
Found: 81.20 5.18

UV spectrum (in ethanol): neutral: Ί \. max. = 250 nm

alkaline: % max. = 285 nm

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IR spectrum: CO absorption at l800, 1760, 17 ¹ IO cm NMR spectrum (in CDCl,): 9 aromatic and olefinic H 1 wherein

7.1 - 7.7 ppm, 1 olefinic H at 6.2 ppm, 1 ali-

phatic H at 6.1 ppm.

Example 5 ^ - (^ - BiphenylyD - ^ - hydroxy-crotonic acid lactone

5 g ^ - (^ - BiphenylyD - ^ - hydroxy-crotonic acid morpholine salt (Melting point: 163 ° C.) 25 ml of acetic anhydride are added. The salt went into solution quickly. Shortly afterwards falls again a precipitate from. Then the batch is concentrated with 1 ml. Sulfuric acid is added and the mixture is heated to 80 ° C shortly afterwards. After cooling down It is poured onto ice water, the precipitate is separated off, dried and crystallized from isopropanol and then from cyclones xan around.

Yield: 1.3 g (37.6 % of theory) melting point; 113-116 ° C.

Example 4 Tablets with 200 mg 4 - »(4-biphenylyl) - ^f } -hydroxy-crotonic acid lactone

Composition:
1 tablet contains

Active ingredient 200.0 mg corn starch 97 »0 mg

Polyvinylpyrrolidone 10.0 mg Magnesium tearate 3 ^ 0 mg

310.0 mg

production method

The mixture of the active ingredient with corn starch is withr one 14% solution of the polyvinylpyrrolidone in water through a sieve

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1.5 mm granulated, dried at M5 ° C and rubbed through the above sieve again. The granules obtained in this way are mixed with magnesium stearate and compressed into tablets. Tablet weight: 310 mg
Stamp: 10 mm, flat

Example 5

Dragees with 200 mg i | - (2 ^l -fluoro- ¹ l-biphenylyl) -4-hydroxy-crotonic acid lactone

Composition: 200.0 mg 1 dragee contains 70.0 mg Active ingredient 8.0 mg Cornstarch 18.0 mg gelatin i », 0 mg Talk 300.0 mg Magnesium stearate production method

The mixture of the active ingredient with corn starch is granulated with a 10% aqueous gelatin solution through a 1.5 mm sieve, dried at 45 ° C and rubbed through the above sieve again. That The granules obtained in this way are mixed with talc and magnesium stearate and pressed into tablet cores.

Core weight: 300.0 mg

Stamp: 10 mm, domed

The tablet cores are coated with a casing using known methods coated, which consists essentially of sugar and talc.

The finished coated tablets are polished with the help of beeswax.

Dragee weight: 580 mg

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Gelatine capsules with 200 mg 4- (4-biphenylyl) -4-hydroxy-crotonic acid relacton

Composition:

1 gelatin capsule contains:

Active ingredient 200.0 mg

Corn starch 190.0 mg

Aerosil 6.0 mg

Magnesium stearate 4.0 mg

400.0 mg

Production method:

The substances are mixed intensively and filled into size 1 gelatine capsules.
Capsule content: 400 mg

Example 7

Suppositories with 100 mg 4- (2'-fluoro-4-biphenylyl) -4-hydroxy crotonic acid lactone _j;

Composition:
1 suppository contains

Active ingredient 100.0 mg

Suppository mass (e.g. Witepsol W 45) 1 450.0 mg

1,550.0 mg

production method

The finely powdered active ingredient is made using an immersion homogenizer stirred into the melted suppository mass cooled to 40 ° C. The mass is slightly pre-prepared at 38 ° C

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poured cooled molds. Suppository weight: 1.55 g

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Claims (1)

Patent application before 1.) New biphenylyl-4-hydroxy-erotonic acid lactones of the general Formula I, (D in the X represents a hydrogen or halogen atom. 2.) Medicines containing at least one compound of the above general formula I in addition to optionally one or more inert carriers. 3.) Process for the production of new biphenylyl-4-hydroxy-crotonic acid lactones of the general formula I, 409841/1042 23U929 (D in the X denotes a hydrogen or halogen atom, characterized in that that a compound of the general formula II, OH CH - CH = CH - COOH (ID in the X is as defined at the outset, or its salts are dehydrated with inorganic or organic bases. ¹ J.) Process according to claim 3, characterized in that the reaction is carried out in a solvent. 5.) Process according to claim 3 and ¹ J, characterized in that acetic anhydride, concentrated sulfuric acid, phosphorus pentoxide or thionyl chloride or a Lewis acid such as boron trifluoride or aluminum chloride is used as the dehydrating agent. 6.) Process according to claim 3 »^ and 5, characterized in that the reaction is carried out at temperatures between 0 and 100 ^° C. 409841/1042