DE2461494A1 - 2-AMINO-2-THIAZOLINE AND PHARMACOLOGICALLY ACTIVE ACIDS - Google Patents

Description

Applicant: Antonio Gallardo S.A., Barcelona-12 Calle Gardoner 68-74-, Spain

2-Amino-2-thiazoline and pharmacologically active acids

This invention relates to preparations containing 2-amino-2-thiazoline and contain pharmacologically active acids.

It is the object of the invention to provide compounds and preparations for the treatment of those diseases in humans and To receive animals that are triggered by the endogenous release of biologically active substances in the body and / or be sustained.

Examples of such diseases are inflammation, rheumatoid arthritis, osteomyelitis, various allergies and asthmatic conditions.

According to one aspect of our invention, a preparation is obtained which is 2-amino-2-thiazoline (or a non-toxic one Salt thereof) and a pharmacologically active acid (or its non-toxic salt, derivative or precursor) contains.

According to a second aspect of our invention, one obtains a combination of 2-amino-2-thiazoline (or its

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non-toxic salt) with a pharmacologically active Acid (or its non-toxic salt, derivative or precursor).

According to a third aspect of our invention, one obtains a salt of 2-amino-2-thia.zolin and a pharmacological one effective acid (but excluding camphorate, camphocarbonate and camphosulfonate).

The preparations given above can also be a physiologically acceptable carrier or such a diluent include.

Carriers or diluents can be a solid substance or be a liquid; Examples are microcrystalline cellulose, milk sugar, carboxymethyl starch, colloidal silicon dioxide, hydroxypropyl cellulose and magnesium stearate. Examples of suitable liquids are Table salt, sodium bisulfite and sorbitol solutions.

The mode of action of 2-amino-2-thiazoline in the conditions in which it is therapeutically effective is not yet clarified, but it has at least three properties that are likely to be involved in its effectiveness.

These properties are (a) sympathomimetic effects (Distefano, Leary and Little, 1959) 5 ("b) Cholinestera inhibition (Gawron and Keil, 1960); and (c) rearrangement to form a free SH group (Shapira, Doherty and Burnett, 1957; Distefano, Leary and Little, 1959).

These properties can be used to explain the pharmacological and therapeutic effect among the most diverse Extrapolate circumstances.

The sympathomimesis, for example, is long with anti-inflammatory (Spector and Willoughby, 1964) and antiasthmatic properties been linked; Recently, anti-anaphylactic effects have also been described (Pelczarska and Eoszkowski, 1973) It could be shown that Estera-

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inhibition reduces the changes to the vessels that be triggered by kininogenases and radiation, by thermal shock and by chemical shock effects and that prevents the formation of kinins both "in vitro" and "in vivo" (Spector and Willoughby, 1959; Willoughby, 1960). .

It is now believed that the sudden release of histamine, which is present in many forms of inflammation and asthma Is a consequence of the activation of SH-dependent enzymes on the surface of mast cells; this activation can through the stabilization of these enzymes through the formation of -S-S bonds be prevented in the case of rearranged aminothiazoline.

Since esterases and -SH-ester-dependent enzymes continue to be present many stages of developing and maintaining chronic inflammatory conditions are involved (e.g. kin inactivation, complementary activation and the formation of chemotaxins and phagocytosis of the complexes Ig G and Ig M, cell destruction with the release of lysosomal enzymes, from which many are also esterases, etc.) 2-Amino-2-thiazoline can have a multi-center attack on these otherwise autoprogressive ones Create processes that occur in conditions such as rheumatoid arthritis.

Consequently, it exhibits the pharmacological profile of 2-amino-2-thiazoline and its salts have more specific properties compared to known drugs alone.

The anti-inflammatory effects of 2-amino-2-thiazoline, 2-Amino-2-thiazoline hydrochloride and 2-amino-2-thiazoline glutamate are used in experiments with rats, e.g. the standard sighting attempt using the Karangin edema (30% Inhibition at 200 mg / kg, calculated as a base) is easily detectable, however, doses of only 5 mg / kg (calculated as base) already a demonstrable inhibition against symptom

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_ _lf _ 246H94

Logic changes and changes in the blood count in the Associated with triggered by Mycobacterium butyricum Polyarthritis.

The effectiveness of 2-amino-2-thiazoline, 2-amino-2-thiazoline hydrochloride and 2-amino-2-thiazoline glutamate against the edema triggered in rats by the lysosome stabilizer nystatin can also be demonstrated (Einsky, Luse and Deenen, 1966; Arrigoni-Martelli, Schiatti and Selva, 1971) 1 which compounds are about ten times more effective per mole than aspirin in inhibiting heat denaturation of serum albumin. This is an attempt that is believed to "enable the distinction between true anti-inflammatory drugs and mere antipyretics" (Mizushima, 1964).

Regardless of this, show 2-amino-2-thiazoline and its Salts also -a powerful antipyretic effect and are what Another benefit is being able to produce better analgesic effects than they are anti-rheumatic Medication is usually attributed. For example, a mixture of 2-amino-2-thiazoline (1 part) and 1,2-diphenyl-4-n-butyl-3,5-pyrazolinedione (2 parts) have stronger anti-inflammatory and analgesic effects than one equivalent amount of the latter anti-inflammatory Means alone.

2-Amino-2-thiazoline can also be prepared by conventional methods known to those skilled in the art, and salts thereof Compounds can be obtained by removing the free acid of 2-amino-2-thiazoline in the presence of a solvent -such as water, a lower alcohol, a lower ketone or a mixture of these solvents with the corresponding acid can react.

In particular obtained according to the invention preparations that 2-amino-2-thiazoline and contain one or more of the following well-known and clinically are to be applied acids

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which in turn alone or together with physiologically compatible Carriers or diluents are used: acetylsalicylic acid, salicylic acid, a, (3-benzoylphenyl) propionic acid, D-a (6-methoxy-2-naphthyl) propionic acid, N- (aa-a-trifluoro-m-tolyl) -anthranilic acid, α- (4-isobutylphenyl) propionic acid, 2- (Ν-α-α-α-trifluoro-m-tolyl) -amino-3-pyridinecarboxylic acid, N-methyl-phenothiazinyl-2-acetic acid, N-acetylcysteine, S-carboxymethylcysteine, theophyllin-7-acetic acid, di-tert-butylnaphthalene-disulfonic acid, thiophene-2-carboxylic acid.

2-Amino-2-thiazoline and its non-toxic salts can alone or in combination with other medicaments for the treatment of diseases that are triggered and / or used are sustained by the endogenous release of biologically active substances in the body, in daily doses of 10 mg to 2 g of 2-amino-2-thiazoline. It can be combined with anti-inflammatory Medication or respiratory function Mix influencing drugs, etc. advantageously; in In this case, the dose of the above drugs can be reduced accordingly. In the case of acidic drugs it is often advisable to use the corresponding salt with 2-amino-2-thiazoline.

The pharmaceutically acceptable diluents or carriers mixed with the active compound or compounds for the purposes of the present invention Manufacture of preparations are known per se, the pharmaceutical carriers used in individual cases, inter alia. depend on the method of administration of the preparations. The inventive preparations can be used for oral, local or parenteral use, but the preferred method of administration is oral. In this case the oral preparations may be in the form of tablets, capsules, morsels, or foaming granules. or the form of

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liquid recipes such as mixtures, extracts, syrups or Emulsions containing all, one or more compounds of the above invention and according to the person skilled in the art well "known" processes can be produced.

The diluents that can be used to make the preparations include those solid and liquid Diluents that contain the active ingredients as well as the colorants that may be used or flavoring substances are compatible. Tablets or capsules can expediently between 5 mg and 500 mg of 2-imino-2-thiazoline or the equivalent amount of the salt thereof.

The liquid preparations according to the invention for oral administration can be in the form of solutions or emulsions. The solutions can be aqueous solutions act a soluble compound of 2-amino-2-thiazoline or its salts, to which sucrose is added to get a syrup. The emulsions can be insoluble Compound of 2-amino-2-thiazoline or its salts contain, together with water, with an emulsifier, flavoring or coloring substances, etc.

The preparations according to the invention are produced in the form of suppositories by the customary methods known to the person skilled in the art and include diluents and excipients compatible with the thiazoline compounds.

Preparations for parenteral injection can be made from soluble salts, which can optionally be freeze-dried, and in water or a suitable parenteral injection fluid be solved with which they are compatible.

The following examples are intended to illustrate the invention.

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example 1 Salts of 2-amino-2-thiazoline

a) 2-Amino-2-thiazoline glutamate

2-Amino-2-thiazoline (2.0 g) was added to a heated solution of glutamic acid (3 ₅ 9 g) in a mixture of water (30 ml) and ethanol (25 ml) and the mixture was boiled until a clear solution was obtained. The hot solution was filtered and cooled and the salt which separated out was filtered off and dried under vacuum. The yield was 3.6 g. Melting point 199-201 ⁰ C.

Using alcohol, isopropanol, acetone or mixtures of these solvents - depending on the solubility of the Salt - the following salts were prepared in an analogous manner:

b) acetyl salicylate - melting point: 92-3 ⁰ C.

c) Di-tert-butyl naphthalene disulfonate - melting point 302-303 ⁰ O.

d) Salicylate - melting point 174-76 ⁰ C.

e) S-carboxymethyl cysteinate - melting point 158-60 ⁰ C.

f) N-acetylcysteinate - melting point 118-21 ⁰ C.

g) theophylline-7-acetate - melting point 224-225 ⁰ C.

h) lp-Ohlorbenzoyl-5-methoxy-2-methyl-indol-3-ylaceta.t melting point 179-80 ⁰ G.

i) 2-thiophene garbic acid salt - melting point 170-72 ⁰ C. j) oc- (3-Benzoylphenyl) propionate - melting point 182-183 C. k) oc- (4 ~ isobutylphenyl) propionate - melting point 138-14- 0 C. 1) N- (aaa-trifluoro-m-tolyl) anthranilate - melting point

116-118 ⁰ C. '
m) 2- (aaa-Trifluoro-m-tolyl) amino-3-pyridine-carboxylic acid salt - Melting point 154-56 ⁰ C.

ή) U-methyl-2-phenothiazinyl-aceta.t - Melting point 158-60 ⁰ C. o) 4-phenyl-l, 2-diphenylpyrazolidin-3,5-dionate - melting point

151-153 ° C.
p) 3-Benzoylphenylacetat - melting point 113-4- ⁰ C.

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- ar-

Example 2

100,000 tablets each containing 50 mg of 2-amino-2-thiazolinoc- (3-b enz oylphenyl) propionate produced.

Recipe;

2-iLmino-2-thiazoline-a- (3-benzoylphenyl) propionate 5000 g

Microcrystalline cellulose 4-500 g

Milk sugar 5500 g

Carboxymethyl starch 600 g

colloidal silicon dioxide 150 g

Hydroxypropyl cellulose 150 g

Magnesium stearate 100 g

Water / ethanol = 50/50 volume / volume as required

Procedure':

The 2-amino-2-thiazolin-oc- (3-benzoylphenyl) propionate, the microcrystalline cellulose, the milk sugar, the carboxymethyl starch and the colloidal silicon dioxide were made by put a sieve with 0.6 mm mesh size and put in a Lödige intensive mixer mixed at low speed. The hydroxypropyl cellulose was dissolved in the dilute alcohol and this Solution added to powder mix while mixing at high speed and using booster paddles. That Granules obtained in this way were dried at 40 ° under vacuum, passed through a vibrating sieve with a mesh size of 1.2 mm, with mixed with the magnesium stearate and pressed into a 7 mm die with a flat beveled die (tablets of 160 mg each. The disintegration time of the tablets was less than 5 minutes.

Example 3 '-

100,000 tablets each containing 75 mg of 2-amino-2-thiazoline glutamate were made and 35 mg of oc- (3-B en ζ oylphenyl) propionic acid prepared.

Recipe

2-amino-2-thiazoline glutamate 7500 g

oc- (3-Benzoylphenyl) propionic acid 3500 g

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Microcrystalline cellulose 8200 g

Milk sugar 4-350 g

Carboxymethyl starch 800 g

colloidal silicon dioxide 250 g

Hydroxypropyl cellulose 250 g

Magnesium stearate 150 g water / ethanol = 50/50 volume / volume as required

Procedure "

The finely ground mixture of 2-amino-2-thiazoline-glutamate and oc- (3-benzoylphenyl) propionic acid was mixed with the microcrystalline cellulose, lactose, carboxymethyl starch and colloidal silicon dioxide in a Lödige intensive mixer at low speed and mixed using the booster paddle to break up any lumps. The hydroxypropyl cellulose was dissolved in the dilute alcohol and the solution added to the powder mix by rapid mixing using the intensifying stir arms. The so etnstandene granules were added at 4-0 ° dried under vacuum through a vibrating screen with 1.2 mm mesh size, mixed with the magnesium stearate and 8-mm die pressed in _a% with a planar bevel temple into tablets of 250 mg. The disintegration time of the tablets was about 6 minutes.

Example 4-

100,000 tablets each containing 75 ^m 2-amino-2-thiazoline glutamate and 150 mg 4-n-butyl-1,2-diphenyl-3,5-pyrazolidinedione were produced.

Recipe:

2-Amino-2-thiazoline-glutamate 7,500 g 4-Butyl-1,2-diphenyl-3,5-pyrazolidinedione 150,000 g

microcrystalline cellulose 10,000 g

Carboxymethyl starch 1300 g

colloidal silicon dioxide 300 g

Hydroxypropyl cellulose 1600 g

Magnesium stearate 300 g water / ethanol = 50/50 volume / volume as required

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procedure

As in Example 3, with the difference that it is too Tablets of 360 mg each in a 9-EM die with a flat Bevel stamp was pressed. The disintegration time the tablet was about 5 minutes.

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Claims (6)

Letter dated 2? . 12 .1974 ^sheet 11 Dipl.-lng. G. Schliebs ^qn the German Patent Office, Munich Patent attorney 246 H94 PATENT CLAIMS (^ .Preparat ", characterized in that it consists of 2 ~ amino-2-thiazoline . (or its non-toxic salt) and a pharmacologically active acid (or its non-toxic Salt ~, derivative or precursor) ". 2. Preparation, characterized in that it consists of a combination of 2-amino-2-thiazoline (or its non-toxic salt) with a pharmacologically active acid (or its non-toxic salt, derivative or precursor). 3. Preparation, characterized in that it consists of a salt of 2-amino-2-thiazoline with a pharmacologically active acid (but excluding camphorate, camphocarbonate and Kamphosulfonate). 4-, preparation according to all claims 1 to 3> characterized in that the pharmacologically active acid, alone or in a mixture of acetyl salicylic acid, salicylic acid, oc- (3-benzoylphenyl) propionic acid, D-α- (6-methoxy- 2-naphthyl) propionic acid, E- (α-α-α-trifluoro-m-tolyl) anthranilic acid, α- (4-; isobutylphenyl) propionic acid, 2- (Ν-α-α-α-trifluoro-m -tolyl) -amino-3-pyridine-carboxylic acid, N-methyl-phenothiazinyl-2-acetic acid, Έ- acetylcysteine, S-carboxymethylcysteine, theophyline-7-acetic acid, di-tert-butylnaphthalene-disulphonic acid, thiophene-2-carboxylic acid , Oysteine-S-carboxylic acid or 4-n-butyl-1,2-diphenylpyrazoline-3,5-cLion. • 5. Preparation according to all of the preceding claims 1 to 4-, characterized in that it continues to be a physiologically acceptable carrier or a physiologically acceptable one Includes diluent. 6. Preparation according to claim 1, characterized in that it consists of 2-amino-2-thiazoliri-a- (3-benzoylphenyl) propionate, microcrystalline cellulose, lactose, carboxymethyl starch, colloidal silicon dioxide, hydroxypropyl cellulose, magnesium stearate and a water / ethanol mixture of 50/50 volume 509830 / Ü84Ü Letter from. December 27, 1974 'Sheet 12 Dipl.-Ing. G. Sdiliebs ^ the German Patent Office, Munich Patent Attorney units consists. 7 · Preparation according to claim 1, characterized in that it from 2-amino-2-thiazolin-glutama.t, α- (3-benzoylphenyl) propionic acid, microcrystalline cellulose, lactose, carboxymethyl starch, colloidal silicon dioxide, hydroxypropyl cellulose, magnesium stearaf and a water / ethanol mixture of 50/5 volume units ". 509830 / 08A0