DE2063901A1 - Phenylalkylaminoalkylthiazoles - as antiphlogistics - Google Patents

Abstract

Medicament having antiphlogistic activity for human, veterinary or agricultural use contains >=1 cpd. of formula (I) (including the optically active and diastereomeric forms and salts and quat. ammonium cpds.): (where R1 and R2 are H or CH3; R3 and R4 are H, halogen or lower alkoxy; Y is CO or CHOH, and the thiazolyl residue is opt. substd. at C by halogen, lower alkyl, phenyl, OH, NO2 and lower carbalkoxy and at the N-atom by lower alkyl, benyl or phenyl).

Description

Antiphlogistically acting phenalkylaminoalkylthiazoles In the patents ... (Application P 16 70 547.8 and P 15 43 538.8) are processes for the preparation of cardiovascular active compounds of the general formula described, where Y is oxygen or OH + hydrogen and the radicals R1 to R4 are identical or different and are hydrogen or halogen atoms or low molecular weight alkyl, ararkyl, phenyl, hydroxyl, low molecular weight alkoxy, nitro or low molecular weight carbalkoxy groups, dio R5 and R6 radicals are identical or different and are hydrogen atoms or methyl groups, R7 and R8 radicals are identical or different and have hydrogen or halogen atoms or low molecular weight alkoxy groups and the symbol X is a heterocyclic ring system, monocyclic or condensed bicyclic, with 1 to 4 heteratoms, the may also contain one or more carbonyl groups.

It has now been found that a certain group of the above Compounds also has a strong anti-inflammatory effect.

The invention relates to thiazole derivatives having an anti-inflammatory action of the general formula where the radicals R1 and R2 are hydrogen atoms or methyl groups, the radicals R3 and R4 are hydrogen atoms, halogen atoms and low molecular weight alkoxy groups, Y is the group OO or CHOH and the thiazolyl radical is optionally also on the carbon atoms which can be substituted by halogen atoms, low molecular weight alkyl groups, phenyl groups, hydroxyl groups, Nitro groups and low molecular weight carbalkoxy groups and also on the nitrogen atom by low molecular weight alkyl groups, benzyl groups and phenyl groups, their optically active or diastereomeric forms, their salts and their quaternary ammontum compounds can be substituted.

The thiazolyl radical can be substituted one or more times as indicated be. These substituents and the radicals R1 to R4 can each be identical or different be.

It has surprisingly been found that the compounds according to the invention have a pronounced anti-inflammatory effect and therefore for the production of anti-inflammatory drugs are used.

For example, the compounds according to the invention show on the inflammation model of the rat paw (carrageenin edema) based on the method of Domenjoz and Staff (Arch. Exp. Pharm.

Path. 230 (1957) 325) for oral application in the dose range of 1 up to 500 mg / kg a strong anti-phlogistic effect, the best of the intended At 3 to 10 mg / kg orally, compounds already inhibit edema by 50%. The well-known anti-inflammatory salicylamide, for example, has a corresponding effect only at a much higher dosage.

As indications for medicaments which use the compounds according to the invention contain, for example, the following are possible: Chronic Polyarthritis Rheumatic diseases Post-traumatic inflammation Swelling in fractures Thrombophlebitis in any form (including postoperative) bursitis Synovitis collagenoses (polymyositis, periarteritis) gout The medicines that one or more of the compounds according to the invention or mixtures thereof with other pharmaceutically active substances and possibly additives Other pharmaceutical carriers can be enteral, parenteral. oral or perlingual can be applied.

Administration can be in the form of tablets, capsules, pills, coated tablets, Pans, ointments, powders, liquids or aerosols are made. As liquids come to Example in question: oily or aqueous solutions or suspensions, emulsions, injectables aqueous or oily solutions or suspensions. Preferred application forms are Tablets.

The single dose can vary depending on the indication and route of administration between 0.1 and 500 mg of active substance and one to several times a day administered.

The acute toxicity of the compounds according to the invention in the mouse (expressed by the LD 50 in mg / kg) is after intraperitoneal administration at 100 to 400 mg / kg (experimental rivet by Miller and Tainter, see Proc. Soc. exper. Biol. A cd.

57, 261, 1944).

The compounds according to the invention can be prepared, for example, by using a compound of the general formula with a compound of the general formula in the presence of formaldehyde or a formaldehyde-yielding substance in a solvent and optionally reduced the keto group to the hydroxyl group by known methods.

This reduction of the keto group can be carried out, for example, by hydrogenation take place in the presence of one of the customary hydrogenation catalysts or for example by means of alkali aluminum hydrides.:.

or alkali borohydrides in a solvent such as water, Alcohol, ether, etc. between 0 and 500 C, or also.

for example by means of aluminum isopropylate in isopropanol between 80 and 1400 C.

The compounds obtained can by means of the customary methods in their salts or quaternary compounds are converted. As an acid component for the salts come from the usual pharmacologically usable acids, such as, for example Hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, citric acid, benistinic acid, Maleic acid, fumaric acid, lactic acid, paratoluene sulfonic acid and the like can be considered. For conversion into the quaternary salts come the usual quaternizing Means, for example, low molecular weight alkyl halides in question.

The free bases can be obtained from the salts, for example by treatment with aqueous sodium hydroxide solution, and from these bases other Salts are produced.

The compounds that contain optically active carbon atoms and usually obtained as racemates, in a manner known per se, for example by means of an optically active acid can be split into the optically active isomers. It but it is also possible to use optically active or diastereomeric starting materials from the outset to use.

The compounds of the present invention become more common using Excipients and using known methods to the desired dosage forms such as tablets, coated tablets, gelatine capsules, oral solutions1 parenteral solutions1 Processed suspensions, suppositories and the like.

When preparing solutions it may be necessary to achieve the desired concentration of active substance, organic solvents alone or in a mixture to use with water.

As physiologically compatible organic solvents, e.g. monohydric or polyhydric alcohols, polyglycols, esters, etc.

Find application.

To stabilize the active substance molecule, aqueous substances are optionally used or aqueous solutions with physiologically acceptable acids to an acidic one pH range from approx. 1 - 4.

to adjust. Other forms of preparation can also be suitable acidic Stabilizers are added.

If necessary, preservatives are added to the dosage forms such as sorbic acid, p-hydroxybenzoic acid ester and the like.

Provided that there are no chemical incompatibilities exist, the medicinal preparations can, for example, also contain other medicinal products Active ingredients such as antispasmodic and analgesic agents can be added.

Example 1 [3-Phenyl-3-hydroxypropyl- (2)] - # 3- [4-phenyl-thiazolyl- (2)] 3-hydroxypropyl- (1) # - amine 6 g (0.015 mol) of # - @ 2- [3-phenyl-3-hydroxypropyl- (2) -amino] -ethyl # - [4-phenyl-thiazolyl- (2)] - ketone.HCl are dissolved in 60 ml of methanol Slurried and reduced by adding 0.6 g (0.016 mol) of sodium borohydride. After 1 hour, the solvent is distilled off and the residue is dissolved in acetone. The fumarate is precipitated from this solution with futmar acid and the base is then released again with sodium hydroxide solution. The oily base is taken up in ether, converted into the hydrochloride with isopropanolic hydrochloric acid and the salt is recrystallized from ethanol.

Mp 178-181 9C, yield 2.5g.

Example 2 [1-Phenyl-1-hydroxypropyl- (2)] - {1- [4-methyl-thiazolyl- (2) 7-1-hydroxypropyl- (3) -amine 15 g (0.044 mol) of @ 2- [1-phenyl-1-hydroxypropyl- (2) -amino] -ethyl @ - [4-methyl-thiazolyl- (2)] - ketone. HCl are reduced in 150 ml of methanol with 1 g of sodium boranate at room temperature. After standing over power is used with conc. HCl acidified, the solvent was distilled off and the residue extracted with boiling ethanol. The HCl salt crystallizes out on cooling. F /. 201-2020; Yield 5.5g.

Example 3 [1-Phenyl-1-hydroxypropyl- (2)] - {1- [2,4-dimethyl-thiazolyl- (5) 7-i-hydroxypropyl- (3) I -amine 10.7 g (0.03 mol) of {2- [1-phenyl-1-hydroxypropyl- (2) -amino] -ethyl1 - / - 2,4-dimethyl-thiazolyl- (5) I-keon. HCl are reduced in 100 ml of ethanol with 1 g of sodium boronate as in Example 5 and worked up. HCl salt. F6. 217-2180, yield 5g.

Example 4 @ - # 2- [3-Phenyl-3-hydroxy-propyl- (2) -amino] -ethyl # - [4-mothylthiazolyl- (2)] - k @ tor 7 g (0.05 mol) of 4-methyl-2-acetyl-thiazole, 9.4 g (0.5 mol) of @ -norephedrine HCl, 2 g (0.067 mol) of paraformaldehyde and 5 drops of isopropanolic HCl are dissolved in 15 ml of isopropanol as in Example 2 reacted and worked up.

The hydrochloride is recrystallized from methanol.

Mp 197-199 ° C. Yield 7 g. Example 5 1- # 2- [3-Phenyl-3-hydroxypropyl (2) -amino] - @ thyl # - [2,4-dimethylthiazolyl- (5)] - ketone.

25 g. (0.16 mol) 2,4-dimethyl-5-acetyl-thiazole, 30 g (0.16 mol) @ -Norephedrine HCl and 5 g (0.16 ol) paraformaldehyde are made isopropanolic in 50 ml of isopropanol with 15 drops HCl is added and the mixture is boiled on a water bath for a total of 1 hour. After 1/2 hour more 1.5 g paraformaldehyde added. The still warm solution becomes Illit 100 nl acetone diluted. The precipitating hydrochloride is from 80 percent. Recrystallized ethanol. Pp. 208-21000.

Yield 6.6g.

Example 6 1- {2- [3-Phenyl-3-hydroxy-propyl- (2) -amino] -ethyl} - [4-methyl-2-hydroxy-thiazolyl- (5)] - ketone.

5 g (0.035 mol) 4-methyl-2-hydroxy-5-acetyl-thiazole, 6.6 g (0.035 Mol) L-norephedrine HCl and 1.5 g (0.05 mol) paraformaldehyde are 2 hours in 20 ml of glacial acetic acid boiled under reflux. The ba, which precipitates when cold, is the hydrochloride recrystallized from ethanol / ethanol (1: 1). p. @ 00 210 @@ Yield 4.5g.

Example 7 lo, o g of the compound according to Example 5 (hydrochloride) are heated to approx. 5o - 600 C in a mixture of 160 g of ethyl alcohol, Dissolved 320 g of 1,2-propylene glycol and 300 ml of water for injections. After cooling down at approx. 200 ° C., the solution is adjusted to pH 2.0 s 0.2 with 25% strength hydrochloric acid and then made up to 2 liters with water for injections.

The solution is passed through a sterilization filter and then in Usually filled into glass ampoules with 2 ml. The filled ampoules are heated to 100 ° C for 30 minutes for sterilization. 1 ampoule with 2 ml contains lo mg of the compound according to Example 5 (hydrochloride).

Example 8 15, o g of the compound according to Example 5 (hydrochloride) in 1985 g of melted suppository base (e.g. hard fat D.A.B. 7) become homogeneous incorporated and poured out in a known manner in molds for 2.0 g suppositories. The suppositories removed from the mold after solidification contain as Single dose of 15.0 mg of the compound according to Example 5 (flydrochloride).

Example 9 200 g of the compound according to Example 5 (hydrochloride), 50 g tartaric acid, 50 g microcrystalline cellulose, 400 g lactose, 470 g corn starch and 60 g of highly disperse silica are mixed and using about 45o g Starch paste (loose) processed into granules in a known manner. The dry one Granulate is passed through a sieve with approx. 1.2 mm mesh size, then with 170 g microcrystalline cellulose, 40 g highly dispersed silica, 50 g polyvinylpyrrolidone, 440 g corn starch, 220 g talc and 5 g magnesium stearate mixed and in the usual way Way compressed into tablets with a diameter of 9 mm and a weight of 220 mg.

1 tablet = 20.0 mg of the compound according to Example 5 (hydrochloride).

Claims (2)

P a t e n t a n s p r ü c h e 1. Anti-inflammatory drugs for human, veterinary and agricultural use, characterized by a content of one or more compounds of the general formula including the optically active or diastereomeric porms, the salts and the quaternary ammonium compounds, where in the formula I the radicals R1 and R2 are hydrogen atoms. or methyl groups, the radicals R3 and R4 are hydrogen atoms, halogen atoms and mean low molecular weight alkoxy groups, Y is the group CO or CHOH and the thiazolyl radical, if appropriate, on the substitutable carbon atoms Halogen atoms, low molecular weight alkyl groups, phenyl groups, hydroxyl groups, nitro groups and low molecular carbalkoxy groups as well as on the nitrogen atom by low molecular ones Alkyl groups, benzyl groups and phenyl groups may be substituted. 2. Use of compounds according to claim 1 for the preparation of pharmaceutical preparations or medicaments, optionally with the addition of others pharmaceutically active substances and optionally other pharmaceutical carriers.