Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1991-11-20
1993-01-05
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
562402, C07C 5700
Patent
active
051772574
DESCRIPTION:
BRIEF SUMMARY
The invention relates to the novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, i.e. the compound of the formula ##STR2## in free form or in salt form, to the use of this compound, to a process for the preparation of this compound and to pharmaceutical preparations containing the compound I in free form or in the form of a pharmaceutically acceptable salt.
The compound I can be in the form of a salt, in particular a pharmaceutically acceptable salt. Corresponding salts are salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal salts, for example sodium or potassium salts, or such as alkaline earth metal salts, for example calcium or magnesium salts, or salts with ammonia, with an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine or an aliphatic amine which, if desired, is C-hydroxylated, for example a mono-, di- or tri-lower alkylamine, such as methyl-, ethyl- or diethylamine, a mono-, di- or tri-hydroxy-lower alkylamine, such as ethanol-, diethanol- or triethanolamine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, an N-(hydroxy-lower alkyl)-N,N-di-lower alkylamine, such as 2-(dimethylamino)ethanol, or an N-(polyhydroxy-lower alkyl)-N-lower alkylamine, such as D-glucamine, or with a quaternary ammonium base, such as a quaternary aliphatic ammonium hydroxide, for example tetrabutylammonium hydroxide. Salts which are not suitable for pharmaceutical uses and which are employed, for example, for the isolation or purification, respectively, of the compound I, in free form or in the form of a pharmaceutically acceptable salt, are also included.
The racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, i.e. the 1:1 enantiomer mixture of (R)- and (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid is known and is proposed, for example in the European Patent Application No. 0 132 566, as an antinociceptive and antiinflammatory pharmaceutical active ingredient having prostaglandin synthesis-inhibiting properties. The novel (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid, in free form or in the form of a pharmaceutically acceptable salt, also has valuable pharmacological properties, for example antinociceptive, antiinflammatory and prostaglandin synthesis-inhibiting activities, to an extent which is comparable to the extent of the activities of the known racemate. Thus, for example, (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid has corresponding desired effects in the writhing test model (induction by phenyl-p-benzoquinone) on the mouse [in accordance with J. Pharmacol. exp. Therap. 125, 237 (1959)], where the ED.sub.50 is 5 mg/kg p.o., and also in the adjuvant arthritis test on the rat, in which an ED.sub.40 of 0.5 mg/kg p.o. is found. Additionally, compared with the known racemate, the (S)-enantiomer provided according to the invention has, however, surprising therapeutic advantages. In particular, the (S)-enantiomer is accumulated in the fatty tissue to a smaller extent. Thus, comparison experiments with .sup.14 C-labelled (S)-4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid and .sup.14 C-labelled racemic 4-(2-bromobenzoyl)-5-hydroxy-benzocyclobutene-1-carboxylic acid on the rat show that on daily administration of in each case 5 mg/kg p.o. over a period of 10 days, radioactive material is incorporated into the fatty tissue on administration of the (S)-enantiomer in a lower concentration than on administration of the racemate. In particular with respect to a chronic administration of the active ingredient, this is to be valued as a considerable therapeutic advantage of the (S)-enantiomer over the racemate.
The compound I, in free form or in the form of a pharmaceutically acceptable salt, can accordingly be used, for example, as active ingredient in antinociceptive, antiinflammatory and prostaglandin synthesis-inhibiting pharmaceutical compositions, which are used, for example, for the treatment of inflammations, such as
REFERENCES:
patent: 4523030 (1985-06-01), Haas
Ullmanns Encyklopadie Der Technischen Chemie, 4th Ed., vol. 17, pp. 451-454 (1979).
von Sprecher Andreas
Wetter Hansjurg
Ciba-Geigy Corporation
Fishman Irving M.
Kaiser Karen G.
Killos Paul J.
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