Novel propane-1,3-diol derivatives and use

Details Novel propane-1,3-diol derivatives and use Novel propane-1,3-diol derivatives and use

1987-07-10

1990-07-31

Fan, Jane T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548204, 548236, 548341, 546335, 546341, 546174, 546175, 546145, 546146, 546147, 544224, 544336, 544335, 514357, 514358, 514255, 514256, 514247, 514374, 514399, C07D27502, A61K 3141

Patent

active

049450980

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to hitherto unknown derivatives of 2-methylenepropane-1,3-diol, to methods for producing said new derivatives, to pharmaceutical compositions containing said new derivatives, to dosage units of said compositions, and to methods for treating patients using said new derivatives.
Recently, a lipid chemical mediator which plays an important role in platelet aggregation and in allergic, asthmatic, inflammatory and hypotensive reactions, was identified. It was named platelet activating factor (PAF), and it turned out to be a mixture of two alkylphospholipids: ##STR2##
Compounds having PAF antagonistic effect (inhibitory effect on PAF activity) are potentially useful as platelet agregation inhibitors, anti-thrombotic, anti-allergic, anti-asthmatic, anti-inflammatory, anti-hypotensive, anti-ulcer, anti-psoriatic, anti-graft rejection and/or anti-conception agents (cf. D. J. Hanahan, Ann. Rev. Biochem., 55, (1986), 483-509. Abstracts from "Second International Conference on Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids", Gatlinburg, Tenn., U.S.A., Oct. 26-29, 1986).
Thus, investigations have been carried out in order to discover compounds similar to PAF in their chemical structure and possessing a PAF antagonistic effect or having a hypotensive effect like PAF. The results of such investigations have been described e.g. in European Patent Publications Nos. 94586, 109255, 142333, 147768 and 157609 and in German patent application No. 3,307,925. All compounds described in these applications are 1,2,3-trisubstituted propanes with three sp.sup.3 -hybridized carbon atoms (like PAF): ##STR3##
Surprisingly, we have now discovered that the desired PAF antagonistic effect can be obtained with derivatives of 2-methylenepropane-1,3-diol of the general formula I ##STR4## where O--A.sup.1 and O--A.sup.2, which can be the same or different, each represents O, O--C(O), O--C(O)NH, O--C(S)NH or O--C(O)O, R.sup.1 represents an alkyl or alkenyl group of 10-22 carbon atoms, n is an integer from 1 to 11, B.sup.+ represents a quaternary ammonium group, either N.sup.+ R.sup.4 R.sup.5 R.sup.6, or N.sup.+ (Het), where R.sup.4, R.sup.5 and R.sup.6 are similar or different alkyl groups of 1-4 carbon atoms, or two or all of R.sup.4, R.sup.5 and R.sup.6 may be incorporated into a cyclic or bicyclic structure, which may contain additional hetero atoms, such as 1-azetidinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-hexamethyleneiminyl, 1-imidazolidinyl, 1-piperazinyl, 1-pyrrolyl, 1-imidazolyl, 4-morpholinyl, triethylenediamin-1-io, 1-quinuclidinio, and where --N.sup.+ (Het) represents an aromatic heterocyclic ring substituent containing at least one nitrogen atom, such as 1-pyridinio, 1-pyridazinio, 1-pyrimidinio, 1-pyrazinio, 3-oxazolio, 3-thiazolio, 1-isoquinolinio, 1-quinolinio, 3-alkyl-1-imidazolio, which may be substituted or unsubstituted; X.sup.- means the anion of a pharmaceutically acceptable inorganic or organic acid, e.g. the anion of an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, or the anion of an organic acid such as acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, in particular a halogen ion, i.e. chlorine, bromine, iodine ions, or the anions of methanesulfonic acid or p-toluenesulfonic acid; and R.sup.2 and R.sup.3 are the same or different, and represent hydrogen or alkyl groups of 1-4 carbon atoms.
Preliminary tests seem to indicate that compounds of formula I, in which R.sup.2 =R.sup.3 =hydrogen, and n is an integer from 4 to 9, have particularly interesting properties.
The expression of an alkyl group or an alkenyl group in the definition of the various symbols in this present specification including claims represents a straight- or branched-chain alkyl or alkenyl group.
Examples of an alkyl group of 10 to 22 carbon atoms represented by R.sup.1 in the formula I are decyl, undecyl, d

REFERENCES:
patent: 4731373 (1988-03-01), Barner et al.

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