7-oxoprostacyclin derivatives which are useful as pharmaceutical

Details 7-oxoprostacyclin derivatives which are useful as pharmaceutical 7-oxoprostacyclin derivatives which are useful as pharmaceutical

1991-02-20

1992-04-14

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Silicon containing doai

514460, 514470, 549214, 549415, 549465, A61K 31557, C07D307937

Patent

active

051048612

DESCRIPTION:

BRIEF SUMMARY
The invention relates to novel prostacyclin derivatives, processes for their preparation, as well as their use as medicinal agents.
European Patent EP 59,756 discloses 7-oxoprostacyclins exhibiting blood-pressure-lowering, bronchodilatory, and thrombocyte-aggregation-inhibiting properties.
It has now been found that the introduction of a 3-oxa group and an acetylene group in the 13,14-position results in stabilization of the prostacyclin molecule, the pharmacological spectrum of efficacy being preserved and the duration of effectiveness of the novel prostacyclins being markedly prolonged.
The compounds of this invention exhibit antihypertensive activity. They are furthermore suitable for inhibition of thrombocyte aggregation, of vasodilation, and of gastric acid secretion.
The advantage of the compounds of this invention resides in their dissociation of activity. They have a similarly antihypertensive effect as iloprost, but do not inhibit thrombocyte aggregation as strongly as iloprost.
The invention concerns 7-oxoprostacyclins of Formula I ##STR3## wherein R.sub.1 is the residue OR.sub.3 wherein R.sub.3 can mean hydrogen or alkyl of 1-10 carbon atoms optionally substituted by halogen, phenyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -dialkylamino, or the residue NHR.sub.4 with R.sub.4 meaning.TM.an alkanoyl or alkanesulfonyl residue of respectively 1-10 carbon atoms, ##STR4## wherein the OH-group can be respectively esterified with a benzoyl or alkanoic acid residue of 1-4 carbon atoms or etherified with a tetrahydropyranyl, tetrahydrofuranyl, (C.sub.1 -C.sub.4 -alkoxy)-C.sub.1 -C.sub.4 -alkyl or tri-(C.sub.1 -C.sub.4 -alkyl)silyl residue, wherein the free or modified OH-group can be in the .alpha.- or .beta.-position, residue of 1-4 carbon atoms or etherified with a tetrahydropyranyl, tetrahydrofuranyl, (C.sub.1 -C.sub.4 alkoxy-C.sub.1 -C.sub.4 -alkyl or tri-(C.sub.1 -C.sub.4 -alkyl)silyl residue, hydrogen, the salts thereof with physiologically compatible bases.
The alkyl group R.sub.3 can be considered to be straight or branched alkyl groups of 1-10 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, heptyl, hexyl, decyl. The alkyl groups R.sub.3 can optionally be mono- to polysubstituted by halogen atoms, alkoxy groups of 1-4 carbon atoms, and dialkylamines of 1-4 carbon atoms. Alkyl groups which are monosubstituted are preferred. Examples for substituents are fluorine, chlorine or bromine atoms, phenyl, dimethylamine, methoxy, ethoxy. Preferred alkyl groups R.sub.3 that can be cited are those of 1-4 carbon atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl and butyl.
Physiologically compatible acid resides are suitable as the acid residue R.sub.4. Preferred acids are organic carboxylic acids and sulfonic acids of 1-15 carbon atoms pertaining to the aliphatic, cycloaliphatic, aromatic, aromatic-aliphatic and heterocyclic series. These acids can be saturated, unsaturated and/or polybasic and/or substituted in the usual way. Examples for the substituents are alkyl, hydroxy, alkoxy, oxo or amino groups or halogen atoms.
The following carboxylic acids can be cited, for example: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclopropanecarboxylic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di- and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted by halogen, trifluoromethyl, hdyroxy, alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carboxylic a

REFERENCES:
patent: 3923861 (1975-12-01), Nelson
patent: 4330553 (1982-05-01), Simonidesz et al.
patent: 4466969 (1984-08-01), Nickolson et al.
patent: 4499293 (1985-02-01), Johnson et al.
patent: 4687864 (1987-08-01), Djuric et al.
Bindra et al., Prostaglandin Synthesis, Academic Press, N.Y., pp. 453, 460, 461, 471 (1977).
Skerballa et al. I, Adv. in Prostaglandin Thromboxane, Leukotriene Research, vol. 15 (Raven Press), pp. 271-273 (1985).

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