Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-07-20
1995-02-14
Fan, Jane T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546268, 546175, 546145, 548195, 548469, 544238, 544333, 544336, 549 14, 514314, 514307, 514252, 514256, 514414, 514433, 514365, C07D41104
Patent
active
053896491
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new therapeutically useful oxathiane derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
The new oxathiane derivatives of the present invention are those compounds of formula (I), hereinafter depicted wherein:
R represents an alkyl group; and
A represents:
(1) a phenyl or naphthyl group which is optionally substituted by one or more substituents selected from halogen atoms and cyano, nitro, trifluoromethyl, carbamoyl, carboxyl, alkoxycarbonyl, alkylsulphonyl, alkyl and phenylalkyl groups; or
(2) a heteroaromatic group containing 1 or 2 nitrogen atoms, for example selected from pyrid-3-yl, quinolin-3-yl, isoquinolin-4-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrazin-3-yl, indol-3-yl and thiazol-5-yl, optionally substituted by an alkyl or alkoxy group, or a halogen atom;
wherein all alkyl groups and moieties, including those in alkoxy and alkoxycarbonyl groups, are straight-chain or branched, and, unless otherwise specified, contain one to about six carbon atoms; and pharmaceutically acceptable salts thereof.
Preferred values for A include 3,4-dichlorophenyl and 3-pyridyl and R is preferably methyl.
When A represents an optionally substituted phenyl group it is preferably a phenyl group which is unsubstituted or substituted on the 3-position or on the 3- and 5-positions by substituents selected from halogen atoms and cyano, nitro, trifluoromethyl, carbamoyl, carboxyl, alkoxycarbonyl and alkylsulphonyl groups.
It is also preferred that the sulphoxide oxygen and the --CSNHR group are in the trans relationship.
In certain cases the substituents A and R can contribute to stereoisomerism. All such forms are embraced by the present invention.
Particularly important compounds of the present invention include the following:
A (.+-.)-trans-3-(3,4-dichlorophenyl)-N-methyl-1,4-oxathiane-3-carbothioamid e 4-oxide
B (.+-.)-trans-N-methyl-3-(3-pyridyl)-1,4-oxathiane-3-carbothioamide 4-oxide.
as well as their stereoisomeric forms and pharmaceutically acceptable salts thereof.
Letters A and B are allocated to compounds for ease of reference in other parts of the specification.
The compounds have valuable pharmacological properties, in particular properties which are indicative of utility in the treatment and/or prophylaxis of disorders associated with:
(1) vascular smooth muscle contraction including hypertension and other cardiovascular disorders such as congestive heart failure, and conditions associated with tissue ischaemia such as angina, peripheral vascular disease and cerebrovascular disease;
(2) respiratory smooth muscle contraction including reversible airways obstruction and asthma;
(3) contraction of smooth muscle of gastrointestinal tract, urinary bladder and uterus, including peptic ulcers, irritable bowel syndrome and diverticular disease; irritable bladder syndrome; and premature labour.
The compounds also have utility in the inhibition of head hair loss associated with male pattern baldness, by topical application.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by in vitro tests which are believed to correlate to pharmacological activity in humans and other animals.
For example, compounds of general formula (I) were submitted to:
VASO-RELAXANT ACTIVITY TEST
The test method used was adapted from those described by Winslow et al [Eur.J.Pharmacol., 131, 219-228 (1986)] and Karaki [J.Pharmacol. Methods, 18, 1-21 (1987)] for differentiating vaso-relaxant activity.
Thoracic aorta was removed from rats and transverse strips, denuded of endothelium, were suspended in a bath containing Krebs solution. The tension was recorded and a contraction induced by addition of 20 mM K.sup.+ (potassium ion) to the bathing solution. The test compound was added to the bath as a solution in increasing cumulative concentration. The concentration in the bathing solution of the test compound which reduced the K.sup.+ -induced contraction by 90% was determined and expressed in .mu.M as the effective c
REFERENCES:
patent: 5120852 (1992-06-01), Aloup et al.
Appel, Current Neurology vol. p. 108 1987.
McLay Iain M.
Walsh Roger J. A.
Fan Jane T.
Nicholson James A.
Parker III Raymond S.
Rhone-Poulenc Rorer Limited
Savitzky Martin F.
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