Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-08
1998-07-28
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546145, 564252, 514631, C07D21702, C07C33502, A61K 3147, A61K 31155
Patent
active
057863644
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE96/00162, filed Feb. 9, 1996.
This invention relates to novel compounds, processes for their preparation, compositions containing them and their use as neuroprotective agents.
Thiourea and isothiourea derivatives have been described before for a variety of therapeutic uses. WO 94112165 (Wellcome) describes simple isothiourea derivatives for use in the treatment of inter alia systemic hypotension, septic shock and inflammatory conditions; WO 95/09619 (Wellcome) (published after the priority date of this application) describes substituted urea and isothiourea derivatives for use in the treatment of cerebral ischaemia; United Kingdom Patent No 1178242 (Wellcome) discloses bisisothioureas having anti-inflammatory activity; European Patent Application No 411615 (Warner Lambert) discloses thiourea derivatives having use in the treatment of symptoms of cognitive decline; European Patent Application No 392802 (Beecham) discloses thiourea derivatives for use in the treatment of bronchial, cerebrovascular or neuronal disorders.
Isothiourea derivatives are also known as chemical intermediates in the preparation of guanidine derivatives (see U.S. Pat. No. 4,211,867 (McNeil Laboratories) and Synthesis (1988) 6, 460-466 (Rasmussen) which disclose the compound 4-dimethylaminophenylcarbamimidothioic acid methyl ester and U.S. Pat. No. 5,223,498 (Boots).
N-Alkoxyphenyl-N'-quinolinyl-thiourea derivatives useful as tuberculostatic agents are disclosed in DE-B-1157626 (Hoechst).
International Patent Application WO 95/05363 (Fisons) (published after the priority date of this application) discloses N-phenyl amidine derivatives which are indicated for the treatment of inter alia neurodegenerative disease.
We have now discovered a new and useful group of isothiourea derivatives.
According to the invention, there are provided compounds of formula I ##STR2## wherein D represents alkyl C1 to 6 substituted by --(CH.sub.2).sub.m --NXY; --O--(CH.sub.2).sub.2 --NH-- substituted by --(CH.sub.2).sub.m --NXY; or --U--(CH.sub.2).sub.a --N(X)--(CH.sub.2).sub.b --; provided that a+b is in the range 1 to 3; to 6, or a group --(CH.sub.2).sub.n Q, tetrahydroisoquinolinyl; selected from the group consisting of alkyl C1 to 6, alkoxy C1 to 6, trifluoromethyl, halogen, nitro and cyano;
We prefer that T represents --U--(CH.sub.2).sub.a --N(X)--(CH.sub.2).sub.b --. We particularly prefer that T represents --U--(CH.sub.2).sub.a --N(X)--(CH.sub.2).sub.b -- and U represents CH.sub.2. We especially prefer that T represents --U--(CH.sub.2).sub.a --N(X)--(CH.sub.2).sub.b --, U represents CH.sub.2 and a and b each represent 1.
We prefer that D represents alkyl C1 to 3, particularly methyl or ethyl, especially ethyl.
When T represents --U--(CH.sub.2).sub.a --N(X)--(CH.sub.2).sub.b --, we prefer that X represents hydrogen, methyl or the group --CH.sub.2 Q.
When T represents a C.sub.3-5 saturated or unsaturated alkylene chain substituted by --(CH.sub.2).sub.m --NXY or --O--(CH.sub.2).sub.2 --NH-- substituted by --(CH.sub.2).sub.m --NXY, we prefer X and Y independently to represent hydrogen, methyl or the group --CH.sub.2 Q, although it is not preferred that X and Y both represent the group --CH.sub.2 Q. We particularly prefer that one of X and Y represents hydrogen or methyl and the other represents the group --CH.sub.2 Q.
We prefer that n represents 1.
We prefer Q to represent phenyl or phenyl substituted by a substituent selected from the group consisting of alkyl C1 to 6, alkoxy C1 to 6, trifluoromethyl, halogen, nitro and cyano. We particularly prefer that Q represents phenyl or phenyl substituted by alkyl C1 to 6 or halogen.
According to the invention, there is also provided a process for the preparation of compounds of formula I and pharmaceutically acceptable salts thereof, which comprises represents alkyl C1 to 6 or the group --(CH.sub.2).sub.n Q, by reacting a corresponding compound of formula I in which X or one or both of X and Y represents hydrogen, with a compound of formula II and L is a leaving group, or saturat
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H.J. May: "Zur Synthese von N-(2-Imidazolin-2-yl)-N-(4-indanyl)amin(In danazolin)," IArzeneimittel Forschung Drug Research., vol. 30, No. 10, 1980, pp. 1733-1737.
Astra Aktiebolag
Davis Zinna Northington
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