Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-11-14
1998-02-24
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514309, 514327, 514331, 514637, 546141, 546149, 546231, 546145, 564245, C07C33532, C07D21706, A61K 31155, A61K 3147
Patent
active
057212473
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE95/01069, filed Sep. 20, 1995.
This invention relates to new isothiourea derivatives, processes for their preparation, compositions containing them and their use in therapy.
Thiourea and isothiourea derivatives have been described before for a variety of therapeutic uses. WO 94/12165 (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).
International Patent Applications WO 94/21621 and WO 95/05363 (Fisons Corporation) (both published after the priority date of this application) disclose guanidine and amidinc compounds respectively 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 a first aspect of the invention, we provide a compound of formula I ##STR2## wherein D represents alkyl C1 to 6; --(CH.sub.2).sub.r A or 1,2,3,4-tetrahydroisoquinolinyl; or to 4 heteroatoms selected from O, S and N, which two groups are optionally substituted by one or more groups selected from alkyl C1 to 6, halogen and trifluoromethyl; bond attached to the phenyl ring in the para position and p represents 0, then R.sup.2 and R.sup.3 do not both represent methyl;
We prefer that R.sup.2 and R.sup.3 independently represent hydrogen, alkyl C1 to 6 or --(CH.sub.2).sub.r A or that --NR.sup.2 R.sup.3 together represent 1,2,3,4-tetrahydroisoquinolinyl.
We prefer that A represents phenyl optionally substituted by one or more groups selected from alkyl C1 to 6, halogen and trifluoromethyl. We particularly prefer that A represents phenyl or phenyl substituted by chlorine.
We prefer that X represents a bond.
We prefer that R.sup.1 represents hydrogen.
We prefer that X is orientated para to the N of the isothiourea moiety.
We prefer that p represents an integer 1 to 3, especially 2.
We prefer that D represents propyl or ethyl, particularly isopropyl or ethyl, especially ethyl.
According to the invention, we further provide a process for the preparation of compounds of formula I, and pharmaceutically acceptable salts thereof, which comprises: ##STR3## wherein R.sup.1, R.sup.2, R.sup.3, p and X are as defined above with a compound of formula III R.sup.3 represents alkyl C1 to 6, --(CH.sub.2).sub.r A or --(CH.sub.2).sub.m OA by reacting a corresponding compound of formula I in which one or both of R.sup.2 and R.sup.3 represents hydrogen with a compound of formula IV, --(CH.sub.2).sub.m OA and L is a leaving group, 4, by reduction of a compound of formula V ##STR4## wherein D, X, R.sup.1, R.sup.2, R.sup.3 and p are as defined above, (d) preparation of a compound of formula I wherein both R.sup.2 and R.sup.3 represent hydrogen, by reduction of a corresponding compound of formula VI ##STR5## wherein R.sup.1, D, p and X are as defined above, (e) preparing a compound of formula I wherein R.sup.2 represents hydrogen and p represents an integer 2 to 4, by reduction of a compound of formula VII ##STR6## wherein R.sup.1, R.sup.3, D, X and p are as defined above, (f) preparing a compound of formula I wherei
REFERENCES:
patent: 2050552 (1936-08-01), Bockmuhl et al.
patent: 4008330 (1977-02-01), Yamamoto
patent: 4211867 (1980-07-01), Rasmussen
patent: 4785008 (1988-11-01), Coquelet et al.
patent: 5223498 (1993-06-01), Balasubramanian
Agarwal et al, Indian Journal of Chemistry, vol. 26 B, Jul. 1987, pp. 642-646.
Hoskinson et al, Journal of Textile Institute, vol. 64, 1973, pp. 144-152.
Mar., J., Advanced Organic Chemistry, 3d ed. John Willey and Sons, N.Y., 10, pp. 315, 1099, 1103-1104.
Bredt, et al., "Isolation if Nitric oxide sysnthetase, a calmodulin-requiring enzyme," Proc. Natl. Acad. Sci. (USA) 87: 682-685, 1990.
Forstermann, et al., "Calmodulin-dependent endothelium derived relaxing factor
itric oximde synthetase activity . . . ," Proc. Natl. Acad. Sci. (USA) 88: 1788-1792, 1991.
Synthesis (1988), No. 6, pp. 460-466 (Rasmussen).
Hoskinson, "Studies on textile insectproofing . . . "Journal of the Textile Institute, vol. 64 No. 3, 1973, pp. 144-154.
Zhelyazov "Synthesis of substituted thiocarbamides and derivatives containing guaididne . . . "Chemical Abstracts, vol. 79 No. 5, Aug. 6, 1973.
Galstukhova "Synthesis of thiourea derivatives. VI 318.
Mayrand "Urea and ehtylene glycol-facilitated transport systems in the human red cell membrane", Journal of General Physiology, vol. 81 No. 2, Feb. 1983 NY pp. 221-237.
Astra Aktiebolag
Davis Zinna Northington
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