Guanidine derivatives useful in therapy

Details Guanidine derivatives useful in therapy Guanidine derivatives useful in therapy

1995-09-21

1999-03-23

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514307, 5142355, 5142372, 514422, 514428, 514326, 544141, 546146, 546208, 540589, 548567, 548518, C07D20504, C07D40114, C07D40314, A61K 3140

Patent

active

058859853

DESCRIPTION:

BRIEF SUMMARY
This is a 371 of PCT/GB 94/00584 filed Mar. 22, 1994.
This invention relates to guanidine derivatives processes for their preparation, compositions containing them and their use in therapy.
The use of certain phenyl guanidine derivatives as pharmaceuticals is known. For example, U.S. Pat. No. 3,976,643 (to Rorer) discloses phenyl guanidines as antihypertensive agents; International patent application WO 91/12797 (to State of Oregon) teaches tri and tetrasubstituted guanidines as neuroprotective agents; U.S Pat. Nos. 4,211,867, 4,414,211, 4,182,865 and 4,345,083 and European Patent 9362 (to McNeil Laboratories) teach heterocyclic derivatives of phenyl guanidines as antihypoglycaemic agents which may also have antisecretory or cardiovascular activity; European Patent 30092 (to ICI) discloses aminoalkylaryl guanidine derivatives as histamine H-2 secretion inhibitors; South African Patent 80/2240 and European Patent 20303 (to Ciba Geigy) disclose heterocyclic substituted guanidines in the treatment of diabetes.
Phenyl substituted guanidine derivatives are also known for other purposes, for example United Kingdom Patent 1341245 (to Golyshin et al) discloses their use as antifungals for use in horticulture.
The papers Maryanoff et al (1986) J Org Chem, 51, 1882-1884 and Rasmussen et al (1988) Synthesis, 6, 460-466 describe synthetic methods for preparing phenyl guanidines.
We have now found a new group of guanidine derivatives that possesses useful pharmaceutical activity.
According to a first aspect of the invention, we provide a compound of formula I ##STR2## wherein W represents a group selected from ##STR3## R.sup.9 represents hydrogen, halogen, alkyl C1 to 6, nitro or trifluoromethyl; trifluoromethyl, thioalkyl C1 to 6, hydroxy, alkoxy C1 to 6, or a group selected from --NR.sup.4 R.sup.5, --O(CH.sub.2).sub.p Q, --O(CH.sub.2).sub.m OQ, --(CH.sub.2).sub.m NR.sup.1 R.sup.2, --O(CH.sub.2).sub.m NR.sup.1 R.sup.2, --NHCO(CH.sub.2).sub.m NH(CH.sub.2).sub.n Q or --(CH.sub.2).sub.p CONR.sup.1 R.sup.2, or --(CH.sub.2).sub.n Q; --(CH.sub.2).sub.n Q, morpholinyl or a group ##STR4## R.sup.3 represents alkyl C1 to 6 or a group --(CH.sub.2).sub.n Q; Q represents phenyl optionally substituted by alkyl C1 to 6, halogen, hydroxy, alkoxy or alkyl C1 to 6; --NH(CH.sub.2).sub.m NHCO--;
Compounds of formula I may exist in tautomeric, enantiomeric and diasteriomeric forms, all of which are included within the scope of the invention.
Certain compounds of formula I are new. However, certain compounds of formula I are known as chemical intermediates from U.S. Pat. Nos. 4,211,867, 4,345,083, 4,182,865 and 4,414,211 (McNeil Laboratories), European Patent No. 9362 (McNeil Laboratories) and South African Patent 80/2240 (Ciba Geigy) or are disclosed in Rasmussen et al (1988) Synthesis, 6, 460-466.
Thus, as a second aspect of the invention we provide a compound of formula I with the provisos that: R.sup.8 does not represent 4-hydroxy, 4-methyl, 4-nitro, hydrogen, 2-chloro, 3-chloro, 4-chloro, 2-methyl, 2-isopropyl, 2-isopropenyl, 2-ethyl, 2-bromo, 3-bromo, 4-bromo, 3-benzyloxy, 4-benzyloxy, 2-methoxy, 3-methoxy, 4-methoxy, or 4-thiomethyl; R.sup.8 does not represent 6-chloro or 4-methyl or 4-benzyloxy; R.sup.8 does not represent 4-methoxy; R.sup.8 does not represent 4-methyl, 5-methyl, 6-methyl, 4-chloro, 5-chloro or 4-methoxy; R.sup.8 does not represent 5-chloro; R.sup.8 does not represent 4-chloro, 4-methyl or 6-methoxy; R.sup.8 does not represent hydrogen, 2-isopropenyl, 3-methoxy, 4-methoxy, 4-dimethylamino, 4-thiomethyl, 3-chloro, 4-fluoro, 3-methyl or 4-benzyloxy; R.sup.8 does not represent 5-chloro or 6-methyl; R.sup.8 does not represent 4-methyl or 6-chloro; R.sup.8 does not represent 4-methyl; R.sup.8 does not represent 4-methoxy; or R.sup.8 does not represent 4-ethoxy,
We prefer W to represent azetidinyl or pyrrolidinyl, especially pyrrolidinyl.
When one of R.sup.8 or R.sup.9 represents halogen, alkyl C1 to 6, nitro, trifluoromethyl, thioalkyl C1 to 6, hydroxy, alkoxy C1 to 6, or --NR.sup.4 R.sup.5, and the other represents hydr

REFERENCES:
patent: 3976643 (1976-08-01), Diamond et al.
patent: 4182865 (1980-01-01), Rasmussen
patent: 4211867 (1980-07-01), Rasmussen
patent: 4345083 (1982-08-01), Rasmussen
patent: 4414211 (1983-11-01), Rasmussen
patent: 5268373 (1993-12-01), Breslin et al.
C.A. Maryanoff et al "A convenient synthesis of Guanidines . . ." J. Org. Chem. 1986, 51, pp. 1882-1884.
C.R. Rasmussen et al. "A versatile synthesis of Novel . . ." Journal of Synthetic Organic Chemistry, Synthesis, No. 6, Jun. 1988, pp. 460-466.
O. Morgenstern et al. "N, N-weknupfte heterobicyclen . . ." Pharmazie (1991), pp. 505-507.
Jonczyk, et al, "Reactions of Organic Anions . . .," Communications (1978) 882-883.
Forstermann, et al, "Induced RAW 264.7 macrophages express soluble . . .," European Journal of Pharmacology, 225 (1992) 161-165.
Bredt, et al, "Isolation of nitric oxide synthetase . . .," Proc. Natl. Acad. Sci. USA, 87 (1990) 682-685.
Pollock, et al, "Purification and characterization of particulate . . .," Proc. Natl. Acad. Sci. USA, 88 (1991) 10480-10484.

Affiliated with

Also associated with

Rating

Guanidine derivatives useful in therapy does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Guanidine derivatives useful in therapy, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Guanidine derivatives useful in therapy will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2125581