Amidine derivatives with nitric oxide synthetase activities

Details Amidine derivatives with nitric oxide synthetase activities Amidine derivatives with nitric oxide synthetase activities

1996-01-30

1998-09-15

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514637, 549 74, 564246, A61K 3138, A61K 31155, C07D33312, C07C25700

Patent

active

058078851

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/01767 filed Aug. 12, 1994.
This invention relates to amidine derivatives, processes for their preparation, compositions containing them and their use in therapy.
Certain nitrogen containing compounds have been described as neuroprotective agents. International Patent Application WO 91/12797 (State of Oregon) teaches tri- and tetrasubstituted guanidines as neuroprotective agents. U.S. Pat. No. 5,266,594 (Dawson et al) (published after the earliest priority date of this application) describes the use of arginine derivatives in the treatment of stroke and other neurodegenerative diseases. Also European Patent Application 547558 (Washington University) describes the use of aminoguanidine in the treatment of immunological and other disorders.
The use of inhibitors of nitric oxide synthetase in the treament of disease has also been described, for example, in International Patent Applications WO 94/12163 (Abbott) and WO 94/12165 (Wellcome) (both published after the earliest priority date of this application) and European Patent Application 446699 (Merrell Dow).
Amidine derivatives have been described for use as herbicides in German Patent Application DE-OS-2321330 (Bayer). N-phenyl amidine derivatives have also been described for use in the treatment of diabetes in U.S. Pat. No. 3,669,974 (USV Pharmaceutical Corp.) and UK Patent Application 2226562 (Boots). N'N"-disubstituted amidines are described for use in the treatment of hypertension, depression and halliconogenic states in International Patent Application WO 92/04054 (University of Oregon). The use of certain symmetric bisamidines as analgesics, in the treatment of inflammation and in the treatment of hypertension is described in UK Patent No. 1180629 (Delalande).
A number of patent documents describe processes for the preparation of amidines or describe the use of amidines as intermediates without disclosing any pharmaceutical use for these compounds. Simple amidine derivatives are described in UK Patent No. 1088095 (Merck) as intermediates in the preparation of useful benzimidazole derivatives. Processes for preparation of other simple N-aryl and N-heteroaryl amidines are described in U.S. Pat. No. 3,299,081 (Merck) and fluorine containing amidine derivatives are described as chemical intermediates in Japanese Patent Application No. 2229147 (Nissan) and in Japanese Patent Application No. 58057357 (Daikin).
We have now found a new group of amidine derivatives that possesses useful pharmaceutical activity.
According to a first aspect of the invention, we provide a compound of formula I ##STR1## wherein D represents phenyl, pyridinyl or a 5 membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, S and N, which three groups are optionally substituted by one or more groups selected from alkyl C1 to 6, alkoxy C1 to 6, halogen and perflouroalkyl C1 to 6; or perfluoroalkyl C1 to 6; --X(CH.sub.2).sub.n NHCO(CH.sub.2).sub.s NR.sup.3 R.sup.4, --X(CH.sub.2).sub.p NR.sup.3 R.sup.4, --X(CH.sub.2).sub.n NHCOR.sup.5 or --(CH.sub.2).sub.q NHC(NH)R.sup.6 ; --(CH.sub.2).sub.r A, --(CH.sub.2).sub.m OA or --CH(CH.sub.3)(CH.sub.2).sub.t A; piperidinyl, morpholinyl, pyrrolidinyl 1,2,3,4-tetrahydroisoquinolinyl; or piperazinyl optionally 4-substituted by alkyl C1 to 6; --(CH.sub.2).sub.r A or --O(CH.sub.2).sub.w A; aromatic ring containing 1 to 4 heteroatoms selected from O, S and N, which four groups are optionally substituted by one or more groups selected from alkyl C1 to 6, halogen, nitro, cyano and trifluoromethyl; ring containing 1 to 4 heteroatoms selected from O, S and N, which three groups are optionally substituted by one or more groups selected from alkyl C1 to 6, alkoxy C1 to 6, halogen and perfluoroalkyl C1 to 6; or perfluoroalkyl C1 to 6; the compound of formula I through the heteroatom; neither X nor Z represent a bond, then n represents an integer in the range 2 to 6 inclusive; NR.sup.3 R.sup.4 or --X(CH.sub.2).sub.n NHCOR.sup.5, and X represents O, then n represents an integer in the range 2 to 6 i

REFERENCES:
patent: 3299081 (1967-01-01), Sletzinger et al.
patent: 3632593 (1972-01-01), Gautier et al.
patent: 3669974 (1972-06-01), Elpern et al.
patent: 3988474 (1976-10-01), Abdallah et al.
patent: 4499105 (1985-02-01), Panneman
patent: 4503076 (1985-03-01), De Vincentiis
patent: 4539319 (1985-09-01), Newsome et al.
patent: 4598077 (1986-07-01), Fujii et al.
patent: 4634705 (1987-01-01), Debernardis et al.
patent: 5266594 (1993-11-01), Dawson et al.
patent: 5286752 (1994-02-01), Johnson et al.
patent: 5308869 (1994-05-01), Keana et al.
Moncada et al. (1991) "Nitric Oxide; Physiology, . . . " Pharmacological Reviews 43:109-142.
Nissan Chem. Ind. KK (1989) "Fluorine-contg cpds." 90-38310/42.
Forstermann et al. (1992) "Induced RAW 264.7 macrophages express" European J. of Pharmacology-Molec. Pharmac.Sect. 225:161-165.
Bredt et al. (1990) "Isolation of nitric oxide synthetase, . . . " Proc. Natl. Acad. Sci. (USA) 87:682-685.
Pollock et al. (1991) "Purification and characterization of . ." Proc. Natl. Acad. Sci. (USA) 88: 10480-10484.

Affiliated with

Also associated with

Rating

Amidine derivatives with nitric oxide synthetase activities does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Amidine derivatives with nitric oxide synthetase activities, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Amidine derivatives with nitric oxide synthetase activities will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-87895