3-amino-1,2-benzoisoxazole derivatives, process for preparation,

Details 3-amino-1,2-benzoisoxazole derivatives, process for preparation, 3-amino-1,2-benzoisoxazole derivatives, process for preparation,

1999-07-21

2000-11-21

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548241, A61K 31423, C07D26120

Patent

active

061503908

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a novel 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I, LTB-4[leukotriene-B-4; 5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid] receptor antagonist, process for preparation thereof, and use thereof for LTB-4 receptor antagonist or therapeutics for osteoporosis. ##STR2## (in which n is integer of 3-5.)
LTB-4, natural product, is metabolite of arachidonate, produced in the path way of 5-lipoxygenase [Ford-Hutchison, A. W. et al., Nature(London), 286, 264-265, 1980]. LTB-4 induces cohesion and degranulation of neutrophil, and promotes chemical taxis and locomotion of leukocyte, and LTB-4 contracts smooth muscle, and participate in the production of peroxide, and is also detected in a large amount at inflammatory lesions of patient, such as psoriasis, enteritis, rheumatoid arthritis, bronchial asthma, and adult respiratory distress syndrome.
Compound for LTB-4 receptor antagonist, therefore, can be utilized effectively as inhibitor and treating medicine at the above mentioned disease (Clint, D. W. et al., J. Med. Chem. 39, 2629-2654, 1996; Suh, H., U.S. Pat. No. 5,455,274, 1995).
Usual LTB-4 receptor antagonists were SM-9064 (Namiki, M. et al., Biochem. Siophys. Res. Comm. 138, 540-546, 1986); U-75302 (Morris, J. et al., Tetrahedron Lett. 29, 143-146, 1988); LY-255283 (Herron, D. K. et al., FASEB J. 2, A1110, 1988); SC-41930 (Djuric, S. W. et al., J. Med. Chem. 32, 1145-1147, 1989); LY-223982 (Gapinski, D. M. et al., J. Med. Chem. 33, 2807-2813, 1990); ONO-LB457 (Konno, M. et al., Adv. Prostaglandin, Thromboxane Leukotriene Res. 21, 411-414, 1991); CP-105696 (Showell, H. J. et al., J. Pharmacol. Exper. Ther. 273, 176-184, 1995); CGS-25019C (Morrissey, M. M., Suh, H. U.S. Pat. No. 5,451,700; Brooks, C. D. et al., J. Med. Chem. 39, 2629-2654, 1996); and so on.
It has been reported that CGS-25019C, which is in the highest critical step, have toxicity to stimulate stomach and intestine among the usual antagonist. So, it is necessary to develop a novel LTB-4 receptor antagonist.
Bone maintain necessary bone mass and the structure as a physical support of body, and play a important role as keeping the concentration of Ca.sup.2+, etc. in blood as a stock of Ca.sup.2+ and so on.
Bone resorption and remodeling is continuously recycled, to carry out the above functions, and is in the dynamic state of metabolite with resorbing and remodeling of bone. When the remodeling of bone does not equilibrate the resorption of bone, the resorption is relatively superior to the remodeling of bone, and it causes the reduction of bone density and mass to osteoporosis, which is in the state of not maintaining of bony strength. Osteoporosis is very frequently occurred in middle aged and old women.
Therapeutics for osteoporosis, so far, have been developed to inhibit the resorption of bone by inhibiting the action of osteoclast cells. Fracturability by the reduction of bone mass may be not recovered only by inhibiting the resorption of bone. For the ideal treatment of osteoporosis, the recovery from the fracturability, there is necessity that the medicine inhibit the resorption of bone and accelerate the remodeling of bone.
We, inventors have synthesized various compounds and examined their effect of antagonizing LTB-4 receptor and of accelerating the bone formation in order to inhibit and treat the disease relevant to LTB-4 and osteoporosis. As a result, the present inventors completed the invention through synthesizing 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I, and identifying their effect of antagonizing LTB-4 receptor and of accelerating the bone formation.


SUMMARY OF THE INVENTION

The present invention has an object to provide novel 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I.
The present invention has another object to provide process for preparation of 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I.
The present invention has another object to provide pharmaceutical composition c

REFERENCES:
Journal of Medicinal Chemistry of Jul. 5, 1996, vol. 39, No. 14 Modulators of Leukotriene Biosysthesis and Receptor Activation by Clint D. Brooks and James B. Summers, pp. 2629-2654.
The In Vitro and In Vivo Pharmacologic Activity of the Potent and Selective Leukotriene B4 Receptor Antagonist CP-105696, Dec. 12, 1994, vol. 273, No. 1 by H. J. Showell et al., The Journal of Pharmacology and Experimental Therapeutics, pp. 176-184.
Suh et al., Bioorg. Med. Chem. Lett. (Feb. 18, 1997), 7(4), 389-392, Feb. 1997.

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