| PATENT ASSIGNEE'S COUNTRY | Korea |
| UPDATE | 11.00 |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 21.11.00 |
| PATENT TITLE |
3-amino-1,2-benzoisoxazole derivatives, process for preparation, and use thereof |
| PATENT ABSTRACT |
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. ##STR1## (in which n is integer of 3-5). |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | 21.07.99 |
| PATENT CT FILE DATE | 04.02.98 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | 06.08.98 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
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. |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. 3-Amino-1,2-benzoisoxazole derivatives, represented by Formula I, as follows: ##STR7## in which n is an integer of 3-5. 2. LTB-4 receptor antagonist composition containing a 3-amino-1,2-benzoisoxazole derivative, represented by Formula I, in effective amount and a pharmaceutical carrier ##STR8## in which n is an integer of 3-5. 3. LTB-4 receptor antagonist composition as claimed in claim 2, wherein one of 3-amino-1,2-benzoisoxazole derivatives is N,N-diisopropyl-4-[4-(3-amino-benzo[d]isoxazol-6-yloxy)butoxy]-3-methoxy-b enzamide (HS-1141). 4. A method of treating osteoporosis by administering to a patient in need thereof an effective amount of a 3-amino-1,2-benzoisoxazole derivative, represented by Formula I ##STR9## in which n is an integer of 3-5. 5. A method of treating osteoporosis as claimed in claim 4, wherein one of 3-amino-1,2-benzoisoxazole derivatives is N,N-diisopropyl-4-[4-(3-amino-benzo[d]isoxazol-6-yloxy)butoxy]-3-methoxy-b enzamide (HS-1141). 6. A process for preparation of a 3-amino-1,2-benzoisoxazole derivative, represented by Scheme I, as follows: ##STR10## in which, I is diisopropylamine; II is dibromobutane(a), dibromopropane(b) or dibromopentane(c); III is sodium iodide (NaI); IV is 2-fluoro-4-hydroxybenzonitrile; V is acetoneoxime; VI is hydrochloric acid; and VII is potassium carbonate (K.sub.2 CO.sub.3). -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
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 containing one of 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I, in effective amount which can antagonize LTB-4 receptor. Also, the present invention has another object to pharmaceutical composition containing one of 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I, in effective amount which can accelerate the bone formation. It should be apparent that another purpose of the present invention and their application be made by those skilled in the art from detailed description of the invention. DETAILED DESCRIPTION OF THE INVENTION The present invention will now be described in detail. Compounds, represented by Formula I, according to the present invention are N,N-diisopropyl-4-[4-(3-aminobenzo[d]isoxazol-6-yloxy)butoxy]-3-methoxyben zamide (HS-1141), represented by Formula II; ##STR3## N,N-diisopropyl-4-[3-(3-aminobenzo[d]isoxazol-6-yloxy)propoxy]-3-methoxyben zamide (HS-1151), represented by Formula III; and ##STR4## N,N-diisopropyl-4-[5-(3-aminobenzo[d]isoxazol-6-yloxy)pentoxy]-3-methoxyben zamide (HS-1132), represented by Formula IV. ##STR5## As demonstrated by the following Experiment, compounds of Formula II to IV according to the present invention can be utilized as inhibitor and therapeutics for the disease relevant to LTB-4 or osteoporosis, because the compounds have effects of LTB-4 receptor antagonist and of accelerating the bone formation. Compounds according to the present invention can be administered in effective amount to inhibit the action of LTB-4 receptor or to treat osteoporosis by various administrable path; and the form and dose thereof can be determined by those skilled in the art in consideration of administrative object; administrable path; and a status and weight of patient. LTB-4 receptor antagonist or therapeutics for osteoporosis, preferably, contains both one of 3-amino-1,2-benzoisoxazole derivatives, represented by Formula I, and pharmaceutically acceptable carriers. These carriers can be selected from the group comprising the standard pharmaceutically acceptable carriers, which is commonly used in, pasteurized solution, tablet, coated tablet, and capsule. These carriers, typically, contain bulking agent, such as starch, milk, sugar, specific clay, gelatin, stearic acid, talc, vegetable fat or oil, gum and glycols, etc. or other kind of known bulking agent. Also, sweetening agent, coloring additives and other component can be contained in the carriers. Composition, which contain these carriers, can be formatted by the known method. But, composition, which contain 3-amino-1,2-benzoisoxazole derivatives for LTB-4 receptor antagonist and therapeutics for osteoporosis, has never been reported. In the present invention, LTB-4 receptor antagonist and therapeutics for osteoporosis containing one of 3-amino-1,2-benzoisoxazole derivatives, can be administered by the known manner, such as oral dose, intravenous, intramuscular, and percutaneous injection, and so on. But it is not limited to these manner. In carrying out the present invention, 3-amino-1,2-benzo-isoxazole derivatives may be contained in a very extensive range of amount in the pharmaceutical composition. Effective amount of 3-amino-1,2-benzo-isoxazole for LTB-4 receptor antagonist or therapeutics for osteoporosis is 10-1000 mg/day. Dose of composition and its frequency can be easily determined by those skilled in the art according to characteristics of administrative form; status and weight of patient; size of inflammatory lesions; path and frequency of administration; and characteristics of specific derivatives to be used. Process for preparation of compound according to the present invention comprises steps, represented by Scheme I, with the following 4-hydroxy-3-methoxybenzoic acid (1) as starting material, and the specific condition of reaction is shown in the Examples, as follows. ##STR6## in which I is diisopropylamine; II is dibromobutane(a), dibromopropane(b) or dibromopentane(c); III is sodium iodide (NaI); IV is 2-fluoro-4-hydroxybenzonitrile; V is acetoneoxime; VI is hydrochloric acid; and VII is potassium carbonate (K.sub.2 CO.sub.3). The present invention has been described by reference to specific examples chosen for the purpose of illustration, but it is apparent that the present invention should not be limited by the specific disclosure herein. The abbreviation used in this specification means, as follows: DMF: dimethyl formamide DMSO: dimethyl sulfoxide GF/C: glass fiber filter type C HBSS media: Hank's balanced salt solution TMS: tetramethylsilane (reference material of NMR spectrum) Compounds according to the present invention was identified by mass spectrum and NMR spectrum using NMR spectrometer (made by Varian Co.) according to the method of Lambert (Lambert et al., Organic Structural Analysis, Macmillan Pub. Co., NY, 1993). |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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