Claims for Patent: RE46792

Summary for Patent: RE46792

Title:	Oxazole compound and pharmaceutical composition
Abstract:	The present invention provides a oxazole compound represented by Formula (1), or a salt thereof: wherein R1 is an aryl group which may have one or more substituents; R2 is an aryl group or a nitrogen atom-containing heterocyclic group each of which may have one or more substituents; and W is a divalent group represented by —Y1-A1- or or —Y2—C(═O)— wherein Y1 is a group such as —C(═O)—, A1 is a group such as a lower alkylene group, and Y2 is a group such as a piperazinediyl group. The oxazole compound has a specific inhibitory action against phosphodiesterase 4.
Inventor(s):	Minoru Okada, Masaya Kato, Norifumi Sato, Tetsuyuki Uno, Hideki Kitagaki, Junpei Haruta, Hidetaka Hiyama, Tomonori Shibata
Assignee:	Otsuka Pharmaceutical Co Ltd
Application Number:	US15/623,249
Patent Claims:	1. An oxazole compound represented by Formula (1) wherein R1 is an aryl group which may have one or more substituents selected from the following (1-1) to (1-11): (1-1) hydroxy groups, (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, (1-5) cyclo C3-8 alkyl lower alkoxy groups, (1-6) cyclo C3-8 alkyloxy groups, (1-7) cyclo C3-8 alkenyloxy groups, (1-8) dihydroindenyloxy groups, (1-9) hydroxy lower alkoxy groups, (1-10) oxiranyl lower alkoxy groups, and (1-11) protected hydroxy groups; R2 is an aryl group or a nitrogen atom-containing heterocyclic group each of which may have one or more substituents selected from the following (2-1) to (2-10): (2-1) hydroxy groups, (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy groups, (2-5) halogen atoms, (2-6) lower alkanoyl groups other than a formyl group, (2-7) lower alkylthio groups, (2-8) lower alkylsulfonyl groups, (2-9) oxo groups, and (2-10) lower alkoxy lower alkoxy groups; and the nitrogen atom-containing heterocyclic group in R2 is selected from imidazolidinyl, hexahydropyrimidinyl, piperazinyl, octahydroisoindolyl, azocanyl, pyrrolyl, dihydropyrrolyl, imidazolyl, dihydroimidazolyl, triazolyl, dihydrotriazolyl, pyrazolyl, pyridyl and N-oxides thereof, dihydropyridyl, pyrimidinyl, dihydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, tetrazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, hexahydroisoindolinyl, benzoimidazolyl, quinolyl, isoquinolyl, indazolyl, quinazolinyl, dihydroquinazolinyl, benzotriazolyl, carbazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxazolidinyl, isooxazolidinyl, dihydrobenzoxazolyl, benzoxazinyl, dihydrobenzoxazinyl, benzoxazolyl, benzooxadiazolyl, thiazolyl, dihydrothiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl, thiazolyzinyl, benzothiazolyl, and benzothiadiazolyl; and W is a divalent group represented by Formula (i) or (ii): —Y1-A1- Formula (i) —Y2—C(═O)— Formula (ii) wherein A1 is a lower alkenylene group, or a lower alkylene group which may have one or more substituents selected from the group consisting of hydroxy groups and lower alkoxycarbonyl groups, Y1 is —C(═O)—, —C(═O)—N(R3)—, —S(O)m—NH—, or —S(O)n— wherein R3 is a hydrogen atom or a lower alkyl group, and m and n are each independently an integer from 0 to 2, and Y2 is a piperazinediyl group, or a divalent group represented by Formula (iii): —C(═O)-A2-N(R5)— Formula (iii) wherein A2 is a lower alkylene group, and R5 is a hydrogen atom or a lower alkyl group; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R1 is a phenyl group which has 1 to 3 substituents selected from the following (1-2), (1-3), (1-4) and (1-5): (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, and (1-5) cyclo C3-8 alkyl lower alkoxy groups; R2 is a phenyl group or a pyridyl group each of which may have 1 to 3 substituents selected from the group consisting of the following (2-2), (2-3), (2-4) and (2-5): (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy groups, and (2-5) halogen atoms; W is a divalent group represented by Formula (i): —Y1-A1- Formula (i) wherein A1 is a lower alkylene group, and Y1 is —C(═O)— or —C(═O)—N(R3)— wherein R3 is a hydrogen atom. 3. The compound according to claim 2, wherein R1 is a phenyl group having two substituents selected from the following (1-2), (1-3), (1-4) and (1-5): (1-2) unsubstituted or halogen-substituted lower alkoxy groups, (1-3) lower alkenyloxy groups, (1-4) lower alkynyloxy groups, and (1-5) cyclo C3-8 alkyl lower alkoxy groups; R2 is a phenyl group or a pyridyl group each of which may have 1 to 2 substituents selected from the following (2-2), (2-3), (2-4) and (2-5): (2-2) unsubstituted or halogen-substituted lower alkoxy groups, (2-3) unsubstituted lower alkyl groups, (2-4) lower alkenyloxy groups, and (2-5) halogen atoms; and W is a divalent group represented by Formula (i): —Y1-A1- Formula (i) wherein A1 is a lower alkylene group, and Y1 is —C(O)— —C(═O)— or —C(═O)—N(R3)— wherein R3 is a hydrogen atom. 4. The compound according to claim 3, wherein R1 is a phenyl group substituted on the phenyl ring with two lower alkoxy groups, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one cyclo C3-8, C3-8 alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl group with one lower alkoxy group and one lower alkenyloxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C3-8 alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group, or a phenyl group substituted on the phenyl ring with two halogen-substituted lower alkoxy groups; R2 is a lower alkoxyphenyl group, a lower alkenyloxyphenyl group, a halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl group, or a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen atom; and W is a divalent group represented by Formula (i): —Y1-A1- Formula (i) wherein A1 is a C1-4 alkylene group, and Y1 is —C(═O)— or —C(═O)—N(R3)— wherein R3 is a hydrogen atom. 5. The compound according to claim 4, wherein R1 is a phenyl group substituted on the phenyl ring with two lower alkoxy groups, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one cyclo C3-8 alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl group with one lower alkoxy group and one lower alkenyloxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C3-8 alkyl lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group, or a phenyl group substituted on the phenyl ring with two halogen-substituted lower alkoxy groups; R2 is a lower alkoxyphenyl group, a lower alkenyloxy phenyl group, a halogen-substituted lower alkoxyphenyl group, a lower alkylpyridyl group, or a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen atom; and W is a divalent group represented by Formula (i): —Y1-A1- Formula (i) wherein A1 is a C1-4 alkylene group, and Y1 is —C(═O)—. 6. The compound according to claim 4, wherein R1 is a phenyl group substituted on the phenyl ring with one lower alkoxy group and one halogen-substituted lower alkoxy group, a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one cyclo C3-8 alkyl lower alkoxy group, or a phenyl group substituted on the phenyl ring with one halogen-substituted lower alkoxy group and one lower alkenyloxy group; R2 is a lower alkoxyphenyl group or a lower alkylpyridyl group; and W is a divalent group represented by Formula (i): —Y1-A1- Formula (i) wherein A1 is a C1-4 alkylene group, and Y1 is —C(═O)—N(R3)— wherein R3 is a hydrogen atom. 7. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt according to any one of claims 1 to 6 as an active ingredient and a pharmaceutically acceptable carrier. 8. A method for treating dermatosis, the method comprising administering the compound or a pharmaceutically acceptable salt according to any one of claims 1 to 6 to a human or an animal in need thereof. 9. A process for producing an oxazole compound represented by Formula (1): wherein R1, R2 and W are the same as defined in claim 1, or a salt thereof, the process comprising a reaction of a compound represented by Formula (2): wherein R2 and W are the same as defined above, and X is a halogen atom, or a pharmaceutically acceptable salt thereof, with a compound represented by Formula (3): wherein R1 is the same as defined above, or a salt thereof. 10. The compound or a pharmaceutically acceptable salt thereof according to claim 6, which is selected from the group consisting of the following compounds: N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-yl ethyl p-methylpicolinamide, N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide, N-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide, N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, N-[2-(4-difluoromethoxy-3-ethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, N-[2-(3-allyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]2-ethoxybenzamide, N-[2-(3-cyclopropylmethoxy-4-d fluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamine, N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, and N-[2-(3-but-3-enyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide. 11. A compound which is N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide, having the structure: 12. A pharmaceutical composition comprising the compound according to claim 11 as an active ingredient and a pharmaceutically acceptable carrier. 13. A method for treating dermatosis, the method comprising administering the compound according to claim 11 to a human or an animal in need thereof. 14. A pharmaceutically acceptable salt of a compound, the compound being N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide and having the structure: 15. A pharmaceutical composition comprising the pharmaceutically acceptable salt according to claim 14 as an active ingredient and a pharmaceutically acceptable carrier. 16. A method for treating dermatosis, the method comprising: administering the pharmaceutically acceptable salt according to claim 14 to a human or an animal in need thereof.