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Last Updated: October 23, 2019

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Claims for Patent: 7,915,263

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Summary for Patent: 7,915,263
Title:Aminopyridine derivatives having aurora A selective inhibitory action
Abstract: The present invention relates to a compound of formula I: ##STR00001## wherein: R.sub.1 is a hydrogen atom, F, CN, etc.; R.sub.1\' is a hydrogen atom or lower alkyl which may be substituted; R.sub.2 is O, S, SO, SO.sub.2, etc.; R.sub.3 is a phenyl which may be substituted; X.sub.1, X.sub.2, and X.sub.3 each independently CH, N, etc. provided, however, that among X.sub.1, X.sub.2 and X.sub.3, the number of nitrogen is 0 or 1; W is the following residue: ##STR00002## wherein: W.sub.1, W.sub.2, and W.sub.3 each independently CH, N, etc., or a pharmaceutically acceptable salt or ester thereof.
Inventor(s): Iwasawa; Yoshikazu (Tsukuba, JP), Kato; Tetsuya (Tsukuba, JP), Kawanishi; Nobuhiko (Moriya, JP), Masutani; Kouta (Tsukuba, JP), Mita; Takashi (Tsukuba, JP), Nonoshita; Katsumasa (Tsukuba, JP), Ohkubo; Mitsuru (Ushiku, JP)
Assignee: Banyu Pharmaceutical Co., Ltd. (Tokyo, JP)
Application Number:11/897,272
Patent Claims:1. A compound of formula I: ##STR00130## wherein: R.sub.1 is a hydrogen atom, F, CN, COOR.sub.a1, CONR.sub.a2R.sub.a2', NR.sub.a3COR.sub.a3', CONR.sub.a4OR.sub.a4', NR.sub.a5CONR.sub.a5'R.sub.a5'', NR.sub.a6COOR.sub.a6', SO.sub.2NR.sub.a7R.sub.a7', NR.sub.a8SO.sub.2R.sub.a8', COR.sub.a9, SO.sub.2R.sub.a10, NO.sub.2, OR.sub.a11, NR.sub.a12R.sub.a12', lower alkyl which may be substituted, or a heterocyclic group which may be substituted, wherein: R.sub.a1, R.sub.a3, R.sub.a4, R.sub.a5, R.sub.a6, and R.sub.a8 are each independently a hydrogen atom or lower alkyl which may be substituted; R.sub.a2, R.sub.a2', R.sub.a5', R.sub.a5'', R.sub.a7, R.sub.a7', R.sub.a12, and R.sub.a12' are each independently a hydrogen atom or lower alkyl which may be substituted, provided, however, that R.sub.a2 and R.sub.a2'; R.sub.a5' and R.sub.a5''; R.sub.a7 and R.sub.a7'; R.sub.a12 and R.sub.a12' each independently, together with the nitrogen atom which they bind to, may form a heterocyclic group which may be substituted; R.sub.a3', R.sub.a4', R.sub.a6', R.sub.a8', R.sub.a9, R.sub.a10 and R.sub.a11 are each independently a hydrogen atom or lower alkyl which may be substituted; R.sub.1' is a hydrogen atom or lower alkyl which may be substituted; R.sub.2 is O, S, SO, SO.sub.2, NH, NR.sub.b, or CR.sub.c1R.sub.c2 wherein R.sub.b is a lower alkyl which may be substituted, and R.sub.c1 and R.sub.c2, which may be the same or different, are a hydrogen atom or lower alkyl; R.sub.3 is a phenyl which may be substituted; X.sub.1 is CH, CX.sub.1a or N wherein X.sub.1a is a lower alkyl which may be substituted; X.sub.2 is CH, CX.sub.2a, or N wherein: X.sub.2a is a lower alkyl; or X.sub.2a is a substituent selected from substituent group A.sub.1, or lower alkyl which is substituted with one or more of the same or different substituents selected from substituent group A.sub.1, wherein substituent group A.sub.1 is halogen atom; cyano; hydroxy; lower alkylamino; di-lower alkylamino; lower alkoxy which may be substituted with one or more hydroxy groups; lower alkylthio; and lower alkylsulfonyl; or X.sub.2a is COOR.sub.x1, CONR.sub.x2R.sub.x3, NHCOR.sub.x1, NHCONR.sub.x2R.sub.x3, NHSO.sub.2NR.sub.x2R.sub.x3, NR.sub.x4R.sub.x5, or CH.sub.2NR.sub.x4R.sub.x5, wherein: R.sub.x1 is a hydrogen atom or lower alkyl which may be substituted; R.sub.x2 and R.sub.x3, which may be the same or different, are each a hydrogen atom, lower alkyl which may be substituted, or cycloalkyl which may be substituted; or alternatively R.sub.x2 and R.sub.x3, together with the nitrogen atom to which they bond, form a 5- or 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S and which may be substituted; and R.sub.x4 and R.sub.x5, which may be the same or different, are a hydrogen atom, lower alkyl that may be substituted, or cycloalkyl that may be substituted; or X.sub.2a is a 5- to 6-membered aliphatic heterocyclic group which contains at least one atom selected from N, O and S and which may be substituted, wherein two hydrogen atoms that are bonded to the same carbon atom of the aliphatic heterocyclic group may be substituted with oxo and neighboring two carbon atoms constituting the aliphatic heterocyclic ring may form a double-bond; or a lower alkyl which is substituted with the aliphatic heterocyclic group; or X.sub.2a is a 5- to 6-membered aromatic heterocyclic group which contains at least one atom selected from N, O and S and which may be substituted; or a lower alkyl which is substituted with the aromatic heterocyclic group; X.sub.3 is CH, CX.sub.3a, or N wherein X.sub.3a is a lower alkyl which may be substituted; provided, however, that among X.sub.1, X.sub.2 and X.sub.3, the number of nitrogen is 0 or 1; W is the following residue: ##STR00131## wherein: W.sub.1 is CH, N, NH, O, or S; W.sub.2 is CH, CW.sub.2a, N, NW.sub.2b, O or S, wherein W.sub.2a and W.sub.2b are each independently a hydrogen atom, halogen atom, cyano, lower alkyl having one to two carbon atoms, cycloalkyl having three to five carbon atoms, or lower alkyl having one to two carbon atoms which may be substituted with one or more halogen atoms; W.sub.3 is C or N; and at least one of W.sub.1, W.sub.2, and W.sub.3 is carbon atom; however, two of W.sub.1, W.sub.2, and W.sub.3 are not simultaneously O and S, or a pharmaceutically acceptable salt or ester thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or ester thereof, wherein R.sub.1' is a hydrogen atom, and X.sub.3 is CH.

3. The compound according to claim 2 or a pharmaceutically acceptable salt or ester thereof, wherein: R.sub.1 is a hydrogen atom, F, CN, COOR.sub.a1, CONR.sub.a2R.sub.a2', NR.sub.a3COR.sub.a3', CONR.sub.a4OR.sub.a4', NR.sub.a5CONR.sub.a5'R.sub.a5'', NR.sub.a6COOR.sub.a6', SO.sub.2NR.sub.a7R.sub.a7', NR.sub.a8SO.sub.2R.sub.a8', COR.sub.a9, SO.sub.2R.sub.a10, NO.sub.2, OR.sub.a11, or NR.sub.a12R.sub.a12', wherein: R.sub.a1, R.sub.a3, R.sub.a4, R.sub.a5, R.sub.a6, and R.sub.a8 are each independently a hydrogen atom or lower alkyl; R.sub.a2, R.sub.a2', R.sub.a5', R.sub.a5'', R.sub.a7, R.sub.a7', R.sub.a12, and R.sub.a12' are each independently a hydrogen atom or lower alkyl which may be substituted with one or more of the same or different substituents selected from substituent group L.sub.1, wherein substituent group L.sub.1is a halogen atom, hydroxy, nitro, cyano, amino, carbamoyl, aminosulfonyl, imino, lower alkylamino, di-lower alkylamino, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthio, and carboxyl; provided, however, that R.sub.a2 and R.sub.a2'; R.sub.a5' and R.sub.a5''; R.sub.a7 and R.sub.a7'; R.sub.a12 and R.sub.a12' each independently, together with the nitrogen atom which they bind to, may form a 5-membered or 6-membered aromatic or aliphatic heterocyclic group which may be substituted with one or more of the same or different substituents selected from substituent group L.sub.2, wherein substituent group L.sub.2is a halogen atom, hydroxy, amino, and hydroxymethyl; R.sub.a3', R.sub.a4', R.sub.a6', R.sub.a8', R.sub.a9, R.sub.a10 and R.sub.a11 are each independently a hydrogen atom or lower alkyl which may be substituted with one or more of the same or different substituents selected from substituent group L.sub.1; or R.sub.1 is a lower alkyl which may be substituted with one or more of the same or different substituents selected from substituent group M, wherein substituent group M is a halogen atom, hydroxy, nitro, cyano, amino, carbamoyl, aminosulfonyl, imino, lower alkylamino, di-lower alkylamino, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthio, and carboxyl; or R.sub.1 is a heterocyclic group selected from the following, wherein Y.sub.1 and Y.sub.2 are the same and different, and each a hydrogen atom or lower alkyl which may be substituted: ##STR00132##

4. The compound according to claim 3 or a pharmaceutically acceptable salt or ester thereof, wherein W is selected from: ##STR00133##

5. The compound according to claim 4 or a pharmaceutically acceptable salt or ester thereof, wherein R.sub.3 is a phenyl of which 2.sup.nd and 3.sup.rd positions are substituted with the same or different two substituents selected from F, Cl, CF.sub.3, and CN.

6. The compound according to claim 5 or a pharmaceutically acceptable salt or ester thereof, wherein substituent group L.sub.1 is a halogen atom, hydroxy, amino, carbamoyl, lower alkylamino, di-lower alkylamino, and lower alkoxy; and substituent group M is a hydroxy, carbamoyl, aminosulfonyl, lower alkylsulfonylamino, and carboxyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt or ester thereof, wherein both X.sub.1 and X.sub.2 are CH; or X.sub.1 is CH and X.sub.2 is N; or X.sub.1 is N and X.sub.2 is CH or CX.sub.2a wherein X.sub.2a is a lower alkyl or a halogen atom.

8. The compound according to claim 7 or a pharmaceutically acceptable salt or ester thereof, wherein R.sub.1 is OH, COOH, or CONR.sub.a2R.sub.a2' wherein R.sub.a2 and R.sub.a2' are the same or different, and each a hydrogen atom or lower alkyl having one to three carbon atoms; or R.sub.1 is selected from the following: ##STR00134## and R.sub.2 is O, S, SO, or SO.sub.2.

9. The compound according to claim 8 or a pharmaceutically acceptable salt or ester thereof, wherein: W is selected from: ##STR00135## wherein W.sub.2a is a hydrogen atom, halogen atom, cyano, or methyl which may be substituted with one to three fluorine atoms.

10. The compound according to claim 9 or a pharmaceutically acceptable salt or ester thereof, wherein both of X.sub.1 and X.sub.2 are CH; or X.sub.1 is CH and X.sub.2 is N; and W is any one of the following: ##STR00136##

11. A compound which is: (a) trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin-2- -yl)methyl)cyclohexanecarboxylic acid; (b) trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamin- o)pyridin-2-yl)methyl)cyclohexanecarboxylic acid; (c) trans-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin-2-yl)m- ethyl)cyclohexanecarboxylic acid; (d) trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazol-3-ylamino- )pyridin-2-yl)methyl)cyclohexanecarboxylic acid; (e) trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyrazin-2-- yl)methyl)cyclohexanecarboxamide; (f) 5-(trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazol-3-ylam- ino)pyridin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (g) 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyridin- -2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (h) 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyrazin- -2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (i) 5-(trans-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazol-3-ylamino)pyr- idin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (j) trans-1-((4-bromo-6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)-4-(3-chlo- ro-2-fluorophenoxy)cyclohexanecarboxylic acid, (k) 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((4-methyl-6-(1H-pyrazol-3-ylamin- o)pyrimidin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one, or (l) 5-(trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazol-3-ylam- ino)pyridin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazole-2(3H)-thione, or a pharmaceutically acceptable salt or ester thereof.

12. A compound which is: ##STR00137## trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin-2- -yl)methyl)cyclohexanecarboxylic acid; or a pharmaceutically acceptable salt or ester thereof.

13. A compound which is: ##STR00138## 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyridin- -2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; or a pharmaceutically acceptable salt or ester thereof.

14. A pharmaceutical composition comprising, together with pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 as active ingredient.

15. An Aurora A selective inhibitor comprising, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 as active ingredient.

16. An antitumor agent comprising, together with a pharmaceutically acceptable carrier or diluent, at least one compound according to claim 1 as active ingredient.

17. A combined preparation for simultaneous, separate, or sequential administration in the treatment of cancer, comprising two separate preparations: a preparation comprising, together with a pharmaceutically acceptable carrier or diluent, a compound according to claim 1; and a preparation comprising, together with a pharmaceutically acceptable carrier or diluent, one antitumor agent selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-complex compounds, antitumor campthotecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other antitumor agents or a pharmaceutically acceptable salt thereof, wherein: the antitumor alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine; the antitumor antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium; the antitumor antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin; the plant-derived antitumor agents are vincristine, vinblastine, vindeshine, etoposide, sobuzoxane, docetaxel, paclitaxel, and vinorelbine; the antitumor platinum-complex compounds are cisplatin, carboplatin, nedaplatin, and oxaliplatin; the antitumor campthotecin derivatives are irinotecan, topotecan, and campthotecin; the antitumor tyrosine kinase inhibitors are gefitinib, imatinib, sorafenib, sunitinib, dasatinib, and erlotinib; the monoclonal antibodies are cetuximab, rituximab, bevacizumab, alemtuzumab, and trastuzumab; the interferons are interferon .alpha., interferon .alpha.-2a, interferon .alpha.-2b, interferon .beta., interferon .gamma.-1a, and interferon .gamma.-n1, the biological response modifiers are krestin, lentinan, sizofiran, picibanil, or ubenimex, and the other antitumor agents are mitoxantrone, L-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin, flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib, capecitabine, and goserelin.

18. The combined preparation according to claim 17 wherein one of or both of the two separate preparations is/are oral preparation(s).

19. The combined preparation according to claim 17 which is further combined with at least one preparation comprising, together with a pharmaceutically acceptable carrier or diluent, an antitumor agent selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-complex compounds, antitumor campthotecin derivatives, antitumor tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other antitumor agents, wherein the definition of each antitumor agent is the same as defined in claim 17, or a pharmaceutically acceptable salt thereof.

20. The combined preparation according to claim 17 wherein: among the combined preparation, one is a preparation which comprises, together with a pharmaceutically acceptable carrier or diluent, (a) trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin-2- -yl)methyl)cyclohexanecarboxylic acid; (b) trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1,3-thiazol-2-ylamin- o)pyridin-2-yl)methyl)cyclohexanecarboxylic acid; (c) trans-4-(2,3-dichlorophenoxy)-1-((6-(1,3-thiazol-2-ylamino)pyridin-2-yl)m- ethyl)cyclohexanecarboxylic acid; (d) trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazol-3-ylamino- )pyridin-2-yl)methyl)cyclohexanecarboxylic acid; or (e) trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyrazin-2-- yl)methyl)cyclohexanecarboxamide; (f) 5-(trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazol-3-ylam- ino)pyridin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (g) 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyridin- -2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (h) 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((6-(1H-pyrazol-3-ylamino)pyrazin- -2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; or (i) 5-(trans-4-((2,3-dichlorophenyl)sulfonyl)-1-((6-(1H-pyrazol-3-ylamino)pyr- idin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one; (j) trans-1-((4-bromo-6-(1,3-thiazol-2-ylamino)pyridin-2-yl)methyl)-4-(3-chlo- ro-2-fluorophenoxy)cyclohexanecarboxylic acid, (k) 5-(trans-4-(3-chloro-2-fluorophenoxy)-1-((4-methyl-6-(1H-pyrazol-3-ylamin- o)pyrimidin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazol-2(3H)-one, or (l) 5-(trans-4-(2-fluoro-3-(trifluoromethyl)phenoxy)-1-((6-(1H-pyrazol-3-ylam- ino)pyridin-2-yl)methyl)cyclohexyl)-1,3,4-oxadiazole-2(3H)-thione, or a pharmaceutically acceptable salt or ester thereof; and the other is a preparation which comprises, together with a pharmaceutically acceptable carrier or diluent, paclitaxel or docetaxel.

Summary for Patent:   Start Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
Japan2006-236472Aug 31, 2006

Details for Patent 7,915,263

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Merck ELSPAR asparaginase VIAL 101063 001 1978-01-10   Start Trial Banyu Pharmaceutical Co., Ltd. (Tokyo, JP) 2026-08-31 RX search
Chiron PROLEUKIN aldesleukin VIAL 103293 001 1992-05-05   Start Trial Banyu Pharmaceutical Co., Ltd. (Tokyo, JP) 2026-08-31 RX search
Genentech RITUXAN rituximab VIAL 103705 001 1997-11-26   Start Trial Banyu Pharmaceutical Co., Ltd. (Tokyo, JP) 2026-08-31 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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