Claims for Patent: 7,935,708

Summary for Patent: 7,935,708

Title:	Dihydropyrazolopyrimidinone derivatives
Abstract:	The invention relates to compounds of a general formula (I): ##STR00001## wherein Ar.sup.1 is an optionally-substituted aryl or heteroaromatic group; R.sup.1 is an optionally-substituted lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R.sup.2 is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R.sup.3 is a hydrogen atom or a lower alkyl group; R.sup.4 is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a group of --N(R.sup.1k)R.sup.1m; T and U are a nitrogen atom or a methine group, etc. The compounds of the invention have excellent Weel kinase-inhibitory effect and are therefore useful in the field of medicines, especially treatment of various cancers.
Inventor(s):	Sagara; Takeshi (Tsukuba, JP), Otsuki; Sachie (Tsukuba, JP), Sunami; Satoshi (Toride, JP), Sakamoto; Toshihiro (Moriya, JP), Niiyama; Kenji (Tsuchiura, JP), Yamamoto; Fuyuki (Tsukuba, JP), Yoshizumi; Takashi (Ushiku, JP), Furuyama; Hidetomo (Tsukuba, JP), Goto; Yasuhiro (Tsukuba, JP), Bamba; Makoto (Tsukuba, JP), Takahashi; Keiji (Tsukuba, JP), Hirai; Hiroshi (Tsukuba, JP), Nishibata; Toshihide (Tsukuba, JP)
Assignee:	MSD K.K. (Chiyoda-Ku, JP)
Application Number:	12/226,707
Patent Claims:	1. A compound of formula (I-2), or a salt or ester thereof: ##STR00221## wherein, A.sup.1 is a single bond, an oxygen atom or a sulfur atom, or is an imino group optionally substituted by a lower alkyl group; A.sup.2 is a nitrogen atom, or is a methine or 1-vinyl-2-ylidene group optionally substituted by a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q.sup.1 is a single bond, a carbonyl group, or a methylene group optionally substituted by a lower alkyl group; Q.sup.2 is a single bond, or an ethylene group optionally substituted by a lower alkyl group; R.sup.1a and R.sup.1b are independently a hydrogen atom, a lower alkyl group or a hydroxy-lower alkyl group, or together form a lower alkylene group wherein one or two or more methylene groups constituting the lower alkylene group may be independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or a group of --N(R.sup.1c)--, and/or substituted by a hydroxyl group or a lower alkyl group; R.sup.1c is a hydrogen atom, a lower alkenyl group or a group of -Q.sup.3-A.sup.3(R.sup.1d)R.sup.1e; A.sup.3 is a nitrogen atom, or is a methine or 1-vinyl-2-ylidene group optionally substituted by a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q.sup.3 is a single bond or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group may be independently replaced by an oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group or a sulfonyl group, and/or substituted by a halogen atom, a cyano group, a hydroxyl group or a lower alkyl group; R.sup.1d and R.sup.1e are independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group, or together form a lower alkylene group wherein one or two or more methylene groups constituting the lower alkylene group may be independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group or a group of --N(R.sup.1f)--, and/or substituted by a hydroxyl group or a lower alkyl group; R.sup.1f is a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkenyl group or a lower alkanoyl group; R.sup.5 and R.sup.6 are independently a hydrogen atom, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoyl group, a hydroxy-lower alkylamino group, a carbamoyl group or a hydroxy-lower alkylcarbamoyl group; R.sup.11 is a group of a formula (a-1) or (a-2): ##STR00222## R.sup.7a, R.sup.7b, R.sup.8a and R.sup.8b are independently a hydrogen atom, a halogen atom or a cyano group; R.sup.8c is a hydrogen atom or a lower alkyl group; R.sup.20 is an aryl group or a heteroaromatic group, which may have a substituent selected from a group consisting of a halogen atom, a cyano group, a nitro group, a carboxyl group, a group of -Q.sup.4-A.sup.4(R.sup.1g)R.sup.1h and a group of -Q.sup.5-Ar.sup.a; A.sup.4 is a nitrogen atom, or is a methine group optionally substituted by a halogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Ar.sup.a is an aryl group or a heteroaromatic group, which may have a substituent selected from a group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group and a lower alkoxy group; Q.sup.4 is a single bond or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group may be independently replaced by an oxygen atom or a carbonyl group, and/or substituted by a lower alkyl group; Q.sup.5 is a single bond, an oxygen atom, a sulfur atom, a carbonyl group or a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group may be independently replaced by an oxygen atom, a sulfur atom or a carbonyl group, and/or substituted by a halogen atom or a lower alkyl group; R.sup.1g and R.sup.1h are independently a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, a lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group or a lower alkylsulfonyl group, or together form a lower alkylene group, wherein one or two or more methylene groups constituting the lower alkylene group may be independently replaced by an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or a group of --N(R.sup.1i)--, and/or substituted by a halogen atom or a lower alkyl group; R.sup.1i is a hydrogen atom, a lower alkyl group or a halo-lower alkyl group. 2. The compound as claimed in claim 1, or a salt thereof, which is as follows: 2-benzyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-- phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 2-(2-chlorophenyl)-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-{[3-methyl-4- -(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrim- idin-3-one. 3. A pharmaceutical composition comprising a therapeutically-effective amount of the compound as claimed in claim 1, or a salt or ester thereof, and a pharmaceutically acceptable carrier or diluent. 4. An anticancer agent comprising the pharmaceutical composition of claim 3. 5. A combined preparation for simultaneous, separate, or sequential administration in the treatment of cancer, comprising following two separate preparations (a) and (b): (a) a preparation comprising, together with a pharmaceutically acceptable carrier or diluent, the compound according to claim 3 or a pharmaceutically acceptable salt or ester thereof; and (b) a preparation comprising, together with a pharmaceutically acceptable carrier or diluent, one anticancer agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum-coordinatedcomplex compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, interferons, biological response modifiers, and other anticancer agents or a pharmaceutically acceptable salt or ester thereof, wherein: the anticancer alkylating agents are nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, and carmustine; the anticancer antimetabolites are methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium; the anticancer antibiotics are actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, and valrubicin; the plant-derived anticancer agents are vincristine, vinblastine, vindeshine, etoposide, sobuzoxane, docetaxel, paclitaxel, and vinorelbine; the anticancer platinum-coordinatedcomplex compounds are cisplatin, carboplatin, nedaplatin, and oxaliplatin; the anticancer camptothecin derivatives are irinotecan, topotecan, and camptothecin; the anticancer tyrosine kinase inhibitors are gefitinib, imatinib, and erlotinib; the monoclonal antibodies are cetuximab, bevacizumab, rituximab, 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 anticancer 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. 6. A pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier or diluent, the compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof; and an anticancer agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum-coordinatedcomplex compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, biological response modifiers, and other anticancer agents, or a pharmaceutically acceptable salt thereof. 7. A radiation sensitizer comprising the pharmaceutical composition as claimed in claim 3. 8. The sensitizer of claim 7 further comprising an anticancer agent selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum-coordinatedcomplex compounds, anticancer camptothecin derivatives, anticancer tyrosine kinase inhibitors, monoclonal antibodies, biological response modifiers, and other anticancer agents, or a pharmaceutically acceptable salt thereof.

Details for Patent 7,935,708

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genzyme Corporation	THYROGEN	thyrotropin alfa	For Injection	020898	11/30/1998		2026-04-27
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2026-04-27
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2026-04-27
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2026-04-27