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Last Updated: March 28, 2024

Claims for Patent: 7,205,308


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Summary for Patent: 7,205,308
Title:Trisubstituted 7-aminopyrazolopyrimidines as cyclin dependent kinase inhibitors
Abstract: In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.
Inventor(s): Guzi; Timothy J. (Chatham, NJ), Paruch; Kamil (Garwood, NJ), Dwyer; Michael P. (Scotch Plains, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Application Number:11/244,772
Patent Claims:1. A compound represented by the structural formula: ##STR00589## or a pharmaceutically acceptable salt, ester or prodrug of said compound, wherein: R is an aryl substituted with one or more heteroaryl; R.sup.2 is selected from the group consisting of R.sup.9, alkynyl, alkynylalkyl, cycloalkyl, --CF.sub.3, --C(O.sub.2)R.sup.6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1 6 R.sup.9 groups which groups can be the same or different with each R.sup.9 being independently selected, aryl substituted with 1 3 aryl or heteroaryl groups which can be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, ##STR00590## heteroaryl substituted with 0 3 aryl or heteroaryl groups which can be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups; R.sup.3 is selected from the group consisting of H, halogen, --NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, ##STR00591## wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.3 and the heterocyclyl moieties whose structures are shown immediately above for R.sup.3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3, CN, --OCF.sub.3, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --OR.sup.5, --NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.nNR.sup.5R.sup.6, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.6; R.sup.4 is H, halo or alkyl; R.sup.5 is H or alkyl; R.sup.6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.4R.sup.5, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.4R.sup.5; or optionally (i) R.sup.5 and R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R.sup.9 groups; R.sup.7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5, --SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.8 is selected from the group consisting of R.sup.6, --C(O)NR.sup.5R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --C(O)R.sup.7 and --S(O.sub.2)R.sup.7; R.sup.9 is selected from the group consisting of halogen, CN, --NR.sup.5R.sup.10, --C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.10, --OR.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; m is 0 to 4, and n is 1 to 4, with the following provisos: (i) that when R is an unsubstituted phenyl, then R.sup.2 is not alkyl, --C(O.sub.2)R.sup.6, aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R.sup.2 is halogen only.

2. A compound represented by the structural formula: ##STR00592## or a pharmaceutically acceptable salt, ester or prodrug of said compound, wherein: R is aryl substituted with heteroaryl; R.sup.2 is heteroaryl; R.sup.3 is selected from the group consisting of H, halogen, --NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, ##STR00593## wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.3 and the heterocyclyl moieties whose structures are shown immediately above for R.sup.3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3, CN, --OCF.sub.3, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --OR.sup.5, --NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.nNR.sup.5R.sup.6, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.6; R.sup.4 is H, halo or alkyl; R.sup.5 is H or alkyl; R.sup.6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.4R.sup.5, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.4R.sup.5; or optionally (i) R.sup.5 and R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R.sup.9 groups; R.sup.7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5, --SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.8 is selected from the group consisting of R.sup.6, --C(O)NR.sup.5R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --C(O)R.sup.7 and --S(O.sub.2)R.sup.7; R.sup.9 is selected from the group consisting of halogen, CN, --NR.sup.5R.sup.10, --C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.10, --OR.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; m is 0 to 4, and n is 1 to 4, with the following provisos: (i) that when R is an unsubstituted phenyl, then R.sup.2 is not alkyl, --C(O.sub.2)R.sup.6, aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R.sup.2 is halogen only.

3. The compound of claim 2, wherein R is phenyl substituted with imidazolyl.

4. The compound of claim 2, wherein R.sup.2 is a pyrazolyl.

5. The compound of claim 4, wherein R.sup.2 is a 1-methylpyrazol-4yl group.

6. The compound of claim 2, wherein R is imidazolyl and R.sup.2 is 1-methyl-1H-pyrazol-4yl.

7. A compound selected from the group consisting of: ##STR00594## ##STR00595## or a pharmaceutically acceptable salt, ester or prodrug thereof.

8. A method of inhibiting cyclin dependent kinases 2 (CDK2) in a patient, comprising administering a therapeutically effective amount of the compound of claim 1 or claim 7, or a pharmaceutically acceptable salt, ester or prodrug thereof, to said patient.

9. A method of inhibiting cyclin dependent kinase 2(CDK2) in a mammal, comprising administering to said mammal an amount of the compound of claim 1, or a pharmaceutically acceptable salt, ester or prodrug thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect.

10. The method of claim 9, further comprising radiation therapy.

11. The method of claim 9, wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA.RTM. (gefitinib), TARCEVA.RTM. (erlotinib hydrochloride), antibodies to EGFR, GLEEVEC.RTM. (imatinib), intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN.TM., Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux.RTM. (cetuximab) Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, and Campath.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or claim 7, or a pharmaceutically acceptable salt, ester or prodrug thereof, in combination with at least one pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12, additionally comprising one or more anti-cancer agents selected from the group consisting of cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA.RTM. (gefitinib), TARCEVA.RTM. (erlotinib hydrochloride), antibodies to EGFR, GLEEVEC.RTM. (imatinib), intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux.RTM. (cetuximab), Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, and Campath.

14. A method of inhibiting cyclin dependent kinases 2 (CDK2) in a patient comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 12 to said patient.

Details for Patent 7,205,308

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Recordati Rare Diseases, Inc. ELSPAR asparaginase For Injection 101063 01/10/1978 ⤷  Try a Trial 2022-09-04
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 06/04/1986 ⤷  Try a Trial 2022-09-04
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b For Injection 103132 ⤷  Try a Trial 2022-09-04
Merck Sharp & Dohme Corp. INTRON A interferon alfa-2b Injection 103132 ⤷  Try a Trial 2022-09-04
Genentech, Inc. RITUXAN rituximab Injection 103705 11/26/1997 ⤷  Try a Trial 2022-09-04
Idec Pharmaceuticals Corp. RITUXAN rituximab Injection 103737 02/19/2002 ⤷  Try a Trial 2022-09-04
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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