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Last Updated: March 28, 2024

Claims for Patent: 9,512,126


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Summary for Patent: 9,512,126
Title:Substituted imidazopyridazines
Abstract: The present invention relates to substituted imidazopyridazine compounds of general formula I in which R.sup.3, R.sup.5 and A are as defined in the claims, to methods of preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients. ##STR00001##
Inventor(s): Koppitz; Marcus (Berlin, DE), Klar; Ulrich (Berlin, DE), Wengner; Antje Margret (Berlin, DE), Neuhaus; Roland (Berlin, DE), Siemeister; Gerhard (Berlin, DE)
Assignee: Bayer Intellectual Property GmbH (Monheim, DE)
Application Number:14/384,828
Patent Claims:1. A compound of general formula I: ##STR00171## in which: A represents ##STR00172## wherein * indicates the point of attachment of said group with the rest of the molecule; R.sup.2 represents a cyclopropyl- group; R.sup.3 represents --C(R.sup.3a)(R.sup.3b)(R.sup.3c); R.sup.3a, R.sup.3b represent, independently from each other, a hydrogen atom or a fluorine atom or a hydroxy-, or a methyl- group, with the proviso that not both of R.sup.3a and R.sup.3b represent a hydrogen atom and not both of R.sup.3a and R.sup.3b represent a hydroxy group; or R.sup.3a, R.sup.3b together represent .dbd.O or .dbd.C(R.sup.3d)(R.sup.3e); or R.sup.3a, R.sup.3b together with the carbon atom they are attached to, form a cyclopropyl- ring; R.sup.3c represents a phenyl group; wherein said phenyl group is substituted, identically or differently, with 1, 2, or 3 R.sup.7 groups; R.sup.3d, R.sup.3e represent a hydrogen atom; R.sup.4 represents a methyl group; R.sup.5 represents --CH.sub.2--CF.sub.3; R.sup.7 represents a fluorine atom, or a hydroxy-, or a methoxy group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2. A compound according to claim 1, wherein R.sup.3a, R.sup.3b together with the carbon atom they are attached to, form a cyclopropyl-ring; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3. A compound according to claim 1, which is selected from the group consisting of: N-cyclopropyl-4-{6-[1-(3-fluoro-4-methoxyphenyl)ethenyl]-8-[(3,3,3-triflu- oropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[difluoro(3-fluoro-4-methoxyphenyl)methyl]-8-[(3,3,3-t- rifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, (RS)--N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[(- 3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamid- e, (R)--N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-[- (3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzami- de, (S)--N-cyclopropyl-4-{6-[(3-fluoro-2-hydroxyphenyl)(hydroxy)methyl]-8-- [(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzam- ide, (RS)--N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl- ]-8-[(3,3, 3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylb- enzamide, (R)--N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxye- thyl]-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-meth- ylbenzamide, (S)--N-cyclopropyl-4-{6-[1-(3-fluoro-2-hydroxyphenyl)-1-hydroxyethyl]-8-[- (3,3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzami- de, (RS)--N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide- , (R)--N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide- , (S)--N-cyclopropyl-4-{6-[fluoro(3-fluorophenyl)methyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide- , N-cyclopropyl-4-{6-[difluoro(3-fluorophenyl)methyl]-8-[(3,3,3-trifluorop- ropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imi- dazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(3-methoxyphenyl)vinyl]-8-[(3,3, 3-trifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(4-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)amino]imi- dazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(4-methoxyphenyl)vinyl]-8-[(3, 3,3-trifluoropropyl)amino]imidazo[1, 2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(2,5-difluorophenyl)(hydroxy)methyl]-8-[(3,3,3-triflu- oropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2,5-difluorobenzoyl)-8-[(3,3,3-trifluoropropyl)amino]- imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(3-fluoro-4-methoxybenzoyl)-8-[(3,3,3-trifluoropropyl)- amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-(2,3-difluorobenzoyl)-8-[(3,3,3-trifluoropropyl)amino]- imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(2,3-difluorophenyl)vinyl]-8-[(3,3,3-trifluoropropy- l)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[difluoro(4-methoxyphenyl)methyl]-8-[(3,3,3-trifluorop- ropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(2,3-difluorophenyl)cyclopropyl]-8-[(3,3,3-trifluor- opropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(2,3-difluorophenyl)(difluoro)methyl]-8-[(3,3,3-trifl- uoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(2,5-difluorophenyl)vinyl]-8-[(3,3,3-trifluoropropy- l)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(2,5-difluorophenyl)cyclopropyl]-8-[(3,3,3-trifluor- opropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[(2,5-difluorophenyl)(difluoro)methyl]-8-[(3,3,3-trifl- uoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, N-cyclopropyl-4-{6-[1-(5-fluoro-2-hydroxyphenyl)ethenyl]-8-[(3,3,3-triflu- oropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, and N-cyclopropyl-4-{6-[1-(5-fluoro-2-hydroxyphenyl)cyclopropyl]-8-[(3,3,3-tr- ifluoropropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4. A method of preparing a compound according to claim 1, said method comprising the step of allowing an intermediate compound of general formula Ia: ##STR00173## in which R.sup.3 and R.sup.5 are as defined in claim 1; and A' is ##STR00174## wherein * indicates the point of attachment of said group with the rest of the molecule; R.sup.4 is as defined in claim 1, and Z' represents a group selected from: --C(.dbd.O)OH and --C(.dbd.O)O--(C.sub.1-C.sub.6-alkyl); to react with a compound of general formula Ib: H.sub.2NR.sup.2 Ib in which R.sup.2 is as defined in claim 1, thereby giving, upon optional deprotection, a compound of general formula I: ##STR00175## in which R.sup.3, R.sup.5 and A are as defined claim 1.

5. A method of preparing a compound according to claim 1, said method comprising the step of allowing an intermediate compound of general formula VII: ##STR00176## in which R.sup.3 and A are as defined in claim 1, and Q.sup.1 is a leaving group, to react with a compound of general formula VIIa: ##STR00177## in which R.sup.5 is as defined in claim 1, thereby giving, upon optional deprotection, a compound of general formula I: ##STR00178## in which R.sup.3, R.sup.5 and A are as defined in claim 1.

6. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XVII: ##STR00179## in which R.sup.3c, R.sup.5 and A are as defined in claim 1; and R' and R'' represent, independent from each other, a C.sub.1-C.sub.6-alkyl- group; or R' and R'' together represent an alkylene group; to a compound of general formula XIII: ##STR00180## in which R.sup.3c, R.sup.5 and A are as defined in claim 1.

7. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XXI: ##STR00181## in which R.sup.3c, R.sup.5 and A are as defined in claim 1; to a compound of general formula XX: ##STR00182## in which R.sup.3c, R.sup.5 and A are as defined in claim 1.

8. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XIX: ##STR00183## in which R.sup.5 and A are as defined in claim 1; to a compound of general formula XX: ##STR00184## in which R.sup.3c, R.sup.5 and A are as defined in claim 1.

9. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XXII: ##STR00185## in which R.sup.5 and A are as defined in claim 1; and R.sup.3g is a hydrogen atom or a C.sub.1-C.sub.6-alkyl- group; to a compound of general formula XX: ##STR00186## in which R.sup.3c, R.sup.5 and A are as defined in claim 1.

10. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XXI: ##STR00187## in which R.sup.5, R.sup.3c and A are as defined in claim 1; to a compound of general formula XVIII: ##STR00188## in which R.sup.3c, R.sup.5 and A are as defined in claim 1, and Hal is a fluorine atom.

11. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XX: ##STR00189## in which R.sup.5, R.sup.3c and A are as defined in claim 1; to a compound of general formula XVI: ##STR00190## in which R.sup.3c, R.sup.3d, R.sup.3e, R.sup.5 and A are as defined in claim 1.

12. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XVI: ##STR00191## in which R.sup.3c, R.sup.3d, R.sup.3e, R.sup.5 and A are as defined in claim 1; to a compound of general formula XXV: ##STR00192## in which R.sup.3c, R.sup.3d, R.sup.3e, R.sup.5 and A are as defined in claim 1.

13. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XVI: ##STR00193## in which R.sup.3c, R.sup.3d, R.sup.3e, R.sup.5 and A are as defined in claim 1; to a compound of general formula XII: ##STR00194## in which R.sup.3c, R.sup.3d, R.sup.3e, R.sup.5 and A are as defined in claim 1, and R.sup.3f is a hydrogen atom.

14. A method of preparing a compound according to claim 1, said method comprising the step of conversion of an intermediate compound of general formula XV: ##STR00195## in which R.sup.3a, R.sup.3c, R.sup.5 and A are as defined in claim 1; to a compound of general formula XI: ##STR00196## in which R.sup.3a, R.sup.3b, R.sup.3c, R.sup.5 and A are as defined in claim 1.

15. A pharmaceutical composition comprising a compound according to claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, and a pharmaceutically acceptable diluent or carrier.

16. A pharmaceutical combination comprising: one or more compounds according to claim 1, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same; and one or more agents selected from: a taxane, Docetaxel, Paclitaxel, or Taxol; an epothilone, Ixabepilone, Patupilone, or Sagopilone; Mitoxantrone; Predinisolone; Dexamethasone; Estramustin; Vinblastin; Vincristin; Doxorubicin; Adriamycin; Idarubicin; Daunorubicin; Bleomycin; Etoposide; Cyclophosphamide; Ifosfamide; Procarbazine; Melphalan; 5-Fluorouracil; Capecitabine; Fludarabine; Cytarabine; Ara-C; 2-Chloro-2'-deoxyadenosine; Thioguanine; an anti-androgen, Flutamide, Cyproterone acetate, or Bicalutamide; Bortezomib; a platinum derivative, Cisplatin, or Carboplatin; Chlorambucil; Methotrexate; and Rituximab.

Details for Patent 9,512,126

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Genentech, Inc. RITUXAN rituximab Injection 103705 11/26/1997 ⤷  Try a Trial 2032-03-14
Idec Pharmaceuticals Corp. RITUXAN rituximab Injection 103737 02/19/2002 ⤷  Try a Trial 2032-03-14
Genentech, Inc. RITUXAN HYCELA rituximab and hyaluronidase human Injection 761064 06/22/2017 ⤷  Try a Trial 2032-03-14
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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