Claims for Patent: 8,962,606

Summary for Patent: 8,962,606

Title:	Substituted benzosulphonamides
Abstract:	The present invention relates to substituted benzosulphonamide compounds of general formula (I): in which R1, R2, R3, R4, R5 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):	Hitchcock; Marion (Berlin, DE), Hartung; Ingo (Berlin, DE), Puhler; Florian (Berlin, DE)
Assignee:	Bayer Intellectual Property GmbH (Monheim, DE)
Application Number:	13/502,548
Patent Claims:	1. A compound of general formula (I): ##STR00059## in which: R1 is a hydrogen atom or a fluorine atom; R2 is a halogen atom or a C.sub.2-alkynyl or cyano group; R3 is an --NH.sub.2, --NH(C.sub.1-C.sub.6-alkyl), --N(C.sub.1-C.sub.6-alkyl).sub.2, --C.sub.1-C.sub.6-alkyl, or --C.sub.3-C.sub.6-cycloalkyl group; R4 is an --NH.sub.2, --NH(C.sub.1-C.sub.6-alkyl), --N(C.sub.1-C.sub.6-alkyl).sub.2, --C.sub.1-C.sub.6-alkyl, or --C.sub.3-C.sub.6-cycloalkyl group; R5 is a hydrogen atom, a halogen atom, or a --C.sub.1-C.sub.6-alkyl or --O--C.sub.1-C.sub.6-alkyl group; A is --(CH.sub.2).sub.n--, in which n=0, or 1; or a tautomer, stereoisomer, N-oxide, salt, hydrate, or solvate thereof. 2. The compound according to claim 1, wherein: R1 is a hydrogen atom or a fluorine atom; R2 is a fluorine atom or a C.sub.2-alkynyl or cyano group; R3 is an --NH.sub.2, --NH(C.sub.1-C.sub.6-alkyl), --N(C.sub.1-C.sub.6-alkyl).sub.2, --C.sub.1-C.sub.6-alkyl, or --C.sub.3-C.sub.6-cycloalkyl group; R4 is an --NH.sub.2, --NH(C.sub.1-C.sub.6-alkyl), --N(C.sub.1-C.sub.6-alkyl).sub.2, --C.sub.1-C.sub.6-alkyl, or --C.sub.3-C.sub.6-cycloalkyl group; R5 is a hydrogen atom, a fluorine atom or a methyl group; A is --(CH.sub.2).sub.n--, in which n=0, or 1; or a tautomer, stereoisomer, N-oxide, salt, hydrate, or solvate thereof. 3. The compound according to claim 1, wherein: R1 is a hydrogen atom or a fluorine atom; R2 is a fluorine atom or a C.sub.2-alkynyl or cyano group; R3 is an --NH.sub.2, --NH(C.sub.1-C.sub.6-alkyl), --N(C.sub.1-C.sub.6-alkyl).sub.2, --C.sub.1-C.sub.6-alkyl, or --C.sub.3-C.sub.6-cycloalkyl group; R4 is an --NH.sub.2, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl or cyclobutyl group; R5 is a hydrogen atom, a fluorine atom or a methyl group; A is --(CH.sub.2).sub.n--, in which n=0, or 1; or a tautomer, stereoisomer, N-oxide, salt, hydrate, or solvate thereof. 4. The compound according to claim 1, wherein: R1 is a hydrogen atom or a fluorine atom; R2 is a fluorine atom or a C.sub.2-alkynyl or cyano group; R3 is an --NH.sub.2, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl or cyclobutyl group; R4 is an --NH.sub.2, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl or cyclobutyl group; R5 is a hydrogen atom, a fluorine atom or a methyl group; A is --(CH.sub.2).sub.n--, in which n=0, or 1; or a tautomer, stereoisomer, N-oxide, salt, hydrate, or solvate thereof. 5. The compound according to claim 1, which is selected from the group consisting of: N-(2-{3-[(ethylsulfonyl)amino]phenoxy}-4-fluoro-6-[(2-fluoro-4-iodophenyl- )amino]phenyl)cyclopropanesulfonamide; N-(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-[(methylsulfonyl)-amino- ]phenoxy}-phenyl)ethane-sulfonamide; N-(3-{2-[(ethylsulfonyl)amino]-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-- phenoxy}phenyl)-ethanesulfonamide; N-(2-{3-[(ethylsulfonyl)amino]phenoxy}-4-fluoro-6-[(2-fluoro-4-iodophenyl- )amino]-phenyl)propane-2-sulfonamide; N-(2-{3-[(ethylsulfonyl)amino]phenoxy}-4-fluoro-6-[(2-fluoro-4-iodophenyl- )amino]-phenyl)cyclobutane-sulfonamide; N-(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-(sulfamoylamino)phenoxy- }phenyl)ethanesulfonamide; N-(2-{3-[(ethylsulfonyl)amino]-2-methylphenoxy}-4-fluoro-6-[(2-fluoro-4-i- odophenyl)amino]phenyl)cyclopropanesulfonamide; N-(3-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-(sulfamoylamino)phenoxy- }-2-methylphenyl)ethanesulfonamide; N-(2-{3-[(ethylsulfonyl)amino]phenoxy}-6-[(4-ethynyl-2-fluorophenyl)amino- ]-4-fluorophenyl)cyclopropanesulfonamide; N-(3-{3-[(4-ethynyl-2-fluorophenyl)amino]-5-fluoro-2-(sulfamoylamino)phen- oxy}phenyl)ethanesulfonamide [Formic Acid salt]; N-{4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-[3-(sulfamoylamino)phenoxy- ]phenyl}cyclopropanesulfonamide; N-(4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{3-[(isopropylsulfonyl)ami- no]phenoxy}phenyl)cyclopropanesulfonamide; N-(4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{3-[(methylsulfonyl)amino]- phenoxy}phenyl)cyclopropanesulfonamide; N-{4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-[4-fluoro-3-(sulfamoylamin- o)phenoxy]phenyl}cyclopropanesulfonamide; N-(5{2-[(cyclopropylsulfonyl)amino]-5-fluoro-3-[(2-fluoro-4-iodophenyl)am- ino]phenoxy}-2-fluorophenyl)cyclopropanesulfonamide; N-(2-fluoro-5-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-(sulfamoylamin- o)phenoxy}phenyl)sulfuric diamide; and N-(4-fluoro-2-[(2-fluoro-4-iodophenyl)amino]-6-{3-[(sulfamoylamino)methyl- ]phenoxy}phenyl)cyclopropanesulfonamide. 6. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (4): ##STR00060## in which R1, R2, R4, R5 and A are as defined in claim 1, to react with a sulphonyl chloride of general formula E: ##STR00061## in which R3 is as defined in claim 1, thereby giving a compound of general formula I: ##STR00062## in which R1, R2, R3, R4, R5 and A are as defined in claim 1. 7. A method of preparing a compound of general formula (I) according to claim 1, said method comprising the step of allowing an intermediate compound of general formula (8): ##STR00063## in which R1, R2, R3, R5 and A are as defined in claim 1, to react with a sulphonyl chloride of general formula D: ##STR00064## in which R4 is as defined in claim 1, thereby giving a compound of general formula I: ##STR00065## in which R1, R2, R3, R4, R5 and A are as defined in claim 1. 8. A method of preparing a compound of general formula (Ic), said method comprising the step of allowing an intermediate compound of general formula (12): ##STR00066## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5, and A are as defined in claim 1, and PG represents an acid labile protecting group, to react with an acid, thereby giving a compound of formula (Ic): ##STR00067## in which R.sup.1, R.sup.2, R.sup.3, R.sup.5 and A are as defined in claim 1. 9. A pharmaceutical composition comprising a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1, and a pharmaceutically acceptable diluent or carrier. 10. A pharmaceutical combination comprising: one or more compounds of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1; and one or more agents selected from: a taxane; an epothilone; Mitoxantrone; Prednisolone; 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; Bortezomib; a platinum derivative; Chlorambucil; Methotrexate; and Rituximab. 11. A method for the treatment of uncontrolled cell growth, proliferation and/or survival, an inappropriate cellular immune response, or an inappropriate cellular inflammatory response, wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is mediated by the mitogen-activated protein kinase (MEK-ERK) pathway, comprising administering to a human in need thereof a therapeutically acceptable amount of a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of same, according to claim 1. 12. The method according to claim 11, wherein the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune response, or inappropriate cellular inflammatory response is a haemotological tumour, a solid tumour and/or metastases thereof. 13. The method according to claim 12, wherein the haemotological tumour, solid tumour and/or metastases thereof is selected from leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours, brain tumours and brain metastases, tumours of the thorax, non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours, renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

Details for Patent 8,962,606

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2029-10-21
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2029-10-21
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2029-10-21