Substituted benzosulphonamides

Patent metadata

Field	Value
Publication number	US-8962606-B2
Application number	US-201013502548-A
Country	US
Kind code	B2
Filing date	Oct 7, 2010
Priority date	Oct 21, 2009
Publication date	Feb 24, 2015
Grant date	Feb 24, 2015

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.

First claim

The invention claimed is:

1. A compound of general formula (I):

in which:

R1 is a hydrogen atom or a fluorine atom;
R2 is a halogen atom or a C 2 -alkynyl or cyano group;
R3 is an —NH 2 , —NH(C 1 -C 6 -alkyl), —N(C 1 -C 6 -alkyl) 2 , —C 1 -C 6 -alkyl, or —C 3 -C 6 -cycloalkyl group;
R4 is an —NH 2 , —NH(C 1 -C 6 -alkyl), —N(C 1 -C 6 -alkyl) 2 , —C 1 -C 6 -alkyl, or —C 3 -C 6 -cycloalkyl group;
R5 is a hydrogen atom, a halogen atom, or a —C 1 -C 6 -alkyl or —O—C 1 -C 6 -alkyl group;
A is —(CH 2 ) 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 2 -alkynyl or cyano group;
R3 is an —NH 2 , —NH(C 1 -C 6 -alkyl), —N(C 1 -C 6 -alkyl) 2 , —C 1 -C 6 -alkyl, or —C 3 -C 6 -cycloalkyl group;
R4 is an —NH 2 , —NH(C 1 -C 6 -alkyl), —N(C 1 -C 6 -alkyl) 2 , —C 1 -C 6 -alkyl, or —C 3 -C 6 -cycloalkyl group;
R5 is a hydrogen atom, a fluorine atom or a methyl group;
A is —(CH 2 ) 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 2 -alkynyl or cyano group;
R3 is an —NH 2 , —NH(C 1 -C 6 -alkyl), —N(C 1 -C 6 -alkyl) 2 , —C 1 -C 6 -alkyl, or —C 3 -C 6 -cycloalkyl group;
R4 is an —NH 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 2 ) 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 2 -alkynyl or cyano group;
R3 is an —NH 2 , methyl, ethyl, n-propyl, iso-propyl, cyclopropyl or cyclobutyl group;
R4 is an —NH 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 2 ) 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-iodophenyl)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)phenoxy}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)amino]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-(sulfamoylamino)phenoxy]phenyl}cyclopropanesulfonamide;
N-(5{2-[(cyclopropylsulfonyl)amino]-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-2-fluorophenyl)cyclopropanesulfonamide;
N-(2-fluoro-5-{5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]-2-(sulfamoylamino)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):

in which R1, R2, R4, R5 and A are as defined in claim 1 ,
to react with a sulphonyl chloride of general formula E:

in which R3 is as defined in claim 1 ,
thereby giving a compound of general formula I:

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):

in which R1, R2, R3, R5 and A are as defined in claim 1 ,
to react with a sulphonyl chloride of general formula D:

in which R4 is as defined in claim 1 ,
thereby giving a compound of general formula I:

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):

in which R 1 , R 2 , R 3 , R 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):

in which R 1 , R 2 , R 3 , R 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 ina

Assignees

• Hitchcock Marion
• Hartung Ingo
• Pühler Florian
• Bayer Ip Gmbh

Inventors

• Hitchcock Marion
• Hartung Ingo
• Pühler Florian

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C311/14 Primary

  Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title