Combination of a C-Met antagonist and an aminoheteroaryl compound for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-9375425-B2
Application number	US-201514662972-A
Country	US
Kind code	B2
Filing date	Mar 19, 2015
Priority date	Jul 8, 2008
Publication date	Jun 28, 2016
Grant date	Jun 28, 2016

Abstract

The invention also relates to a composition comprising an antibody antagonist to c-Met and an aminoheteroaryl compound, particularly as a medicament. The present invention also comprises a pharmaceutical composition comprising said anti c-Met antibody and said aminoheteroaryl compound as combination products for simultaneous, separate or sequential use. The invention relates to the use of the composition of the invention for the treatment of cancer in a mammal.

First claim

The invention claimed is:

1. A composition comprising an antibody antagonist to c-Met, or a cMet-binding fragment thereof, and an aminoheteroaryl compound, wherein:
i) said antibody antagonist to c-Met comprises a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 comprising, respectively, the amino acid sequences SEQ ID Nos. 7, 8, and 9; and a light chain comprising CDR-L1, CDR-L2 and CDR-L3 comprising, respectively, the amino acid sequences SEQ ID Nos. 15, 16, and 17;
and
ii) said aminoheteroaryl compound is selected from the group consisting of compounds of formula I:

wherein:
Y is N or CR 12 ;
R 1 is hydrogen, halogen, C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heteroalicyclic, —O(CR 6 R 7 ) n R 4 , —C(O)R 4 , —C(O)OR 4 , —CN, —NO 2 , —S(O) m R 4 , —SO 2 NR 4 R 5 , —C(O)NR 4 R 5 , —NR 4 C(O)R 5 , —C(═NR 6 )NR 4 R 5 , C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl; and each hydrogen in R 1 is optionally substituted by one or more R 3 groups;

R 2 is hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NC R 4R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 , and each hydrogen in R 2 is optionally substituted by R 8 ;
each R 3 is independently halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O)2OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 , each hydrogen in R 3 is optionally substituted by R 8 , and R 3 groups on adjacent atoms may combine to form a C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R 4 , R 5 , R 6 and R 7 is independently hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12 membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R 4 , R 5 , R 6 and R 7 bound to the same carbon atom may be combined to form a C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R 4 , R 5 , R 6 and R 7 is optionally substituted by R 8 ;
each R 8 is independently halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —NH 2 , —CN, —OH, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic) or —O—(CH2)n(5-12 membered heteroaryl); and each hydrogen in R 8 is optionally substituted by R 11 ;
each R 9 and R 10 is independently hydrogen, halogen, C 1-12 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO2, —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 ; R 9 or R 10 may combine with a ring atom of A or a substituent of A to form a C 3-12 cycloalkyl, 3-12 membered heteroalicyclic, C 6-12 aryl or 5-12 membered heteroaryl ring fused to A; and each hydrogen in R 9 and R 10 is optionally substituted by R 3 ;
each R 11 is independently halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 )nC 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic), —O—(CH 2 ) n (5-12 membered heteroaryl) or —CN, and each hydrogen in R 11 is optionally substituted by halogen, —OH, —CN, —C 1-12 alkyl which may be partially or fully halogenated, —O—C 1-12 alkyl which may be partially or fully halogenated, —CO, —SO or —SO 2 ;
R 12 is hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 , and each hydrogen in R 12 is optionally substituted by R 3 ;
each R 13 is independently halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 9 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —(CR 6 R 7 ) n OR 4 , —(CR 6 R 7 ) n C(O)NR 4 R 5 , —(CR 6 R 7 ) n NCR 4 R 5 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 , —C(O)NR 4 R 5 , —(CR 6 R 7 ) n (3-12 membered heteroalicyclic), —(CR 6 R 7 ) n (C 3-12 cycloalkyl), —(CR 6 R 7 ) n (C 6-12 aryl), —(CR 6 R 7 ) n (5-12 membered heteroaryl), —(CR 6 R 7 ) n C(O)NR 4 R 5 , or —(CR 6 R 7 ) n C(O)R 4 , R 13 groups on adjacent atoms may combine to form a C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic group, and each hydrogen in R 13 is optionally substituted by R 3 ;
each m is independently 0, 1 or 2;
each n is independently 0, 1, 2, 3 or 4;
each p is independently 1 or 2;
and a pharmaceutically acceptable salt, hydrate or solvate thereof.

2. The composition according to claim 1 , wherein the composition is a pharmaceutical composition.

3. A pharmaceutical composition comprising at least:
i) one antibody antagonist to c-Met, or a cMet-binding fragment thereof; and
ii) an aminoheteroaryl compound,

as combination products for simultaneous, separate or sequential use; wherein:
i) said antibody antagonist to c-Met comprises a heavy chain comprising CDR-H1, CDR-H2 and CDR-H3 comprising, respectively, the amino acid sequences SEQ ID Nos. 7, 8, and 9; and a light chain comprising CDR-L1, CDR-L2 and CDR-L3 comprising, respectively, the amino acid sequences SEQ ID Nos. 15, 16, and 17;
and
ii) said aminoheteroaryl compound is selected from the group consisting of compounds of formula I:

wherein:
Y is N or CR 12 ;
R 1 is hydrogen, halogen, C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heteroalicyclic, —O(CR 6 R 7 ) n R 4 , —C(O)R 4 , —C(O)OR 4 , —CN, —NO 2 , —S(O) m R 4 , —SO 2 NR 4 R 5 , —C(O)NR 4 R 5 , —NR 4 C(O)R 5 , —C(═NR 6 )NR 4 R 5 , C 1-8 alkyl, C 2-8 alkenyl, or C 2-8 alkynyl; and each hydrogen in R 1 is optionally substituted by one or more R 3 groups;
R 2 is hydrogen, halogen, C 1-12 alkyl,

Assignees

• Goetsch Liliane
• Pf Medicament

Inventors

• Goetsch Liliane

Classifications

• A61K31/4545 Primary

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• A61P35/00

  Antineoplastic agents · CPC title