US 2003/0166725 A1Published application

Compounds active at the glucocorticoid receptor

OwnerTheresa Apelgvist, Mikael Gillner +7inventors

InventorsTheresa Apelgvist, Mikael Gillner, Annika Gustavsson, Lars Hagberg, Eva Koch, Marita Nilsson, Benjamin Pelcman, Jinchang Wu, Philip R. Kym

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Abstract

This invention relates to novel compounds that are liver selective glucocorticoid receptor antagonists, to methods of preparing such compounds, and to methods for using such compounds in therapy and in the regulation of metabolism, especially lowering blood glucose levels. The compounds referred to are compounds according to the formula (I).

Claims45

Dependent claims

A compound according to the formula I:

66
wherein:
R1 is selected from:
COOH, C(O)NHOH, C(O)COOH, SO3H, P(O)(OH)(OR8), P(O)(OH)[N(R9)(R10)], and heteroaryl, wherein any heteroaryl residue may be optionally substituted in one or more positions independently of each other by a group selected from C1-6-alkyl, perfluoro-C1-6-alkyl, halogen, cyano, nitro, R8O, R8S, R8S(O), R8S(O)2 and (R9)(R10)N;
R2 and R3 are independently of each other selected from:
hydrogen, halogen, C1-6-alkyl, hydroxy, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, perfluoro-C1-6-alkyl, halo-C1-6-alkyloxy, perfluoro-C1-6-alkyloxy, and halo-C1-6-alkylthio, provided that one of R2 or R3 is other than hydrogen;
R4, R5, R6 and R7 are independently of each other selected from:
(i) C1-12-alkyl and perfluoro-C1-6-alkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A;
(ii) C3-8-cycloalkyl, C2-6-alkenyl, and C2-6-alkynyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from B;
R4 and R5 are optionally, and independently of each other, selected from:
(iii) C3-8-heterocycloalkyl, optionally substituted by a group selected from B;
(iv) aryl and heteroaryl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from C;
R4 is optionally selected from:
halogen, R8O, R8S, R8S(O), R8S(O)2, (R9)(R10)N, R8C(Z)N(R11), (R9)(R10)NC(Z)N(R11), R8S(O)2N(R11), and (R9)(R10)NS(O)2N(R11);
R6 and R7 are optionally, and independently of each other, selected from:
hydrogen, halogen, R8O, R8S, R8S(O), R8S(O)2, (R9)(R10)N, R8C(Z)O, R8OC(Z)O, R8C(Z)N(R11), R8OC(Z)N(R11), R8S(O)nO, (R9)(R10)NC(Z)O, (R9)(R10)NS(O)2O, R8S(O)2N(R11), and (R9)(R10)NS(O)2N(R11), provided that R8 is not hydrogen in R8OC(Z)O, R8S(O)nO, and R8S(O)2N(R11), and that only one of R6 and R7 is hydrogen, and that if R6 is HO, R7 is hydrogen, and that if R7 is HO, Re is hydrogen;
R8, R9, R10 and R11 are independently of each other selected from:
(v) hydrogen,
(vi) C1-12-alkyl and perfluoro-C1-6-alkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A;
(vii) C3-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, and C3-4-heterocycloalkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from B;
(viii) aryl and heteroaryl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from C;
or where any pair of R8, R9, R10 and R11 together with the atom or atoms to which they are bound form a ring having 3-7 ring members, and which ring optionally contain 1-3 heteroatoms, or 1-3 double bonds, and which optionally is substituted by a group selected from B;
A is selected from:
halogen, perfluoro-C1-6-alkyl, C3-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, aryl, C3-8-heterocycloalkyl, heteroaryl, cyano, nitro, azido, Z, R8O, R8C(Z), R8C(Z)O, R8OC(Z), R8S, R8S(O), R8S(O)2, R8S(O)2O, R8OS(O)2, (R9)(R10)N, (R9)(R10)NC(Z), (R9)(R10)NC(Z)O, R8C(Z)N(R11), R8OC(Z)N(R11), (R9)(R10)NC(Z)N(R11), (R9)(R10)NS(O)2, R8S(O)2N(R11), (R9)(R10)NS(O)2N(R11), and R8SC(Z)N(R11), wherein any perfluoro-C1-6alkyl, C3-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, and C3-8-heterocycloalkyl residue is optionally substituted in one or more positions independently of each other by a group selected from B, and also wherein any aryl and heteroaryl residue is optionally substituted in one or more positions independently of each other by a group selected from C;
B is defined as:
A, or a C1-6-alkyl optionally substituted in one or more positions independently of each other by a group selected from D, provided that if B is directly attached to a double or to a triple bond, or to a carbon directly attached to a heteroatom, B is not HO, HS, R9HN, (R9)(R10)NC(Z)NH, (R9)(R10)NS(O)2NH, or R8S(O)2NH, and also provided that if B is directly attached to a double or to a triple bond, B is not Z;
C is defined as:
A, or a C1-6-alkyl optionally substituted in one or more positions independently of each other by a group selected from D, provided that C is not Z;
D is selected from:
halogen, cyano, nitro, azido, Z, R8O, R8C(Z), R8C(Z)O, R8OC(Z), R8S, R8S(O), R8S(O)2, R8S(O)2O, R8OS(O)2, (R9)(R10)N, (R9)(R10)NC(Z), (R9)(R10)NC(Z)N(R11), (R9)(R10)NS(O)2, R8S(O)2N(R11), and (R9)(R10)NS(O)2N(R11);
Y is selected from:
hydrogen, halogen, hydroxy, C1-6-alkoxy, halo-C1-6-alkyloxy, perfluoro-C1-6-alkyloxy, C1-6-acyloxy, C1-6-alkylthio, halo-C1-6-alkylthio, perfluoro-C1-6-alkylthio, Citalkylsulphonyloxy, azido, and (R9)(R10)N;
Z is a substituent connected by a double bond, and is selected from:
O═, S═, R8N═, (R9)(R10)NN═, R8ON═, (R9)(R10)NS(O)2N═, NCN═, O2NCH═, and (R9)(R10)C═;
n is 0, 1, 2 or 3;
or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof.

33 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound according to the formula I:

66
wherein:
R1 is selected from:
COOH, C(O)NHOH, C(O)COOH, SO3H, P(O)(OH)(OR8), P(O)(OH)[N(R9)(R10)], and heteroaryl, wherein any heteroaryl residue may be optionally substituted in one or more positions independently of each other by a group selected from C1-6-alkyl, perfluoro-C1-6-alkyl, halogen, cyano, nitro, R8O, R8S, R8S(O), R8S(O)2 and (R9)(R10)N;
R2 and R3 are independently of each other selected from:
hydrogen, halogen, C1-6-alkyl, hydroxy, C1-6-alkoxy, C1-6-alkylthio, halo-C1-6-alkyl, perfluoro-C1-6-alkyl, halo-C1-6-alkyloxy, perfluoro-C1-6-alkyloxy, and halo-C1-6-alkylthio, provided that one of R2 or R3 is other than hydrogen;
R4, R5, R6 and R7 are independently of each other selected from:
(i) C1-12-alkyl and perfluoro-C1-6-alkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A;
(ii) C3-8-cycloalkyl, C2-6-alkenyl, and C2-6-alkynyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from B;
R4 and R5 are optionally, and independently of each other, selected from:
(iii) C3-8-heterocycloalkyl, optionally substituted by a group selected from B;
(iv) aryl and heteroaryl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from C;
R4 is optionally selected from:
halogen, R8O, R8S, R8S(O), R8S(O)2, (R9)(R10)N, R8C(Z)N(R11), (R9)(R10)NC(Z)N(R11), R8S(O)2N(R11), and (R9)(R10)NS(O)2N(R11);
R6 and R7 are optionally, and independently of each other, selected from:
hydrogen, halogen, R8O, R8S, R8S(O), R8S(O)2, (R9)(R10)N, R8C(Z)O, R8OC(Z)O, R8C(Z)N(R11), R8OC(Z)N(R11), R8S(O)nO, (R9)(R10)NC(Z)O, (R9)(R10)NS(O)2O, R8S(O)2N(R11), and (R9)(R10)NS(O)2N(R11), provided that R8 is not hydrogen in R8OC(Z)O, R8S(O)nO, and R8S(O)2N(R11), and that only one of R6 and R7 is hydrogen, and that if R6 is HO, R7 is hydrogen, and that if R7 is HO, Re is hydrogen;
R8, R9, R10 and R11 are independently of each other selected from:
(v) hydrogen,
(vi) C1-12-alkyl and perfluoro-C1-6-alkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A;
(vii) C3-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, and C3-4-heterocycloalkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from B;
(viii) aryl and heteroaryl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from C;
or where any pair of R8, R9, R10 and R11 together with the atom or atoms to which they are bound form a ring having 3-7 ring members, and which ring optionally contain 1-3 heteroatoms, or 1-3 double bonds, and which optionally is substituted by a group selected from B;
A is selected from:
halogen, perfluoro-C1-6-alkyl, C3-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, aryl, C3-8-heterocycloalkyl, heteroaryl, cyano, nitro, azido, Z, R8O, R8C(Z), R8C(Z)O, R8OC(Z), R8S, R8S(O), R8S(O)2, R8S(O)2O, R8OS(O)2, (R9)(R10)N, (R9)(R10)NC(Z), (R9)(R10)NC(Z)O, R8C(Z)N(R11), R8OC(Z)N(R11), (R9)(R10)NC(Z)N(R11), (R9)(R10)NS(O)2, R8S(O)2N(R11), (R9)(R10)NS(O)2N(R11), and R8SC(Z)N(R11), wherein any perfluoro-C1-6alkyl, C3-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, and C3-8-heterocycloalkyl residue is optionally substituted in one or more positions independently of each other by a group selected from B, and also wherein any aryl and heteroaryl residue is optionally substituted in one or more positions independently of each other by a group selected from C;
B is defined as:
A, or a C1-6-alkyl optionally substituted in one or more positions independently of each other by a group selected from D, provided that if B is directly attached to a double or to a triple bond, or to a carbon directly attached to a heteroatom, B is not HO, HS, R9HN, (R9)(R10)NC(Z)NH, (R9)(R10)NS(O)2NH, or R8S(O)2NH, and also provided that if B is directly attached to a double or to a triple bond, B is not Z;
C is defined as:
A, or a C1-6-alkyl optionally substituted in one or more positions independently of each other by a group selected from D, provided that C is not Z;
D is selected from:
halogen, cyano, nitro, azido, Z, R8O, R8C(Z), R8C(Z)O, R8OC(Z), R8S, R8S(O), R8S(O)2, R8S(O)2O, R8OS(O)2, (R9)(R10)N, (R9)(R10)NC(Z), (R9)(R10)NC(Z)N(R11), (R9)(R10)NS(O)2, R8S(O)2N(R11), and (R9)(R10)NS(O)2N(R11);
Y is selected from:
hydrogen, halogen, hydroxy, C1-6-alkoxy, halo-C1-6-alkyloxy, perfluoro-C1-6-alkyloxy, C1-6-acyloxy, C1-6-alkylthio, halo-C1-6-alkylthio, perfluoro-C1-6-alkylthio, Citalkylsulphonyloxy, azido, and (R9)(R10)N;
Z is a substituent connected by a double bond, and is selected from:
O═, S═, R8N═, (R9)(R10)NN═, R8ON═, (R9)(R10)NS(O)2N═, NCN═, O2NCH═, and (R9)(R10)C═;
n is 0, 1, 2 or 3;
or pharmaceutically acceptable salts, stereoisomers or prodrugs thereof.

33 more elements