US 2006/0235024 A1Published application

Acetylinic piperazine compounds and their use as metabotropic glutamate receptor antagonists

AssigneesAstraZeneca AB, NPS Pharmaceuticals, Inc.

InventorsChris Bryan, Methvin Isaac, Tomislav Stefanac, Abdelmalik Slassi, Louise Edwards

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Abstract

The present invention relates to new acetylinic piperazine compounds of formula I, their pharmaceutically acceptable salts, and hydrates: wherein R1, R2, R3, R4, M, and n are as defined in the description. The invention also relates to processes for the preparation of the compounds and to new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and to the use of the compounds in therapy.

Claims27

Dependent claims

A compound according to formula I:

wherein
R1 is selected from the group consisting of hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
R2 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
R3 is selected from the group consisting of:
H, C(O)OC1-6alkylhalo, C(O)OC1-6alkyl, C(O)OC2-6alkenyl, C(O)OC2-6alkynyl, C(O)OC0-6alkylC3-6cycloalkyl, C(O)OC0-6alkylaryl, C(O)OC1-6alkylOR5, C(O)OC1-6alkyl(CO)R5, C(O)OC1-6alkylCO2R5, C(O)OC1-6alkylcyano, C(O)OC0-6alkylNR5R6, C(O)OC1-6alkyl(CO)NR5R6, C(O)OC2-6alkylNR5(CO)R6, C(O)C1-6alkylNR5(CO)NR5R6, C(O)OC2-6alkylSR5, C(O)OC1-6alkyl(SO)R5, C(O)OC1-6alkylSO2R5, C(O)OC1-6alkyl(SO2)NR5R6, C(O)OC1-6alkylNR5(SO2)R6, C(O)OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, C(O)OC1-6alkylNR5(CO)OR6, C(S)OC1-6alkylhalo, C(S)OC1-6alkyl, C(S)OC2-6alkenyl, C(S)OC2-6alkynyl, C(S)OC0-6alkylC3-6cycloalkyl, C(S)OC0-6alkylaryl, C(S)OC1-6alkylOR5, C(S)OC1-6alkyl(CO)R5, C(S)OC1-6alkylCO2R5, C(S)OC1-6alkylcyano, C(S)OC0-6alkylNR5R6, C(S)OC1-6alkyl(CO)NR5R6, C(S)OC2-6alkylNR5(CO)R6, C(S)C1-6alkylNR5(CO)NR5R6, C(S)OC2-6alkylSR5, C(S)OC1-6alkyl(SO)R5, C(S)OC1-6alkylSO2R5, C(S)OC1-6alkyl(SO2)NR5R6, C(S)OC1-6alkylNR5(SO2)R6, C(S)OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, and C(S)OC1-6alkylNR5(CO)OR6;
R4 is selected from the group consisting of hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5 (CO)R6, OC2-6alkylNR5 (CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, ═NR5, ═NOR5, ═O, ═S, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
M is selected from the group consisting of ═O, (CR5R6)m and (CR5R6)mC(O);
R5 and R6 are independently selected from the group consisting of hydrogen, C1-6alkyl, OC1-6alkyl, C3-7cycloalkyl, OC3-7cycloalkyl, C1-6alkylaryl, OC1-6alkylaryl, aryl, and heteroaryl;
any C1-6alkyl, aryl or heteroaryl defined under R1, R2, R3, R4, R5 and R6 may be substituted by one or more A;
A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C0-6alkylcyano, C0-4alkylC3-6cycloalkyl, C1-6alkyl, C1-6alkylhalo, OC1-6alkylhalo, C2-6alkenyl, C0-3alkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, OC1-6alkylCO2R5, O(CO)OR5, OC1-6alkyl(CO)R5, C1-6alkyl(CO)R5, NR5OR6, C1-6alkylNR5R6, OC2-6alkylNR5R6, C0-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, O(CO)NR5R6, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S;
m is 1, 2, or 3;
n is an integer between 0 and 8, inclusive;
or
a pharmaceutically acceptable salt or hydrate thereof.

11 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound according to formula I:

wherein
R1 is selected from the group consisting of hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
R2 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5(CO)R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
R3 is selected from the group consisting of:
H, C(O)OC1-6alkylhalo, C(O)OC1-6alkyl, C(O)OC2-6alkenyl, C(O)OC2-6alkynyl, C(O)OC0-6alkylC3-6cycloalkyl, C(O)OC0-6alkylaryl, C(O)OC1-6alkylOR5, C(O)OC1-6alkyl(CO)R5, C(O)OC1-6alkylCO2R5, C(O)OC1-6alkylcyano, C(O)OC0-6alkylNR5R6, C(O)OC1-6alkyl(CO)NR5R6, C(O)OC2-6alkylNR5(CO)R6, C(O)C1-6alkylNR5(CO)NR5R6, C(O)OC2-6alkylSR5, C(O)OC1-6alkyl(SO)R5, C(O)OC1-6alkylSO2R5, C(O)OC1-6alkyl(SO2)NR5R6, C(O)OC1-6alkylNR5(SO2)R6, C(O)OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, C(O)OC1-6alkylNR5(CO)OR6, C(S)OC1-6alkylhalo, C(S)OC1-6alkyl, C(S)OC2-6alkenyl, C(S)OC2-6alkynyl, C(S)OC0-6alkylC3-6cycloalkyl, C(S)OC0-6alkylaryl, C(S)OC1-6alkylOR5, C(S)OC1-6alkyl(CO)R5, C(S)OC1-6alkylCO2R5, C(S)OC1-6alkylcyano, C(S)OC0-6alkylNR5R6, C(S)OC1-6alkyl(CO)NR5R6, C(S)OC2-6alkylNR5(CO)R6, C(S)C1-6alkylNR5(CO)NR5R6, C(S)OC2-6alkylSR5, C(S)OC1-6alkyl(SO)R5, C(S)OC1-6alkylSO2R5, C(S)OC1-6alkyl(SO2)NR5R6, C(S)OC1-6alkylNR5(SO2)R6, C(S)OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, and C(S)OC1-6alkylNR5(CO)OR6;
R4 is selected from the group consisting of hydroxy, halo, nitro, C1-6alkylhalo, OC1-6alkylhalo, C1-6alkyl, OC1-6alkyl, C2-6alkenyl, OC2-6alkenyl, C2-6alkynyl, OC2-6alkynyl, C0-6alkylC3-6cycloalkyl, OC0-6alkylC3-6cycloalkyl, C0-6alkylaryl, OC0-6alkylaryl, CHO, (CO)R5, O(CO)R5, O(CO)OR5, O(CN)OR5, C1-6alkylOR5, OC2-6alkylOR5, C1-6alkyl(CO)R5, OC1-6alkyl(CO)R5, C0-6alkylCO2R5, OC1-6alkylCO2R5, C0-6alkylcyano, OC2-6alkylcyano, C0-6alkylNR5R6, OC2-6alkylNR5R6, C1-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, C0-6alkylNR5 (CO)R6, OC2-6alkylNR5 (CO)R6, C0-6alkylNR5(CO)NR5R6, C0-6alkylSR5, OC2-6alkylSR5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5, C0-6alkylSO2R5, OC2-6alkylSO2R5, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, C0-6alkylNR5(SO2)NR5R6, OC2-6alkylNR5(SO2)NR5R6, (CO)NR5R6, O(CO)NR5R6, NR5OR6, C0-6alkylNR5(CO)OR6, OC2-6alkylNR5(CO)OR6, ═NR5, ═NOR5, ═O, ═S, SO3R5 and a 5- or 6-membered ring containing atoms independently selected from the group consisting of C, N, O and S;
M is selected from the group consisting of ═O, (CR5R6)m and (CR5R6)mC(O);
R5 and R6 are independently selected from the group consisting of hydrogen, C1-6alkyl, OC1-6alkyl, C3-7cycloalkyl, OC3-7cycloalkyl, C1-6alkylaryl, OC1-6alkylaryl, aryl, and heteroaryl;
any C1-6alkyl, aryl or heteroaryl defined under R1, R2, R3, R4, R5 and R6 may be substituted by one or more A;
A is selected from the group consisting of hydrogen, hydroxy, halo, nitro, oxo, C0-6alkylcyano, C0-4alkylC3-6cycloalkyl, C1-6alkyl, C1-6alkylhalo, OC1-6alkylhalo, C2-6alkenyl, C0-3alkylaryl, C0-6alkylOR5, OC2-6alkylOR5, C1-6alkylSR5, OC2-6alkylSR5, (CO)R5, O(CO)R5, OC2-6alkylcyano, OC1-6alkylCO2R5, O(CO)OR5, OC1-6alkyl(CO)R5, C1-6alkyl(CO)R5, NR5OR6, C1-6alkylNR5R6, OC2-6alkylNR5R6, C0-6alkyl(CO)NR5R6, OC1-6alkyl(CO)NR5R6, OC2-6alkylNR5(CO)R6, C0-6alkylNR5(CO)R6, C0-6alkylNR5(CO)NR5R6, O(CO)NR5R6, C0-6alkyl(SO2)NR5R6, OC2-6alkyl(SO2)NR5R6, C0-6alkylNR5(SO2)R6, OC2-6alkylNR5(SO2)R6, SO3R5, C1-6alkylNR5(SO2)NR5R6, OC2-6alkyl(SO2)R5, C0-6alkyl(SO2)R5, C0-6alkyl(SO)R5, OC2-6alkyl(SO)R5 and a 5- or 6-membered ring containing one or more atoms independently selected from the group consisting of C, N, O and S;
m is 1, 2, or 3;
n is an integer between 0 and 8, inclusive;
or
a pharmaceutically acceptable salt or hydrate thereof.

11 more elements