Cyclic amine compounds as CCR5 antagonists

A compound represented by the formula:

• 53
• [wherein R4a is (1) a C1-6 alkyl group which may be substituted by halogen(s), C1-6 alkoxy(s), oxo(s), amino(s), phenyl(s), pyridyl(s) or tetrazolyl(s), (2) a C1-6 alkenyl group, (3) a C3-8 cycloalkyl group which may be substituted by halogen(s), C1-6 alkyl(s) or C1-6 alkoxy(s), (4) a phenyl group which may be substituted by halogen(s), C1-6 alkyl(s), C1-6 alkoxy(s), nitro(s), cyano(s), hydroxyl(s), C1-4 alkanoyl-amino(s), carbamoyl(s) or sulfamoyl(s), (5) an amino group which may be substituted by C1-6 alkyl(s), (6) a C1-6 alkoxy group which may be substituted by phenyl(s), (7) a C3-8 cycloalkyloxy group (8) a heterocyclic group which may be substituted by halogen(s), C1-6 alkyl(s) or hydroxyl(s), G1a is CO or SO2, R3a is a C6-10 aryl group which may be substituted by (1)halogen(s), (2) C1-6 alkyl(s) which may be substituted by halogen(s), (3) C1-6 alkoxy(s) which may be substituted by halogen(s), (4) C1-6 alkyl-thio(s), or (5) C1-6 alkylsulfonyl(s), L is methine or a nitrogen atom, B2 is a bond, —CH2—, —SO2—, —SO—, —S—, —O—, —CO—, —NRb1—SO2— (wherein Rb1 is a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C3-6 cycloalkyl group), —CH(OH)—, —NRb2— (wherein Rb2 is a hydrogen atom or a C2-4 alkanoyl group), —NRb1—CO— (wherein Rb1 has the meaning given above), —NRb1—CO—O— (wherein Rb1 has the meaning given above), —CH2SO2— or —CH2S—, Ra′ is {circle over (1)} an aromatic hydrocarbon group which may be substituted by halogen(s), SO2NRb3Rb4 (wherein each of Rb3 and Rb4 is (1) a C1-6 alkyl group which may be substituted by 1) halogen(s), 2) hydroxyl(s) or 3) C1-6 alkoxy(s), (2) a C3-8 cycloalkyl group which may be substituted by 1) halogen(s), or 2) C1-6 alkoxy(s), (3) a C1-6 alkoxy group or (4) a hydrogen atom, or Rb3 and Rb4 may combine each other together with a nitrogen atom to form a cyclic-amino group), SO2Rb5 (wherein Rb5 is (1) a C1-6 alkyl group which may be substituted by halogen(s), hydroxyl(s) or C1-6 alkoxy(s), (2) a C3-8 cycloalkyl group which may be substituted by halogen(s) or C1-6 alkoxy(s)), CONRb3Rb4 (wherein Rb3 and Rb4 have the meanings given above) or —NRb7—SO2Rb6 (wherein Rb6 is (1) a C1-6 alkyl group which may be substituted by halogen(s) or C1-6 alkoxy(s), (2) a C3-8 cycloalkyl group which may be substituted by halogen(s) or C1-6 alkoxy(s), Rb7 is (1) a C1-6 alkyl group which may be substituted by halogen(s) or C1-6 alkoxy(s), (2) a C3-8 cycloalkyl group which may be substituted by halogen(s) or C1-6 alkoxy(s) or (3) a hydrogen atom), a C1-6 alkoxy group, an amino group which may be substituted by a C2-4 alkanoyl(s), nitro group, cyano group, tetrazolyl group or morpholinyl group or {circle over (2)} an aromatic heterocyclic group which may be substituted by substituent(s) selected from the above mentioned substituents of aromatic hydrocarbon group] or salt thereof.

A prodrug of a compound of the formula:

• 55
• (wherein R1 is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1 and R2 may combine each other together with A to form a heterocyclic group which may be substituted;
• A is N or N+—R5. Y− (R5 is a hydrocarbon group;
• Y− is a counter anion);
• R3is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
• n is 0 or 1;
• R4 is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group(s) other than oxo;
• G1 is a bond, CO or SO2;
• G2 is CO, SO2, NHCO, CONH or OCO;
• J is methine or a nitrogen atom;
• and each of Q and R is a bond or a divalent C1-3 aliphatic hydrocarbon which may be substituted;
• provided that J is methine when G2 is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo when G1 is a bond) or a salt thereof.

A pharmaceutical composition containing a compound represented by the formula:

• 56
• (wherein R1 is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2 is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1 and R2 may combine each other together with A to form a heterocyclic group which may be substituted;
• A is N or N+—R5. Y− (R5 is a hydrocarbon group;
• Y− is a counter anion);
• R3 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
• n is 0 or 1;
• R4 is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group(s) other than oxo;
• G1 is a bond, CO or SO2;
• G2 is CO, SO2, NHCO, CONH or OCO;
• J is methine or a nitrogen atom;
• and each of Q and R is a bond or a divalent C1-3 aliphatic hydrocarbon which may be substituted;
• provided that J is methine when G2 is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo when G1 is a bond), a salt thereof or a prodrug thereof.

A method for producing a compound of the formula:

• 57
• (wherein R1 is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2 is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1 and R2 may combine to each other together with A atom to form a heterocyclic group which may be substituted;
• A is N or N+—R5.Y− (R5 is a hydrocarbon group;
• Y− is a counter anion);
• R3 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
• n is 0 or 1;
• R4 is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group(s) other than oxo;
• G1 is a bond, CO or SO2;
• G2 is CO, SO2, or NHCO;
• J is methine or a nitrogen atom;
• and each of Q and R is a bond or a divalent C1-3 aliphatic hydrocarbon which may be substituted;
• provided that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo when G1 is a bond) or a salt thereof, which comprises reacting a compound of the formula:
• 58
• (wherein each symbol has the meaning given above) or a salt thereof with a compound of the formula:
• 59
• (wherein R6 is a carboxyl group, or sulfonic acid group or a salt thereof or a reactive derivatives thereof, and other symbols have the meanings given above) or a salt thereof.

A method for producing a compound of the formula:

• 60
• (wherein R1 is a hydrogen atom, a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, R2 is a hydrocarbon group which may be substituted, a non-aromatic heterocyclic group which may be substituted, or R1 and R2 may combine to each other together with A atom to form a heterocyclic group which may be substituted;
• A is N or N+—R5.Y− (R5 is a hydrocarbon group;
• Y− is a counter anion);
• R3 is a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;
• n is 0 or 1;
• R4 is a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an alkoxy group which may be substituted, an aryloxy group which may be substituted, or an amino group which may be substituted, E is a divalent aliphatic hydrocarbon group which may be substituted by group other than oxo;
• G1 is a bond, CO or SO2;
• G2 is CO, SO2, NHCO, CONH or OCO;
• J is methine or a nitrogen atom;
• and each of Q and R is a bond or a divalent C1-3 aliphatic hydrocarbon which may be substituted;
• provided that J is methine when G2 is OCO, that one of Q and R is not a bond when the other is a bond and that each of Q and R is not substituted by oxo when G1 is a bond) or a salt thereof, which comprises reacting a compound of the formula:
• 61
• (wherein x is a leaving group, and other symbols have the meanings given above) or a salt thereof with a compound of the formula:
• 62
• (wherein each symbol has the meaning given above) or a salt thereof or a compound of the formula:
• 63
• (wherein R5 is a hydrocarbon group, and other symbols have the meanings given above).