Non peptidic renin inhibitors nitroderivatives

A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

• A1-(Xa—ONO2)j (I)
• wherein:
• j is an integer equal to 1, 2, or 3;
• A1 is selected from the group consisting of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik) and (Il):
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• Y and Z represent independently from each other hydrogen (H);
• —F;
• -Me group;
• or Y and Z may together form a cyclopropyl ring;
• in case k represents the integer 1, Y and Z both represent hydrogen;
• X represents —(CH2)mN1(L)(CH2)m—;
• —CH2CH(K)CH2—;
• —CH2CH2—;
• —CH2OCH2—;
• —CH2SCH2—;
• —CH2SOCH2—;
• —CH2SO2CH2—;
• —CON(L)CO—;
• CON(L)CHR6—;
• —CHR6—N(L)CO—;
• W represents a six-membered, non benzofused, phenyl or heteroaryl ring, substituted by V in position 3 or 4;
• V represents a bond;
• —(CH2)r—;
• -A-(CH2)s—;
• —CH2-A-(CH2)t—;
• (CH2)-A-;
• —(CH2)2-A-(CH2)u-;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• A-(CH2)2—B—CH2—;
• —CH2-A-(CH2)2—B—;
• —(CH2)3-A-(CH2)0—;
• —(CH2)4-A-CH2—;
• -A-(CH2)2—B—(CH2)2—;
• —CH2-A-CH2—CH2—B—CH2—;
• —CH2-ACH2—CH2-CH2—B—;
• —CH2—CH2-A-CH2—CH2—B—;
• —O—CH2—CH(OCH3)—CH2—O—;
• —O—CH2—CH(CH3)—CH2—O—;
• —O—CH2—CH(CF3)—CH2—O—;
• —O—CH2—C(CH3)2 CH2—O—;
• —O—CH2—C(CH3)2—O—;
• —O—C(CH3)2—CH2—O—;
• —O—CH2—CH(CH3)2O—;
• —O—CH(CH3)—CH2—O—;
• —O—CH2—C(CH2—CH2)—O—;
• —O—C(CH2—CH2)—CH2—O—;
• A and B represent —O—;
• —S—;
• —SO—;
• —SO2—;
• U represents aryl;
• heteroaryl;
• T represent —CONR1;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —COO—;
• Q represents lower alkylene;
• lower alkenylene;
• M represents aryl-O(CH2)vR5;
• heteroaryl-O(CH2)vR5;
• aryl-O(CH2)vO(CH2)wR5;
• heteroaryl-(CH2)vO(CH2)wR5;
• aryl-OCH2CH(R7)CH2R5;
• heteroaryl-OCH2CH(R7)CH2R5;
• wherein heteroayl means preferably a lower alkyl substituted pyridyl;
• L represent —R3;
• —COR3;
• —CO2R3;
• —CONR2R3;
• —SO2R3;
• —SO2NR2R3;
• COCH(aryl)2;
• K represents hydrogen;
• —CH2OR3;
• —CH2NR2R3;
• —CH2NR2COR3;
• CH2NR2SO2R3;
• —CO2R3;
• —CH2OCONR2R3;
• —CONR2R3;
• —CH2NR2COR2R3;
• CH2SO2NR2R3;
• —CH2SR3;
• —CH2SOR3;
• —CH2SO2R3;
• R1 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl, cycloalkyl-lower alkyl;
• R2 and R2′ independently represent hydrogen, lower alkyl;
• lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl;
• R3 represents hydrogen, lower alkyl;
• lower alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl, heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy, —OCOR2, —COOR2, lower alkoxy, cyano, —CONR2R2′, CO-morpholin-4-yl, —CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• COOR2;
• —CONH2;
• R5 represents —O—;
• —OH, lower alkoxy, —OCOR2, —CO2R2, NR2R2′, OCONR2R2′, NCONR2R2′, cyano, —CONR2R2′, SO3H, —SONR2R2′;
• —CO-morpholin-4-yl, —CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH2, NR4R4′ with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• when R5 is —O—, it is bound to one group —Xa—ONO2;
• R6 represents hydrogen, lower alkyl;
• lower alkoxy;
• whereby these groups may be unsubstituted or monosubstituted with hydroxy, —CONH2, —COON, imidazolyl,—NH2,—CN, —NH(NH)NH2;
• R7 represents —O—;
• —OH, OR2, OCOR2, OCOOR2;
• or R6 and R5 form together with the carbon atoms to which they are attached a 1,3-dioxolane ring which is substituted in position 2 with R2 and R2′;
• or R6 and R5 form together with the carbon atoms to which they are attached a 1,3-dioxolan-2-one ring;
• when R7 is —O—, it is bound to one group —Xa—ONO2;
• k represents the integer 0 or 1;
• m and n represent the integer 0 or 1 with the proviso that in case m represents the integer 1, n is the integer 0;
• in case n represents the integer 1, m is the integer 0;
• in case k represents the integer 0, n represents the integer 0;
• in case X does not represent —CH2)m—N(L)-(CH2)m—, n represents the integer 0;
• p, t and v independently represent the integer 1, 2, 3 or 4;
• r represents the integer 1, 2, 3, 4, 5 or 6;
• s represents the integer 1, 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• w represents the integer 1 or 2;
• wherein
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• X and W represent a nitrogen atom or a —CH— group;
• V represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t-;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2-;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• A and B represent independently —O—;
• —S—;
• —SO—;
• —SO2—;
• U represents aryl;
• heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene or alkenylene;
• M represents aryl-O(CH2)vR7—;
• heteroaryl-O(CH2)vR7;
• aryl-O(CH2)vO(CH2)wR7;
• heteroaryl-(CH2)vO(CH2)wR7;
• aryl-OCH2CH(R6)CH2R5—;
• heteroaryl-OCH2CH(R6)CH2R5—;
• L when x is 1 represents —R3;
• —COR3;
• —COOR3;
• —CONR2R3;
• —SO2R3;
• —SO2NR2R3;
• COCH(Aryl)2;
• R1 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• or lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• R2 and R2′ independently represent hydrogen, lower alkyl;
• lower alkenyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• R3 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• cycloalkyl-lower alkyl;
• aryl-lower alkyl;
• heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl;
• heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy;
• —OCOR2;
• —COOR2;
• lower alkoxy;
• cyano;
• —CONR2R2′;
• —CO-morpholin-4-yl;
• —CO-((4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• COOR2;
• —CONH2;
• R5 represents —O—;
• —OH;
• lower alkoxy;
• —OCOR2;
• —COOR2;
• —NR2R2′;
• —OCONR2R2′;
• —NCONR2R2′;
• cyano;
• —CONR2R2′;
• —SO3H;
• —SONR2R2′;
• —CO-morpholin-4-yl;
• —CO-(4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• when R5 is —O—, it is bound to one group —Xa—ONO2;
• R6 represents —O—;
• —OH;
• OR2;
• OCOR2;
• OCOOR2;
• or R6 and R5 form together with the carbon atoms to which they are attached a 1,3-dioxolane ring which is substituted in position 2 with R2 and R2′;
• or R6 and R5 form together with the carbon atoms to which they are attached a 1,3-dioxolan-2-one ring;
• when R6 is —O—, it is bound to one group —Xa—ONO2;
• R7 represents lower alkoxy;
• m and n represent the integer 0 or 1, with the proviso that in case m represents the integer 1, n is the integer 0, and in case n represents the integer 1, m is the integer 0;
• p, t, and v represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• w represents the integer 1 or 2;
• x and z represent the integer 0 or 1;
• wherein:
• —N1- is a nitrogen atom bound to one group —Xa—ONO2;
• X and W represent a nitrogen atom or a —CH— group;
• V represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t-;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• A and B represent independently —O—;
• —S—;
• —SO—;
• —SO2—;
• U represents aryl;
• heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene;
• lower alkenylene;
• M represents hydrogen;
• cycloalkyl;
• aryl;
• heterocyclyl;
• heteroaryl;
• L represents —R3;
• —COR3;
• —COOR3;
• —CONR2R3;
• —SO2R3;
• —SO2NR2R3;
• COCH(Aryl)2;
• R1 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• R2 and R2′ independently represent hydrogen, lower alkyl;
• lower alkenyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• R3 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• cycloalkyl-lower alkyl;
• aryl-lower alkyl;
• heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl;
• heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy;
• —OCOR2;
• —COOR2;
• lower alkoxy;
• cyano;
• —CONR2R2′;
• —CO-morpholin-4-yl;
• —CO-((4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• —COOR2;
• —CONH2;
• m and n represent the integer 0 or 1, with the proviso that in case m represents the integer 1, n is the integer 0, and in case n represents the integer 1, m is the integer 0;
• p and t represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• Y, Z represent independently hydrogen, F, or o methyl group;
• or Y and Z may together form a cyclopropyl ring;
• X represents —CH2CH(K)CH2—, —CH2CH2—, —CH2OCH2—;
• —CH2SCH2—, —CH2SOCH2—, —CH2SO2CH2—, —CO—NL-CHR6—;
• —CHR6—NL-CO—;
• W represents a six membered non benzofused phenyl, or heteroaryl ring substituted by V in position 3 or 4;
• V represents a bond, represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t-;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—, —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• —O—CH2—CH(OCH3)—CH2—O—;
• —O—CH2—CH(CH3)—CH2—O—;
• —O—CH2—CH(CF3)—CH2—O—;
• —O—CH2—C(OCH3)2—CH2—O—;
• —O—CH2—C(CH3)2—CH2—O—;
• —O—CH2—C(CH3)2—O—;
• —OC(CH3)2—O—;
• —O—CH2—CH(CH3)—O—;
• —O—CH(CH3)CH2—O—;
• —O—CH2—C(CH2CH2)—O—;
• —O—C(CH2CH2)—CH2—O—;
• A and B independently represent —O—, —S—, —SO—, —SO2—;
• U represents aryl, heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene, lower alkenylene;
• M represents aryl-O(CH2)vR5, heteroaryl-O(CH2)vR5, aryl-OCH2CH2O(CH2)wR5;
• heteroaryl-OCH2CH2O(CH2)wR5;
• L represents —R3;
• —COR3;
• —COOR3;
• —CONR2R3;
• —SO2R3;
• —SO2NR2R3;
• COCH(Aryl)2;
• K represents hydrogen;
• —CH2OR3;
• —CH2NR2R3;
• —CH2NR2COR3;
• —CH2NR2SO2R3;
• —CO2R3;
• —CH2OCONR2R3;
• —CONR2R3;
• —CH2NR2COR2R3;
• —CH2SO2NR2R3;
• —CH2SR3;
• —CH2SOR3;
• —CH2SO2R3;
• R1 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl, cycloalkyl-lower alkyl;
• R2 and R2′ independently represent hydrogen, lower alkyl, lower alkenyl, cycloalkyl, cycloalkyl-lower alkyl;
• R3 represents hydrogen, lower alkyl;
• lower alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl, heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy, —OCOR2, —COOR2, lower alkoxy, cyano, —CONR2R2′, —CO-morpholin-4-yl, —CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• —COOR2;
• —CONH2;
• R5 represents —O—;
• —OH, —OCOR2, —CO2R2, —NR2R2′, —OCONR2R2′, NCONR2R2′, cyano, —CONR2R2′, SO3H, —SONR2R2′;
• —CO-morpholin-4-yl, —CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH2, —NR4R4′ with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• when R5 is —O—, it is bound to one group —Xa—ONO2;
• R6 represents hydrogen, lower alkyl;
• lower alkoxy;
• whereby these groups may be unsubstituted or monosubstituted with hydroxy, —CONH2, —COOH, imidazolyl,—NH2,—CN, —NH(NH)NH2;
• p and t independently represent the integer 1, 2, 3 or 4;
• r represents the integer 1, 2, 3, 4, 5 or 6;
• s represents the integer 1, 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• w represents the integer 1 or 2;
• wherein:
• —N1- is a nitrogen atom bound to one group —Xa—ONO2;
• X and W represent a nitrogen atom or a —CH— group;
• V represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• A and B represent independently —O—;
• —S—;
• —SO—;
• —SO2—;
• U represents aryl;
• heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• (CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene or alkenylene;
• M represents aryl-O(CH2)vR5—;
• heteroaryl-O(CH2)vR5;
• aryl-O(CH2)2O(CH2)wR5;
• heteroaryl-(CH2)2O(CH2)wR5;
• L represents —R3;
• —COR3;
• —COOR3;
• —CONR2R3;
• —SO2R3;
• —SO2NR2R3;
• COCH(Aryl)2;
• R1 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• or lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• R2 and R2′ independently represent hydrogen, lower alkyl;
• lower alkenyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• R3 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• cycloalkyl-lower alkyl;
• aryl-lower alkyl;
• heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl;
• heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy;
• —OCOR2, —COOR2;
• lower alkoxy;
• cyano;
• —CONR2R2′;
• —CO-morpholin-4-yl;
• —CO-((4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• —COOR2;
• —CONH2;
• R5 represents —O—;
• —OH;
• —OCOR2;
• —COOR2;
• —NR2R2′;
• —OCONR2R2′;
• —NCONR2R2′;
• cyano;
• —CONR2R2′;
• —SO3H;
• —SONR2R2′;
• —CO-morpholin-4-yl;
• —CO-((4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• when R5 is —O—, it is bound to one group —Xa—ONO2;
• m1 and n1 represent the integer 0 or 1, with the proviso that in case m1 represents the integer 1,
• n1 is the integer 0, and in case n1 represents the integer 1, m1 is the integer 0;
• p, t, represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• w represents the integer 1 or 2;
• x represents the integer o or 1;
• z represents the integer 0 or 1;
• if z is the integer 0, n1 is the integer 1;
• wherein:
• —N1- is a nitrogen atom bound to one group —Xa—ONO2;
• X and Y independently represent hydrogen, —F, or a methyl group;
• X and Y do not represent both hydrogen at the same time or X and Y may together form a cyclopropyl ring;
• W represents a phenyl or heteroaryl ring, the heteroaryl ring being a six-membered and non-fused ring, the phenyl ring and the heteroaryl ring are substituted with V in position 3 or 4;
• V represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2-B—;
• —CH2—CH2-A-CH2CH2B—;
• —O—CH2—CH(OCH3)—CH2—O—;
• —O—CH2-CH(CH3)—CH2—O—;—O—CH2—CH(CF3)—CH2—O—;
• —O—CH2—C(CH3)2—CH2—O—;
• —O—CH2—C(CH3)2—O—;
• —O—C(CH3)2—CH2—O—;
• —O—CH2—CH(CH3)—O—;
• —O—CH(CH3)CH2—O—;
• —O—CH2—C(CH2CH2)—O—;
• —O—C(CH2CH2)—CH2—O—;
• U represents aryl, heteroaryl;
• A and B independently represent —O—, —S—, —SO—, —SO2—;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• —(CH2)pOCO—NR1;
• —(CH2)pN(R2)CO—NR1—
• R1 and R2 independently represent hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl-lower alkyl;
• heteroaryl-lower alkyl;
• cycloalkyl-lower alkyl;
• Q represents lower alkylene, lower alkenylene;
• M represents hydrogen;
• cycloalkyl;
• aryl;
• heterocyclyl or heteroaryl;
• p and t independently represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• Z, Y, X and W represent independently a nitrogen atom, or a —CH— group;
• at least two of the Z, Y, X and W represent a —CH— group;
• V represents a bond;
• —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• A and B represent independently —O—;
• —S—;
• —SO—;
• —SO2—;
• U represents aryl;
• heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene or alkenylene;
• M represents hydrogen;
• cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• L when k is 1 represents —R3;
• —COR3;
• —COOR3;
• —CONR2R3;
• —SO2R3;
• —SO2NR2R3;
• COCH(Aryl)2;
• R1 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• or lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• R2 and R2′ independently represent hydrogen, lower alkyl;
• lower alkenyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• R3 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• cycloalkyl;
• aryl;
• heteroaryl;
• heterocyclyl;
• cycloalkyl-lower alkyl;
• aryl-lower alkyl;
• heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl;
• heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy;
• —OCOR2;
• —COOR2;
• lower alkoxy;
• cyano;
• —CONR2R2′;
• —CO-morpholin-4-yl;
• —CO-((4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• —COOR2;
• —CONH2;
• k represents the integer 0 or 1;
• m and n represent the integer 0 or 1, with the proviso that in case m represents the integer 1, n is the integer 0, and in case n represents the integer 1, m is the integer 0;
• p and t represent the integer 1, 2, 3 or 4;
• r represents the integer 1, 2, 3, 4, 5 or 6;
• s represents the integer 1, 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• wherein:
• —N1- is a nitrogen atom bound to one group —Xa—ONO2;
• W is a six-membered non benzofused phenyl, or heteroaryl ring substituted by V in position 3 or 4;
• V represents a bond, represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t-;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• —O—CH2—CH(OCH3)—CH2—O—;
• —O—CH2—CH(CH3)—CH2—O—;
• —O—CH2—CH(CF3)—CH2—O—;
• —O—CH2—C(CH3)2—CH2—O—;
• —O—CH2—C(CH3)2—O—;
• —O—C(CH3)2—CH2—O—;
• —O—CH2—CH(CH3)—O—;
• —O—CH(CH3)CH2—O—;
• —O—CH2—C(CH2CH2)—O—;
• —O—C(CH2CH2)—CH2—O—;
• A and B independently represent —O—, —S—, —SO—, —SO2—;
• U represents aryl, heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene, lower alkenylene;
• M represents hydrogen;
• cycloalkyl;
• aryl, hetrocyclyl;
• heteroaryl;
• aryl-O(CH2)vR5, heteroaryl-O(CH2)vR5, aryl-OCH2CH2O(CH2)wR5;
• heteroaryl-OCH2CH2O(CH2)wR5;
• L represents hydrogen;
• —CH2OR3;
• —CH2NR2R3;—CH2—NR2COR3;
• —CH2NR2SO2R3;
• —COOR3;
• —CH2OCONR2R3;
• —CONR2R3;
• —CH2NR2CONR2R3;
• —CH2SO2NR2R3;
• —CH2SR3;
• —CH2SOR3;
• —CH2SO2R3;
• R1 represents hydrogen;
• lower alkyl;
• lower alkenyl;
• lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• R2 and R2′ represent independently hydrogen;
• lower alkyl;
• lower alkenyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• R3 represents hydrogen, lower alkyl;
• lower alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl-lower alkyl, aryl-lower alkyl, heteroaryl-lower alkyl;
• heterocyclyl-lower alkyl;
• aryloxy-lower alkyl, heteroaryloxy-lower alkyl, whereby these groups may be unsubstituted, or mono, di-or trisubstituted with hydroxy, —OCOR2, —COOR2, lower alkoxy, cyano, —CONR2R2′, —CO-morpholin-4-yl, —CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• —COOR2;
• —CONH2;
• R5 represents —O—;
• —OH, —OCOR2, —CO2R2, —NR2R2′, —OCONR2R2′, —NCONR2R2′, cyano, —CONR2R2′, SO3H, —SONR2R2′;
• —CO-morpholin-4-yl, —CO-((4-loweralkyl)piperazin-1-yl), —NH(NH)NH2, —NR4R4′with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• when R5 is —O—, it is bound to one group —Xa—ONO2;
• p and t independently represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• w represents the integer 1 or 2;
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• W is a six-membered non benzofused phenyl, or heteroaryl ring substituted by V in position 3 or 4;
• V represents a bond, represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• —O—CH2—CH(OCH3)—CH2—O—;
• —O—CH2—CH(CH3)—CH2—O—;
• —O—CH2—CH(CF3)-CH2—O—;
• —O—CH2-C(CH3)2—CH2—O—;
• —O—CH2—C(CH3)2—O—;
• —O—C(CH3)2—CH2—O—;
• —O—CH2—CH(CH3)—O—;
• —O—(CH3)CH2—O—;
• —O—CH2—C(CH2CH2)—O—;
• —O—C(CH2CH2)—CH2—O—;
• A and B independently represent —O—, —S—, —SO—, —SO2—;
• U represents aryl, heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene, lower alkenylene;
• M represents hydrogen;
• cycloalkyl;
• aryl;
• heterocyclyl;
• heteroaryl;
• R1 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl, cycloalkyl-lower alkyl;
• p and t independently represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• X and W represent a nitrogen atom or a —CH— group;
• V represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• A and B represent independently —O—;
• —S—;
• —S(O)—;
• —S(O)2—;
• U represents aryl;
• heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• —(CH2)pOCONR1—;
• —(CH2)pN(R1′)CONR1—;
• Q represents lower alkylene;
• lower alkenylene;
• M represents hydrogen, cycloalkyl;
• aryl;
• heterocyclyl;
• heteroaryl;
• aryl-O(CH2)vR2—;
• heteroaryl-O(CH2)vR2;
• aryl-O(CH2)2O(CH2)wR2;
• heteroaryl-(CH2)2O(CH2)wR2;
• aryl-OCH2CH(R5)CH2R2;
• heteroaryl-OCH2CH(R5)CH2R2;
• R1 and R1′ independently represent hydrogen;
• lower alkyl;
• lower alkenyl;
• or lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• R2 represents —O—;
• —OH;
• lower alkoxy;
• —OCOR3;
• —COOR3;
• —NR3R3′;
• —OCONR3R3′;
• —NCONR3R3′;
• cyano;
• —CONR3R3;
• —SO3H;
• —CO-morpholin-4-yl;
• —CO-((4-loweralkyl)piperazin-1-yl);
• —NH(NH)NH2, —NR4R4′ or lower alkyl with the proviso that a carbon atom is attached at the most to one heteroatom in case this carbon atom is sp3-hybridized;
• when R2 is —O—, it is bound to one group —Xa—ONO2;
• R3 and R3′ represent independently hydrogen;
• lower alkyl;
• lower alkenyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• R4 and R4′ independently represent hydrogen;
• lower alkyl;
• cycloalkyl;
• cycloalkyl-lower alkyl;
• hydroxy-lower alkyl;
• COOR2;
• —CONH2;
• R5 represents —O—;
• —OH;
• —OR2;
• —OCOR2;
• —OCOOR2;
• or R5 and R2 form together with the carbon atoms to which they are attached a 1, 3 dioxalane ring which is substituted in position 2 with R3 and R3′;
• or R5 and R2 form together with the carbon atoms to which they are attached a 1, 3 dioxola-2-one ring;
• when R5 is —O—, it is bound to one group —Xa—ONO2;
• p, t, represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• w represents the integer 1 or 2;
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• X represents —O—, —S—, —SO—, —SO2—;
• W is a six-membered non benzofused phenyl, or heteroaryl ring substituted by V in position 3 or 4;
• V represents a bond, represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• —O—CH2—CH(OCH3)—CH2—O—;
• —O—CH2—CH(CH3)—CH2—O—;
• —O—CH2—CH(CF3)—CH2—O—;
• —O—CH2—C(CH3)2—CH2—O—;
• —O—CH2—C(CH3)2—O—;
• —O—C(CH3)2—CH2—O—;
• —O—CH2—CH(CH3)—O—;
• —O—CH(CH3)CH2—O—;
• —O—CH2—C(CH2CH2)—O—;
• —O—C(CH2CH2)—CH2—O—;
• A and B independently represent —O—, —S—, —SO—, —SO2—;
• U represents aryl, heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• Q represents lower alkylene, lower alkenylene;
• M represents hydrogen, cycloalkyl, aryl;
• heterocycyl;
• heteroaryl;
• R1 represents hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl, cycloalkyl-lower alkyl;
• p and t independently represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• wherein:
• —N1— is a nitrogen atom bound to one group —Xa—ONO2;
• X and W represent independently a nitrogen atom or a —CH— group;
• V represents —(CH2)r;
• -A-(CH2)s;
• —CH2-A-(CH2)t—;
• —(CH2)s-A-;
• —(CH2)2-A-(CH2)u—;
• -A-(CH2)v—B—;
• —(CH2)3-A-CH2—;
• -A-CH2CH2—B—CH2—;
• —CH2-A-CH2CH2—B—;
• —(CH2)3-A-CH2—CH2—;
• —(CH2)4-A-CH2—;
• -A-CH2CH2—B—CH2—CH2—;
• —CH2-A-CH2CH2—B—CH2—;
• —CH2-A-CH2—CH2—B—;
• —CH2—CH2-A-CH2CH2B—;
• A and B independently represent —O—, —S—, —SO—, —SO2—;
• U represents aryl, heteroaryl;
• T represents —CONR1—;
• —(CH2)pOCO—;
• —(CH2)pN(R1)CO—;
• —(CH2)pN(R1)SO2—;
• —CO2—;
• —(CH2)pOCONR1—;
• —(CH2)pN(R1′)CONR1—;
• Q represents lower alkylene, lower alkenylene;
• M represents hydrogen;
• cycloalkyl;
• aryl;
• heterocycyl;
• heteroaryl;
• R1 and R1′ represent independently hydrogen;
• lower alkyl;
• lower alkenyl;
• lower alkynyl;
• cycloalkyl;
• aryl;
• cycloalkyl-lower alkyl;
• p and t independently represent the integer 1, 2, 3 or 4;
• r represents the integer 3, 4, 5 or 6;
• s represents the integer 2, 3, 4 or 5;
• u represents the integer 1, 2 or 3;
• v represents the integer 2, 3 or 4;
• Xa is equal to —Xb—Ya— wherein Xb is —CO— or —COO—;
• Ya is a bivalent radical having the following meaning:
• a)
• straight or branched C1-C2O alkylene, preferably C1-C10, being optionally substituted with one or more of the substituents selected from the group consisting of:
• halogen atoms, hydroxy, —ONO2 or Ta, wherein Ta is —OC(O)(C1-C10 alkyl)-ONO2 or —O(C1-C10 alkyl)-ONO2;
• -cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains Tb, wherein Tb is straight or branched alkyl with from 1 to 10 carbon atoms, preferably CH3;
• b)
• c)
• wherein n0 is an integer from 0 to 20, and n1 is an integer from 1 to 20;
• d)
• wherein:
• n1 is as defined above and n2 is an integer from 0 to 2;
• Xc══—OCO— or —COO— and R2 is H or CH3;
• e)
• wherein:
• n1, n2,R2 and Xc are as defined above;
• Yb is —CH2—CH2— or —CH═CH—(CH2)n2-;
• f)
• wherein:
• n1 and R2 are as defined above, R3 is H or —COCH3;
• with the proviso that when Ya is selected from the bivalent radicals mentioned under b)-f), the —ONO2 group is linked to a —(CH2)n1 group;
• g)
• wherein Xd is —O— or —S—, n3 is an integer from 1 to 6, preferably from 1 to 4, R2 is as defined above;
• h)
• wherein:
• n4 is an integer from 0 to 10;
• n5 is an integer from 1 to 10;
• R4, R5, R6, R7 are the same or different, and are H or straight or branched C1-C4 alkyl, preferably R4, R5, R6, R7are H;
• wherein the —ONO2 group is linked to
• wherein n5 is as defined above;
• Yc is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting in: