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US 6,528,533 B2Granted
Azo amino acids derivatives
AssigneeVertex Pharmaceuticals Incorporated
InventorsDavid Lauffer, Michael Mullican
Life of this patent
Estimating the term…
Abstract
The present invention relates to azo amino acid derivatives for treating or preventing neuronal damage associated with neurological diseases. The invention also provides compositions comprising the compounds of the present invention and methods of utilizing those compositions for treating or preventing neuronal damage.
Claims12
A compound having formula (I):
- or a pharmaceutically acceptable salt thereof, wherein:
- one of A and B is a (C1-C10)-straight or branched alkyl substituted with pyridine or a (C2-C10)-straight or branched alkenyl or alkynyl substituted with pyridine;
- and
- the other of A and B (C1-C10)-straight or branched alkyl substituted with phenyl or a (C2-C10)-straight or branched alkenyl or alkynyl substituted with phenyl;
- X is NR1;
- R1 is E, (C1-C10)-straight or branched alkyl, (C2-C10)-straight or branched alkenyl or alkynyl, or (C5-C7)-cycloalkyl or cycloalkenyl;
- wherein 1 or 2 hydrogen atoms in said alkyl, alkenyl or alkynyl are optionally and independently replaced with E, (C5-C7)-cycloalkyl or cycloalkenyl;
- and wherein 1 to 2 of the —CH2— groups in said alkyl, alkenyl, or alkynyl groups is optionally and independently replaced by —O—, —S—, —S(O)—, —S(O)2—, ═N—, —N═ or —N(R3)—;
- or R1 is hydrogen;
- wherein R3 is selected from hydrogen, (C1-C4)-straight or branched alkyl, (C3-C4)-straight or branched alkenyl or alkynyl, or (C1-C4) bridging alkyl, wherein a bridge is formed between the nitrogen atom to which said R3 is bound and any carbon atom of said alkyl, alkenyl or alkynyl to form a ring, and wherein said ring is optionally benzofused;
- wherein E is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, O or S;
- and wherein no more than 4 ring atoms are selected from N, O or S;
- wherein 1 to 4 hydrogen atoms in E are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O—[(C1-C6)-straight or branched alkyl], O—[(C3-C6)-straight or branched alkenyl], (CH2)n—N(R4)(R5), (CH2)n—NH(R4)—(CH2)n—Z, (CH2)n—N(R4—(CH2)n—Z)(R5—(CH2)n—Z), (CH2)n—Z, O—(CH2)n—Z, (CH2)n—O—Z, S—(CH2)n—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C1-C6)-straight or branched alkyl], C(O)O—(CH2)n—Z or C(O)—N(R4)(R5);
- wherein each of R4 and R5 are independently hydrogen, (C1-C6)-straight or branched alkyl, (C3-C5)-straight or branched alkenyl, or wherein R4 and R5, when bound to the same nitrogen atom, are taken together with the nitrogen atom to form a 5 or 6 membered ring, wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from N, O or S;
- wherein said alkyl, alkenyl or alkynyl groups in R4 and R5 are optionally substituted with Z,
- each n is independently 0 to 4;
- each Z is independently selected from a saturated, partially saturated or unsaturated, monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 ring atoms independently selected from C, N, O or S;
- and
- wherein no more than 4 ring atoms are selected from N, O or S;
- wherein 1 to 4 hydrogen atoms in Z are optionally and independently replaced with halo, hydroxy, nitro, cyano, C(O)OH, (C1-C3)-straight or branched alkyl, O—(C1-C3)-straight or branched alkyl, C(O)O—[(C1-C3)-straight or branched alkyl], amino, NH[(C1-C3)-straight or branched alkyl], or N—[(C1-C3)-straight or branched alkyl]2;
- J is selected from hydrogen, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl or alkynyl, or cyclohexylmethyl, wherein 1 to 2 hydrogen atoms in said alkyl, alkenyl or alkynyl is optionally and independently replaced with E;
- K is (C1-C10)-straight or branched alkyl substituted with phenyl or a (C2-C10)-straight or branched alkenyl or alkynyl substituted with phenyl;
- wherein J and K are optionally and independently substituted with up to 3 substituents selected from halogen, OH, O—(C1-C6)-alkyl, O—(CH2)n—Z, NO2, C(O)OH, C(O)—O—(C1-C6)-alkyl, C(O)NR4R5, NR4R5 and (CH2)n—Z;
- G, when present, is —S(O)2—, —C(O)—, —S(O)2—Y—, —C(O)—Y—, —C(O)—C(O)—, or —C(O)—C(O)—Y—;
- Y is oxygen, or N(R6);
- wherein R6 is hydrogen, E, (C1-C6)-straight or branched alkyl, (C3-C6)-straight or branched alkenyl or alkynyl;
- or wherein R6 and D are taken together with the atoms to which they are bound to form a 5 to 7 membered ring system wherein said ring optionally contains 1 to 3 additional heteroatoms independently selected from O, S, N, NH, SO, or SO2;
- and wherein said ring is optionally benzofused;
- D is a saturated, partially saturated or unsaturated, or aromatic monocyclic or bicyclic ring system, wherein each ring comprises 5 to 7 carbon ring atoms;
- wherein 1 to 4 hydrogen atoms in D are optionally and independently replaced with halogen, hydroxyl, hydroxymethyl, nitro, SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6)-straight or branched alkyl, (C2-C6)-straight or branched alkenyl, O—[(C1-C6)-straight or branched alkyl], O—[(C3-C6)-straight or branched alkenyl], (CH2)n—N(R4)(R5), (CH2)n—NH(R4)—(CH2)n—Z, (CH2)n—N(R4—(CH2)n—Z)(R5—(CH2)n—Z), (CH2)nZ, O—(CH2)n—Z, (CH2)n—O—Z, S—(CH2)n—Z, CH═CH—Z, 1,2-methylenedioxy, C(O)OH, C(O)O—[(C1-C6)-straight or branched alkyl], C(O)O—(CH2)n—Z or C(O)—N(R4)(R5);
- m is 0 to 3;
- and
- x is 0 or 1;
- provided that when J is hydrogen or G is selected from S(O)2—, C(O)C(O)—, SO2—Y, C(O)—Y, or C(O)C(O)—Y, wherein Y is O;
- then D is not hydrogen.
32 more elements
A compound selected from Table A below:
- TABLE A Compd. No. A B R1 J G 134 phenylpropyl (pyrid-3-yl)-propyl H CH3 —CH2— 135 phenylpropyl (pyrid-3-yl)-propyl H CH3 —C(O)— 136 phenylpropyl (pyrid-3-yl)-propyl H CH3 —C(O)—O—CH2— 137 phenylpropyl (pyrid-3-yl)-propyl H CH3 —C(O)—C(O)— 141 phenylpropyl (pyrid-3-yl)-propyl H benzyl —CH2— 142 phenylpropyl (pyrid-3-yl)-propyl H benzyl —C(O)— 143 phenylpropyl (pyrid-3-yl)-propyl H benzyl —C(O)—O—CH2— 144 phenylpropyl (pyrid-3-yl)-propyl H benzyl —C(O)—C(O)— 148 phenylpropyl (pyrid-3-yl)-propyl CH3 benzyl —CH2— 149 phenylpropyl (pyrid-3-yl)-propyl CH3 Benzyl —C(O)— 150 phenylpropyl (pyrid-3-yl)-propyl CH3 benzyl —C(O)—O—CH2— 151 phenylpropyl (pyrid-3-yl)-propyl CH3 Benzyl —C(O)—C(O)— 155 phenylpropyl (pyrid-3-yl)-propyl CH3 CH3 —CH2— 156 phenylpropyl (pyrid-3-yl)-propyl CH3 CH3 —C(O)— 157 phenylpropyl (pyrid-3-yl)-propyl CH3 CH3 —C(O)—O—CH2— 158 phenylpropyl (pyrid-3-yl)-propyl CH3 CH3 —C(O)—C(O)—.
Dependencies are inferred from the claim text.