US 2004/0009979 A1 · Use of compounds for the elevation of pyruvate dehydrogenase activity

Abstract

The use of compounds of formula (I), and salts thereof; and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (I); and pharmaceutically acceptable salts of said compound or said prodrugs; in formula (I), Ring C is phenyl or a carbon linked heteroaryl ring substituted as defined within; R1 is an ortho substituent as defined within; n is 1 or 2; A-B is a linking group as defined within; R2 and R3 are as defined within; R4 is hydroxy, hydrogen, halo, amino or methyl; in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans is described. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are also described. 1

The use of compounds of the formula (1):

42
wherein:
ring C is as defined in (a) or (b);
R1 is as defined in (c) or (d);
n is 1 or2;
R2 and R3 are as defined in (e) or (f);
A-B is as defined in (g) or (h) and
R4 is as defined in (i) or (j)
wherein
(a) ring C is phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
wherein said phenyl or heteroaryl is substituted on carbon at one or both positions meta to the position of A-B attachment or on carbon at the position para to the position of A-B attachment by P1 or p2 (wherein P1 and p2 are as defined hereinafter), and further, wherein said phenyl or heteroaryl is optionally substituted on carbon at any remaining meta position(s) or para position by P1 or P3, (wherein P1 and P3 are as defined hereinafter);
(b) ring C is selected from the following five groups:
(i) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is unsubstituted except by (R1)n wherein R1 and n are as defined hereinafter;
(ii) a carbon-linked triazine optionally substituted on a ring carbon at a position meta or para to A-B attachment by 1 substituent selected from P1, p2, p3 and p4, wherein P1, p2, p3 and P4 are as defined hereinafter;
(iii) a 6-membered carbon-linked heteroaryl group containing 1-3 nitrogen atoms wherein one or more ring nitrogen atoms are oxidised to form the N-oxide, which heteroaryl group is optionally substituted at any of the positions meta or para to A-B attachment by 1-3 substituents selected from P1, P2, P3 and P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
(iv) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is substituted at a position meta or para to A-B attachment by 1 substituent selected from P3 and P4, wherein P3 and P4 are as defined hereinafter;
and
(v) phenyl or carbon-linked heteroaryl selected from pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein said phenyl or heteroaryl is substituted at any of the positions meta or para to A-B attachment by 2-3 substituents selected from P1, P2, P3 and P4, provided that if one or more of the substituents is P1 or P2 then at least one of the other substituents is P4, wherein P1, P2, P3 and P4 are as defined hereinafter;
P1 is cyano, trifluoromethyl, nitro, trifluoromethoxy or trifluoromethylsulphanyl;
P2 is —Y1Ar1, wherein Ar1 is selected from the group consisting of phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is optionally substituted at carbon, with 1-4 substituents selected from Q1, wherein Q1 is as defined hereinafter;
and Y1 is selected from —CO—, —SO— and —SO2—;
P3 is C1-4alkyl, haloC2-4alkyl, C1-4alkoxy, haloC2-4alkoxy, C2-4alkenyloxy, halo or hydroxy;
P4 is selected from the following eight groups:
1) halosulphonyl, cyanosulphanyl;
2) —X1—R5 wherein X1 is a direct bond, —O—, —S—, —SO—, —SO2—, —OSO2—, —SO2O—, —NR6—, —N+O−R6—, —CO—, —COO—, —OCO—, —CONR7—, —NR8CO—, —OCONR9—, —CONR10SO2—, —NR11SO2—, —CH2—, —NR12COO—, —CSNR13—, —NR14CS—, —NR15CSNR16—, NR17CONR18— or —NR19CONR20SO2— (wherein R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R5 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl with the proviso that P4 is not trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
3) —X1—C1-6alkyl-X2—R21 wherein X1 is as defined hereinbefore, X2 is a direct bond, —O—, —S—, —SO—, —SO2—, —OSO2—, —SO2O—, —NR22—, —N+O−R22—, —CO—, —COO—, —OCO—, —CONR23—, —NR24CO—, —NR25COO—, —SO2NR26—, —NR27SO2—, —CH2—, —SO2NR28CO—, —OCONR29—, —CSNR+—, —NR−CS—, —NR32CSNR33—, —NR34CONR35—, —CONR36SO2—, —NR37CONR38SO2—, —SO2NR39CONR40— or —SO2NR39CNNR40— (wherein R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39 and R40, each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be as defined hereinbefore;
optionally substituted by one or more groups selected from hydroxy, amino halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R21 is hydrogen or C1-4alkyl which C1-4alkyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl or R21 is R41 wherein R41 is phenyl or a 4-12 membered heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S which heterocylic moiety may be aromatic or non-aromatic and which phenyl or heterocylic moiety is optionally substituted by 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter with the proviso that P4 is not C1-4alkyl, haloC1-4alkyl, C1-4alkoxy or haloC1-4alkoxy:
4) —X1—C2-6alkenyl-X2—R21 wherein X1, X2 and R21 are as defined hereinbefore with proviso that P4 is not C2-4alkenyloxy;
5) —X1—C2-6alkynyl-X2—R21 wherein X1, X2 and R21 are as defined hereinbefore:
6) —X1—C3-7cycloalkyl-X2—R21 wherein X1, X2 and R21 are as defined hereinbefore;
7) —X1—C1-6alkylC3-7cycloalkyl-X2—R21 wherein X1, X2 and R21 are as defined hereinbefore;
and
8) —Y2Ar2 wherein Y2 is X1 wherein X1 is as defined hereinbefore and Ar2 is selected from the following six groups:
(i) phenyl, a carbon-linked 6-membered heteroaryl ring containing 1-2 nitrogen atoms and a carbon-linked 5-membered heteroaryl ring containing 1-2 heteroatoms selected independently from O, N and S, wherein said phenyl or heteroaryl ring is substituted at carbon, with 1-4 substituents selected from Q1 and Q2 including at least one substituent selected from Q2 wherein Q1 and Q2 are as defined hereinafter;
(ii) a carbon-linked triazine or a carbon-linked 5-membered heteroaryl ring containing 3-4 heteroatoms selected independently from O, N and S;
wherein said heteroaryl ring is optionally substituted with 1-4 substituents selected from Q1 and Q2 wherein Q1 and Q2 are as defined hereinafter;
(iii) a 4-12 membered non-aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S wherein said heterocyclic moiety is optionally substituted with 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter, with the proviso that if Ar2 is a nitrogen linked heterocyclic ring Y2 is not —SO2—;
(iv) a 5-membered heteroaryl ring containing 1-4 heteroatoms selected independently from O, N and S, which heteroaryl ring contains at least one nitrogen atom substituted by a group selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, benzoyl or phenylsulphonyl and which heteroaryl ring is optionally substituted by 1-3 substituents selected from Q3 wherein Q3 is as defined hereinafter;
(v) a carbon linked 7-12 membered aromatic heterocyclic moiety containing 1-4 heteroatoms selected independently from O, N and S wherein said heterocyclic moiety is optionally substituted with 1-6 substituents selected from Q3 wherein Q3 is as defined hereinafter;
and
(vi) Ar1 with the proviso that if Ar2 has a value Ar1 then Y2 is not —CO—, —SO— or —SO2—;
Q1 is C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C2-alkenyloxy, cyano, nitro, halo or trifluoromethylsulphanyl;
Q2 is selected from the following ten groups:
1) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
2) halosulphonyl, cyanosulphanyl;
3) —X3—R5 wherein X3 is a direct bond, —O—, —S—, —SO—, —SO2—, —OSO2—, —SO2O—, —NR42—,—N+O−R42—, —CO—, —COO—, —OCO—, —CONR43—, —NR44CO—, —NR45COO—, —SO2NR46—, —NR47SO2—, —CH2—, —SO2NR48CO—, —OCONR49—, —CSNR50—, —NR51CS—, —NR52CSNR53—, —NR54CONR55—, —CONR56SO2—, —NR57CONR58SO2—, —SO2NR57CNNR58— or —SO2NR59CONR60— (wherein R42, W43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55 R56, R57, R58, R59, and R60 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R5 is as defined hereinbefore but with the proviso that Q2 is not trifluoromethylsulphanyl, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
4) R41 wherein R41 is as defined hereinbefore;
5) —X3—C1-6alkyl-X2—R21 wherein X3, X2 and R21 are as defined hereinbefore but with the proviso that Q2 is not C1-4alkyl, haloC1-4alkyl, C1-4alkoxy or haloC1-4alkoxy;
6) —X3-C2-6alkenyl-X2—R21 wherein X3, X2 and R21 are as defined hereinbefore but with the proviso that Q2 is C2-4alkenyloxy;
7) —X3—C2-6alkynyl-X2—R21 wherein X3, X2 and R21 are as defined hereinbefore;
8) —X3—C3-7cycloalkyl-X2—R21 wherein X3, X2 and R21 are as defined hereinbefore;
9) —X3—C1-6alkylC3-7cycloalkyl-X2—R21 wherein X3, X2 and R21 are as as defined hereinbefore;
and
10) —X3—R41 wherein R41 and X3 are as defined hereinbefore;
Q3 is selected from the following four groups:
1) oxygen (forming an oxo group when linked to a ring carbon and forming an N-oxide when a ring nitrogen is oxidised);
2) cyano, nitro or halo;
3) halosulphonyl, cyanosulphanyl;
and
4) —X4—R61 wherein X4 is a direct bond, —O—, —S—, —SO—, —SO2—, —OSO2—, —SO2O—, —NR62—, —N+O−R62—, —CO—, —COO—, —OCO—, —CONR63—, —NR64CO—, —NR65COO—, —SO2NR66—, —NR67SO2—, —CH2—, —SO2NR68CO—, —OCONR69—, —CSNR70—, —NR71CS—, —NR72CSNR73—, —NR74CONR75—, —CONR76SO2—, —NR77CONR78SO2—, —SO2NR79CNNR80— or —SO2NR79CONR80— (wherein R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79 and R80 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R61 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl;
(c) R1 is linked to ring C at a carbon ortho to the position of A-B attachment and is selected from the group consisting of C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, C2-4alkenyloxy, cyano, nitro, halo, trifluoromethylsulphanyl and hydroxy;
(d) R1 is linked to ring C at a ring carbon atom ortho to the position of A-B attachment and is selected from the following two groups:
1) —X5—R81 wherein X5 is a direct bond, —O—, —S—, —SO—, —SO2—, —OSO2—, —SO2O—, —NR82—, —CO—, —COO—, —OCO—, —CONR83—, —NR84CO—, —NR85COO—, —SO2NR86—, —NR87SO2—, —CH2—, —SO2NR88CO—, —OCONR89—, -CSNR90—, —NR91CS—, —NR92CSNR93—, —NR94CONR95—, —CONR96SO2—, —NR97CONR98SO2—, —SO2NR99CNNR100— or —SO2NR99CONR100— (wherein R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99 and R100 each independently represents hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R81 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl and C2-6alkynyl which C1-4alkyl, C3-7cycloalkyl, C2-6alkenyl or C2-6alkynyl is optionally substituted with one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy and hydroxyC1-6alkyl with the proviso that R1 is not trifluoromethylsulphanyl, hydroxy, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy or C2-4alkenyloxy;
and
2) —X6—R101 wherein X6 is selected from a direct bond, —CO—, —O—, —OCH2—, —S—, —SO—, —SO2— and —NR102 (wherein R102 is hydrogen or C1-4alkyl which C1-4alkyl may be optionally substituted by one or more groups selected from hydroxy, amino, halo, C1-4alkoxycarbonyl, carboxy, C1-6alkoxy or C1-3alkylsulphanyl) and R101 is phenyl which is optionally substituted by 1-4 substituents selected from cyano, nitro, trifluoromethylsulphanyl, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, C2-6alkenytoxy, halo, hydroxy and amino;
n is 1 or 2;
(e) either R2 and R3 are independently C1-3alkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, provided that R2 and R3 are not both methyl;.
or R2 and R3, together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring optionally substituted by from 1 to 2m−2 fluorine atoms wherein m is the number of carbon atoms in said ring;
(f) R2 and R3 are both methyl or one of R2 and R3 is hydrogen or halo and the other is halo or C1-3alkyl optionally substituted by from 1 to 2k+l atoms selected from fluoro and chloro wherein k is the number of carbon atoms in the said C1-3alkyl, with the proviso that when either R2 or R3 is halo R4 is not hydroxy and with the proviso that when either R2 or R3 is hydrogen, R4is not hydrogen;
(g) A-B is selected from —NHCO—, —OCH2—, —SCH2—, —NHCH2—, trans-vinylene, and ethynylene;
(h) A-B is —NHCS— or —COCH2—;
(i) R4 is hydroxy;
(j) R4 is hydrogen, halo, amino or methyl;
but excluding compounds wherein ring C is selected from (a) and R1 is selected only from (c) and R2 and R3 are selected from (e) and A-B is selected from (g) and R4 is selected from (i);
and salts thereof;
and pharmaceutically acceptable in vivo cleavable prodrugs of said compound of formula (1);
and pharmaceutically acceptable salts of said compound or said prodrugs;
in the manufacture of a medicament for use in the elevation of PDH activity in warm-blooded animals such as humans.

75 more elements

Use of compounds for the elevation of pyruvate dehydrogenase activity

Life of this patent

Use of compounds for the elevation of pyruvate dehydrogenase activity

Life of this patent

Abstract

Claims17