US 6,667,342 B1 · Benzenesulfonamide-derivatives and their use as medicaments

Abstract

Compounds of formula (I), pharmaceutically acceptable salts or in vivo hydrolysable esters thereof, wherein: Ring X is phenyl or a six membered heteroaryl ring containing one or two ring nitrogens where said nitrogens are optionally oxidised to form the N-oxide; R1 and R2 are substituents as defined within; R3 and R4 are defined within and are alkyl or halo alkyl or together form a halocycloalkyl ring; R5 is a substituent as defined within; Y—Z is a linking group as defined within; are useful in the production of a elevation of PDH activity in a warm-blooded animal such as a human being. Pharmaceutical compositions, methods and processes for preparation of compounds of formula (I) are described.

A compound of the formula (I):

wherein:
Ring X is phenyl;
R1 and R2 are independently as defined in (a) or (b);
R3 and R4 are as defined in (c) or (d);
R5 is as defined in (e) or (f);
Y—Z is as defined in (g) or (h)
wherein:
(a) either R1 and R2 are each selected independently from hydrogen, C1-3alkyl, pyridyl and phenyl which is unsubstituted or substituted by one or two substituents selected independently from C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano,
or R1 and R2 together with the nitrogen atom to which they are attached form morpholino, thiomorpholino, piperidinyl, pyrrolidinyl or imidazolyl;
(b) either R1 and R2 are each selected independently from phenyl substituted by one or more P (wherein P is as defined hereinbelow), phenyl substituted by one or more groups selected from C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano and additionally substituted by one or more groups selected from P, a heterocyclic group other than unsubstituted pyridyl which is optionally substituted on a ring carbon by one or more Q (wherein Q is as defined hereinbelow) and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), naphthyl optionally substituted by one or more Q, C4-6alkyl, C3-6cycloalkyl optionally substituted with one or more Q, C2-6alkenyl, C2-6alkynyl, C1-6alkyl substituted by one or more V (wherein V is as defined hereinbelow), R6T— (wherein R6 and T are as defined hereinbelow) and R7C1-6alkylT— (where R7 is as defined hereinbelow),
or R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group other than unsubstituted morpholino, unsubstituted thiomorpholino, unsubstituted piperidinyl, unsubstituted pyrrolidinyl or unsubstituted imidazolyl which is optionally substituted on a ring carbon by one or more Q (wherein Q is as defined hereinbelow) and wherein if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow);
(c) either R3 and R4 are independently Ckalkyl optionally substituted by from 1 to 2k+1 atoms selected from fluoro and chloro wherein k is 1-3, provided that R3 and R4 are not both methyl;
or R3 and R4 together with the carbon atom to which they are attached, form a Cmcycloalkyl ring optionally substituted by from 1 to 2m−2 fluorine atoms wherein m is 3-5;
(d) R3 and R4 are both methyl;
(e) R5 is C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, haloC1-4alkoxy, cyano, nitro, C2-4alkenyloxy or trifluoromethylthio;
(f) R5 is halo, hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(N—C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl(N—C1-6alkyl)amino, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-66alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, formyl, C1-6alkanoyl, C2-6alkenyl, C2-6alkynyl, C5-6alkyl, haloC5-6alkyl, C5-6alkoxy, haloC5-6alkoxy or C5-6alkenyloxy;
(g) Y—Z is —NHC(O)—, —OCH2—, —SCH2—, —NHCH2— or trans-vinylene;
(h) Y—Z is —NHC(S)—;
R6 is selected from C1-6alkyl (optionally substituted with one or more R8), C3-6cycloalkyl optionally substituted with one or more R8, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R7 is a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8;
R8 is trifluoromethyl, C1-6alkyl, halo, hydroxy, trifluoromethoxy, cyano, C1-6alkoxy, formyl, C1-6alkanoyl, C1-6alkanoyloxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(N—C1-6alkyl)amino, nitro, carboxy, carbamoyl, C1-6alkoxycarbonyl, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carbamoylC1-6alkyl, N-(C1-6alkyl)carbamoylC1-6alkyl, N-(C1-6alkyl)2carbamoyl-C1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxyC 16alkyl, phenylC1-6alkyl or phenylC1-6alkoxy;
P is selected from C2-6alkyl-M— substituted with one or more R9, C2-6alkenyl-M— optionally substituted with one or more R9, C2-6alkynyl-M— optionally substituted with one or more R9 (with the proviso that in the three previous groups R9 is not a substituent on the carbon atom attached to M), R10—CH2—M—, R11—M—, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, nitro, carboxy, C1-6alkoxycarbonyl, amino, C1-6alkylamino, (C1-6alkyl)2amino, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkanoylamino, C1-6alkanoyl(N—C1-6alkyl)amino, trifluoromethyl, trifluoromethoxy, formyl, C1-6alkanoyl, C5-6alkyl, C2-6alkenyl, C2-6alkynyl N-(C1-6alkyl)aminosulphonyl, hydroxymethyl, hydroxyacetyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkanoylaminosulphonyl, C1-6alkanoyl(N—C1-6alkyl)aminosulphonyl, C1-6alkylsulphonylaminocarbonyl, C1-6alkylsulphonyl(N—C1-6alkyl)aminocarbonyl, C5-6alkoxy, C5-6alkenyloxy, phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8 and a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow);
Q is selected from any of the values defined for P, C1-4alkyl, C1-4alkoxy, C2-4alkenyloxy, hydroxy, halo and cyano;
V is selected from any of the values defined for Q, phenyl optionally substituted by one or more Q, naphthyl optionally substituted by one or more Q, a heterocyclic group optionally substituted on a ring carbon by one or more Q and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinbelow) and C3-6cycloalkyl optionally substituted with one or more Q;
T is selected from —O—, —C(O)—, —NH—, —N(N—C1-6alkyl)—, —C(O)NH—, —NHC(O)—, —C(O)N(N—C1-6alkyl)—, —N(N—C1-6alkyl)C(O)—, —SO2—, —C(S)—, —C(S)NH—, —NHC(S)—, —C(S)N(N—C1-6alkyl)— and —N(N—C1-6alkyl)C(S)—;
M is selected from —O—, —N(R12)—, —C(O)—, —N(R12)C(O)—, —C(O)N(R12)—, —S(Q)n—, —OC(O)—, —C(O)O—, —N(R12)C(O)O—, —OC(O)N(R12)—, —C(S)N(R12)—, —N(R12)C(S)—, —SO2N(R12)—, —N(R12)SO2—, —N(R12)C(O)N(R12)—, —N(R12)C(S)N(R12)—, —SO2NHC(O)—, —SO2N(R12)C(O)—, —C(O)NHSO2— and —C(O)N(R12)SO2—, or M is a direct bond;
D is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, benzoyl, (heterocyclic group)carbonyl, phenylsulphonyl, (heterocyclic group)sulphonyl, phenyl and a carbon linked heterocyclic group, and wherein any C1-6alkyl group may be optionally substituted by one or more R9, and wherein any phenyl or heterocyclic group may be optionally substituted on a ring carbon by one or more groups selected from R8 and if a heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from E;
E is selected from C1-6alkyl, C1-6alkanoyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, carbamoyl, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, C1-6alkoxyC1-6alkanoyl, phenylC1-6alkyl, benzoyl, phenylC1-6alkanoyl, phenylC1-6alkoxycarbonyl and phenylsulphonyl;
R9 is selected from hydroxy, amino, C1-6alkylamino, (C1-6alkyl)2amino, carboxy, C1-6alkoxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, formyl, sulphamoyl, N—C1-6alkylaminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphonylamino, C1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R8, naphthyl optionally substituted by one or more R8, C1-6alkylsulphanyl, C1-6alkylsulphinyl and C1-6alkylsulphonyl;
R10 is carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, C1-6alkylsulphanyl, C1 6alkylsulphinyl, C1-6alkylsulphonyl, C1-6alkoxycarbonyl, C1-6alkanoylamino, a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R8 or naphthyl optionally substituted by one or more R8;
R11 is a heterocyclic group optionally substituted on a ring carbon by one or more R8 and if said heterocyclic group contains an —NH— moiety that nitrogen may be optionally substituted by a group selected from D (wherein D is as defined hereinabove), phenyl optionally substituted by one or more R8, C3-6cycloalkyl optionally substituted by one or more R8, or naphthyl optionally substituted by one or more R8;
R12 is hydrogen or C1-6alkyl optionally substituted with R13 with the proviso that R13 is not a substituent on the carbon attached to the nitrogen atom of M;
R13 is halo, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkylamino, (C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkanoyl(N—C1-6alkyl)amino, C1-6alkylsulphonylamino, C1-6alkylsulphonyl(N—C1-6alkyl)amino, thiol, C1-6alkylsulphanyl, C1-6alkylsulphinyl, C1-6alkylsulphonyl, sulphamoyl, N-(C1-6alkyl)aminosulphonyl, N-(C1-6alkyl)2aminosulphonyl, carboxy, carbamoyl, N-(C1-6alkyl)carbamoyl, N-(C1-6alkyl)2carbamoyl, C1-6alkoxycarbonyl, C1-6alkanoyl or formyl;
n is 0-2;
and
wherein a heterocyclic group is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH2— group can optionally be replaced by a —C(O)—, a ring nitrogen atom may optionally bear a C1-6alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides;
with the proviso that where R1 and R2 are both as defined in (a), R3 and R4 are both as defined in (c), R5 is as defined in (e) and Ring X is phenyl, then Y—Z must be —NHC(S)—;
or a pharmaceutically acceptable salt thereof,
and provided said compound is not 4-(3-hydroxy-3-methyl-1-butynyl)-N-(3-methyl-2-pyridinyl)-benzenesulphonamide, N-{4-[N,N-bis-(sec-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide or N-{4-[N,N-bis-(iso-butyl)aminosulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide.

36 more elements

Benzenesulfonamide-derivatives and their use as medicaments

Life of this patent

Benzenesulfonamide-derivatives and their use as medicaments

Life of this patent

Abstract

Claims11