Substituted n-(2-arylamino)aryl sulfonamide-containing combinations

A combination of:

• component A:
• one or more omega-carboxyaryl-substituted diphenyl urea compounds of general formula (I):
• A-D-B (I)
• wherein
• D is —NH—C(O)—NH—,
• A is a substituted moiety of up to 40 carbon atoms of the formula:
• -L-(M-L1)q, where L is a 5 or 6 membered cyclic structure bound directly to D, L1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3;
• and each cyclic structure of L and L1 contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and
• B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur,
• wherein L1 is substituted by at least one substituent selected from the group consisting of —SO2Rx, —C(O)Rx, and —C(NRy) Rz,
• Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo,
• Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
• Rx is Rz, or NRaRb where Ra and Rb are
• a) independently hydrogen,
• a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or
• —OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
• or
• b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
• or
• c) one of Ra or Rb is —C(O)—, a C1-C5 divalent alkylene group or a substituted C1-C5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C1-C5 divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;
• where B is substituted, L is substituted or L1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;
• wherein each W is independently selected from the group consisting of —CN, —CO2R7, —C(O)NR7R7, —C(O)—R7, —NO2, —OR7, —SR7, —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —OR7, —SR7, —NR7R7, —NO2, —NR7C(O)R7, —NR7C(O)OR7 and halogen up to per-halo;
• with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,
• wherein Q is O, S, N(R7)—, —(CH2)m, —C(O)—, —CH(OH)—, —(CH2)mO—, —(CH2)mS—, —(CH2)mN(R7)—, —O(CH2)m—CHXa—, —CXa2—, —S—(CH2)m— and —N(R7)(CH2)m—, where m=1-3, and Xa is halogen;
• and
• Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zn1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —CN, —CO2R7, —C(O)R7, —C(O)NR7R7, —NO2, —OR7, —SR7 —NR7R7, —NR7C(O)OR7, —NR7C(O)R7, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —CN, —CO2R7, —COR7, —C(O)NR7R7, —OR7, —SR7, —NO2, —NR7R7, —NR7C(O)R7, and —NR7C(O)OR7, with R7 as defined above, with the proviso that said compound of general formula (I) is not:
• or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
• optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially;
• and
• component B:
• one or more N-(2-arylamino) aryl sulfonamide compounds of general formula (II):
• where G is R1a, R1b, R1c, R1d, R1e, Ar1, Ar2 or Ar3;
• Ro is H, halogen, C1-C6 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, said alkyl, cycloalkyl, alkenyl, and alkynyl groups optionally substituted with 1-3 substituents selected independently from halogen, OH, CN, cyanomethyl, nitro, phenyl, and trifluoromethyl, and said C1-C6 alkyl and C1-C4 alkoxy groups also optionally substituted with OCH3 or OCH2CH3;
• X is F, Cl or methyl;
• Y is I, Br, Cl, CF3, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, phenyl, pyridyl, pyrazolyl, OMe, OEt, or SMe, where all said methyl, ethyl, C1-C3 alkyl, and cyclopropyl groups of X and Y are optionally substituted with OH, all said phenyl, pyridyl, pyrazolyl groups of Y are optionally substituted with halogen, acetyl, methyl, and trifluoromethyl, and all said methyl groups of X and Y are optionally substituted with one, two, or three F atoms;
• and Z is H or F,
• where R1a is methyl, optionally substituted with 1-3 fluorine atoms or 1-3 chlorine atoms, or with OH, cyclopropoxy, or C1-C4 alkoxy, where the C1-C4 alkyl moieties of said C1-C4 alkoxy groups are optionally substituted with one hydroxy or methoxy group, and where all C2-C4 alkyl groups within said C1-C4 alkoxy are optionally further substituted with a second OH group;
• R1b is CH(CH3)—C1-3 alkyl or C3-C6 cycloalkyl, said methyl, alkyl, and cycloalkyl groups optionally substituted with 1-3 substituents selected independently from F, Cl, Br, I, OH, C1-C4 alkoxy, and CN;
• R1c is (CH2)nOmR′, where m is 0 or 1;
• where, when m is 1, n is 2 or 3, and when m is 0, n is 1 or 2;
• and where R′ is C1-C6 alkyl, optionally substituted with 1-3 substituents selected independently from F, Cl, OH, OCH3, OCH2CH3, and C3-C6 cycloalkyl;
• R1d is C(A)(A′)(B)— where B, A, and A′ are, independently, H or C1-4 alkyl, optionally substituted with one or two OH groups or halogen atoms, or A and A′, together with the carbon atom to which they are attached, form a 3- to 6-member saturated ring, said ring optionally containing one or two heteroatoms selected, independently, from O, N, and S and optionally substituted with one or two groups selected independently from methyl, ethyl, and halo;
• R1e is benzyl or 2-phenyl ethyl, in which the phenyl group is optionally substituted
• where q is 1 or 2, R2, R3 and R4 are, independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3, OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, and methylsulfonyl, and R4 may also be nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, 5-methyl-1,3,4-thiadiazol-1H-tetrazolyl, N-morpholinyl carbonylamino, N-morpholinylsulfonyl, and N-pyrrolidinylcarbonylamino;
• R5 and R6 are, independently, H, F, Cl, or methyl;
• Ar1 is
• where U and V are, independently, N, CR2 or CR3;
• R2, R3 and R4 are, independently, H, F, Cl, Br, CH3, CH2F, CHF2, CF3, OCH3, OCH2F, OCHF2, OCF3, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, sec-butyl, tert-butyl, and methylsulfonyl, and R4 may also be nitro, acetamido, amidinyl, cyano, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, 1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol, 1,3,4-thiadiazol, 5-methyl-1,3,4-thiadiazol 1H-tetrazolyl, N-morpholinylcarbonylamino, N-morpholinylsulfonyl and N-pyrrolidinylcarbonylamino;
• R5 and R6 are, independently, H, F, Cl or methyl;
• Ar2 is
• where the dashed line represents a double bond which may be located formally either between V and the carbon between U and V, or between U and the carbon between U and V;
• where U is —S—, —O— or —N═ and where, when U is —O— or —S—, V is —CH═, —CCl═ or —N═;
• and when U is —N═, V CH═, or —NCH3—;
• R7 and R8 are, independently, H, methoxycarbonyl, methylcarbamoyl, acetamido, acetyl, methyl, ethyl, trifluoromethyl, or halogen.
• Ar3 is
• where U is —NH—, —NCH3— or —O—;
• and R7 and R8 are, independently, H, F, Cl, or methyl;
• or a physiologically acceptable salt, solvate, hydrate or stereoisomer thereof;
• optionally in the form of a pharmaceutical formulation which is ready for use to be administered simultaneously, concurrently, separately or sequentially;
• and, optionally,
• component C:
• one or more further pharmaceutical agents.