Claims
- 1. A compound of formula wherein m, n and p are each independently 0 or 1 and q is 0, 1, 2, 3, 4 or 5; * indicates an asymmetric carbon atom which can be R or S; —A1═A2—A3═A4— is a bivalent radical of formula —N═CH—CH═CH— (a-1) —CH═N—CH═CH— (a-2) —CH═CH—CH═N— (a-3) —CH═CH—N═N— (a-4) —N═CH—N═CH— (a-5) —N═CH—CH═N— (a-6); B is a bivalent radical of formula D is Ar1 or Het1; Q is a direct covalent bond or a bivalent radical of formula wherein X1 and X2 are each independently S or O, t is 0, 1 or 2; X3 is independently S, O or NR26; X4 and X5 are each independently N or CH, L is Ar1 or Het1; R1 is selected from hydrogen, halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(3-6)cycloalkylC(1-6)alkyl, C(3-6)cycloalkyloxy, haloC(1-6)alkyl, cyano, guanidine, nitro and NR17R18; p1 R2 and R3 are each independently selected from hydrogen, halo, C(1-6)alkyloxy and C(1-6)alkyl where the alkyl moiety may be optionally substituted by one or more hydroxy; R4 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl and C(3-6)cycloalkenyl; R5, R6, R9 and R10 are each independently selected from hydrogen, hydroxy, halo, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, cyano, (C═O)R25, (C═O)OR16, (SO2)R16, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1; or R5 and R6 or R9 and R10 together with the carbon atom to which they are attached, form a Het1 or a C(2-14)carbocyclic radical optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy and heterocycle selected from the group consisting of indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl; R7 and R8 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, hydroxyC(1-6)alkyl and C(1-6)alkyloxy; R11 is selected from hydrogen, hydroxy and C(1-6)alkyloxy; R12 is selected from hydrogen and hydroxy; R13 is selected from hydrogen, hydroxy, halo, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, aminocarbonyloxy, aminoC(1-6)alkyl, NR17R18, N3, Ar1 and Het1; R14 and R15 are each independently selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(6-14)arylC(1-6)alkyl, (C═O)R16, (C═O)OR16, (C═S)R16, (SO2)R16, Ar1 and Het1; or R14 and R15 together with the N atom to which they are attached, form a heterocycle selected from the group consisting of indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl optionally substituted by 1, 2 or 3 substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl and C(1-6)alkyloxy, C(6-14)arylthio, C(6-14)aryloxy, cyano, (C═O)R16, (C═O)OR16, (SO2)R16, NR17R18, Ar1 and Het1; R16 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, NR17R18, C(6-14)aryloxy, Ar1 or Het1; R17 and R18 are each independently selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, (C═O)R19, (SO2)R19, Ar1 and Het1; or R17 and R18 together with the N atom to which they are attached, form a heterocycle selected from the group consisting of indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl optionally substituted by 1, 2 or 3 substituents independently selected from hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, NR20R21, (C═O)R19, (═NH), S—Ar1, Ar1 and Het1; R19 is selected from C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, phenyloxy, NR20R21, Ar1 and Het1; R20 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, NH(C═O)R22 and C(1-6)alkyloxy; R21 is selected from hydrogen, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(1-6)alkyloxycarbonyl, Ar1 and Het1; Ar1 is a C(6-14)aryl (or C(6-14)arylidene when D is Ar1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy and heterocycle selected from the group consisting of indanyl, pyridinyl, tetrahydropyridinyl, isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl; Het1 is a heterocycle selected from the group consisting of indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl (or heterocyclidene selected from the group consisting of a bivalent radical of indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl when D is Het1) optionally substituted by one or more substituents independently selected from halo, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, cyano, (═O), (═NH), (C═O)R22, (SO2)R22, NH(C═O)R22, NR23R24, C(6-14)aryl, C(6-14)arylthio, C(6-14)aryloxy and heterocycle selected from the group consisting of indanyl, pyridinyl, tetrahydropyridinyl isothiazolyl, pyrrolyl, triazolylphenyl, piperidinyl, thiazolyl, piperazinyl, isoxazolyl, pyrazolyl, morpholinyl, imidazolyl, oxadiazolyl, dioxolanyl, pyrimidinyl, dihydropyrimidinyl, oxazolidinyl, benzimidazolyl, benzothiazolyl, benzodioxolanyl, benzopyridinyl, benzopyranyl, furanyl, thionyl, triazospirodecanyl, isoquinolinyl and tetrazolyl; R22 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(1-6)alkyloxy, haloC(1-6)alkyl, NR23R24 and R23 and R24 are each independently selected from hydrogen, C(1-6)alkyl and R25 is selected from hydrogen, hydroxy, C(1-6)alkyl, C(2-6)alkenyl, C(2-6)alkynyl, C(3-6)cycloalkyl, C(3-6)cycloalkenyl, C(1-6)alkyloxy, C(6-14)aryloxy, Ar1 and Het1; R26 is selected from hydrogen, C(1-6)alkyl and phenyl; or a N-oxide, addition salt, quaternary amine or stereochemically isomeric form thereof.
- 2. A compound according to claim 1 wherein Q is a bivalent radical of formula (c-1), (c-2), (c-3), (c-4), (c-5), (c-6), (c-7), (c-8), (c-9), (c-10), (c-11) or (c-12).
- 3. A compound according to claim 1 wherein B is a group of formula (b-2).
- 4. A compound according to claim 1 wherein —A1═A2—A3═A4— is a radical of formula (a-1).
- 5. A compound according to claim 1 wherein groups R1, R2, R3 and R4 are hydrogen.
- 6. A compound according to claim 1 wherein m and n are 0 and p is 0 or 1.
- 7. A compound according to claim 1 wherein D is a phenylidene moiety, optionally substituted with halo or pyridinylidene.
- 8. A compound according to claim 1 wherein L is a phenyl, optionally substituted with one or more substituents independently selected from halo, C(1-3)alkyloxy, C(1-3)alkyl (wherein the alkyl moiety may be optionally substituted with one or more halo substituents), NR23R24 (wherein R23 and R24 are independently selected from hydrogen and C(1-3)alkyl), (C═O)R22 (wherein R22 is NR23R24 (wherein R23 and R24 are independently selected from hydrogen and C(1-3)alkyl)), (SO2)R22 (wherein R22 is C(1-6)alkyl or halo C(1-6)alkyl) and NH(C═O)R22 (wherein R22 is or naphtalenyl or Het1.
- 9. A compound according to claim 1 wherein Q is a bivalent radical of formula (c-1), (c-2), (c-3), (c-4), (c-5), (c-6), (c-7), (c-8), (c-9) or (c-10).
- 10. A compound according to claim 1 whereinB is a group of formula (b-2); —A1═A2—A3═A4— is a radical of formula (a-1); groups R1, R2, R3 and R4 are hydrogen; m and n are 0 and p is 0 or 1; D is phenylidene (wherein the phenylidene moiety may be optionally substituted with halo); L is phenyl (wherein the phenyl moiety may be optionally substituted with one or more substituents independently selected from halo, C(1-3)alkyloxy, C(1-3)alkyl, (SO2)R22 (wherein R22 is C(1-3)alkyl (wherein the alkyl moiety may be optionally substituted with one or more halo), R22 is trifluoromethyl), NH(C═O)R22 (wherein R22 is and Het1;Q is a bivalent radical of formula (c-1), (c-3), (c-4), (c-5), (c-7) or (c-10).
- 11. A compound according to claim 1 selected fromN-(4-benzoylphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; (B)-N-(4-benzoylphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; (E)-4,5-dihydro-N-[4-[(hydroxyimino)phenylmethyl]phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide; 4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide; [5S(B)]-4,5-dihydro-N-[4-(hydroxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide; 4,5-dihydro-N-[4-(phenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide; N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; [5S(A)]-N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; N-[4-(cyanophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; 4,5-dihydro-N-[(4-(4-methoxybenzoyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide; 4,5-dihydro-N-[((4-methoxyphenylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide; 4,5-dihydro-3-(3-pyridinyl)-N-[4-[[2-pyridinylmethyl)amino]carbonyl]phenyl]-5-isoxazolecarboxamide (±)-[cyano-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]-phenyl]phenylmethyl]acetate (±)-(E)-4,5-dihydro-N-[4-(1-oxo-3-phenyl-2-propenyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (±)-N-[4-(3,4-dimethoxybenzoyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; (±)-N-[4-(2,4-difluorobenzoyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; (±)-N-[4-(4,5-dihydro-1-methyl-3-phenyl-1H-pyrazol-5-yl)phenyl-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; (±)-N-[4-[(2,4-difluorophenyl)hydroxymethyl]phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide; (B)-4,5-dihydro-3-(3-pyridinyl)-N-[4-(2-pyridinylcarbonyl)phenyl]-5-isoxazolecarboxamide; (B2)-4,5-dihydro-N-[4-(hydroxy-2-pyridinylmethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide.
- 12. A composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as claimed in claim 1.
- 13. A process for preparing a compound of formula (I) or a N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof as claimed in claim 1, characterized by,a.) reacting an intermediate of formula (II) wherein W1 is C(1-3)alkyloxy, hydroxy or a halogen atom, with an appropriate reagent of formula (III), in a reaction inert solvent and optionally in the presence of a suitable base; wherein R2, R3, R4, D, Q, L, m, n and p are as defined in claim 1, and Z represents wherein —A1═A2—A3═A4—, q and R1 are as defined in claim 1;b.) a 1,3-dipolar addition between a compound of formula wherein Z is as defined in part a.) above, and a compound of formula wherein B is (b-1), (b-2) or (b-3) and (b-1), (b-2), (b-3), D, Q, L, R2, R3, m, n and p are as defined in claim 1, in a reaction inert solvent and in the presence of a base;c.) a cyclization of a compound of formula and D, Q, L, R2, R3, m, n and p are as defined in claim 1 and Z is as defined in part a.) above, in a reaction inert solvent;d.) reacting an intermediate of formula (XVII) wherein W4 is a suitable leaving group with a compound of formula (XVIII), in a reaction-inert solvent in the presence of a catalyst; wherein B, D, L, R2, R3, m, n and p are as defined in claim 1 and Z is as defined in part a.) above;e.) reacting an intermediate of formula wherein W6 is hydroxy or a halogen atom, and B, D, L, R2, R3, m and n are as defined in claim 1 and Z is as defined in part a.) above, with an appropriate functional primary or secondary amine derivative in a reaction inert solvent and in the presence of a suitable base;and where necessary or desired, any one or more of the following further steps in any order may be performed:(i) removing any remaining protecting group(s); (ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or a protected form thereof; (iii) converting a compound of formula (I) or a protected form thereof into a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof; (iv) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof into a compound of formula (I) or a protected form thereof; (v) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof into another N-oxide, a pharmaceutically acceptable addition salt a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof; where the compound of formula (I) is obtained as a mixture of (R) and (S) enantiomers resolving the mixture to obtain the desired enantiomer.
- 14. A new method for the treatment of T cell mediated diseases comprising administering an effective amount of a compound of formula (I) or a N-oxide, pharmaceutically acceptable addition salt, quaternary amine or stereochemically isomeric form thereof as defined in claim 1.
- 15. A method for the treatment of conditions selected from rheumatic diseases, systemic inflammatory diseases, T cell leukemia, transplant rejection and graft versus host disease comprising administering to a host in need thereof an effective amount of a compound of formula I or a N-oxide, pharmaceutically acceptable addition salt, quarternary amine or stereochemically isomeric form thereof as defined in claim 1.
Priority Claims (1)
Number |
Date |
Country |
Kind |
98203394 |
Oct 1998 |
EP |
|
CROSS REFERENCE TO RELATED APPLICATIONS
This application is the national stage filing of PCT Application No. PCT/EP99/07803, filed Oct. 7, 1999 which application claims priority from EPO application No. 98203394.6, filed Oct. 9, 1998.
PCT Information
Filing Document |
Filing Date |
Country |
Kind |
PCT/EP99/07803 |
|
WO |
00 |
Publishing Document |
Publishing Date |
Country |
Kind |
WO00/21959 |
4/20/2000 |
WO |
A |
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
5814627 |
Schwab et al. |
Sep 1998 |
A |
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