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US 6,787,554 B2Granted
Triazolo[4,3-a]pyrido[2,3-d]pyrimidin-5-one derivatives
AssigneeWarner-Lambert Company
InventorBernard Gaudillière
Life of this patent
Estimating the term…
Abstract
The invention relates to triazolo[4,3-a]pyrido[2,3-d]pyrimidine-5-one derivatives, their regioisomers, their salts and their solvates if they exist, their preparation, compositions containing them and their use. These derivatives possess properties inhibiting PDE4 and/or the release of TNFα, and may therefore be used for the treatment or prevention of numerous conditions by virtue of the inhibition of the PDE4 enzyme and the resulting increase in the cAMP level.
Claims18
A compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- X is hydrogen, hydroxy, halo, nitro, mercapto, cyano, carboxy, (C1-C6)alkyl, (C1-C6) alkoxy, (C1-C6)alkylthio, C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, —NR3R4, —(N—A)n—C(O)—Q1—Q2—Q3 or a 3 to 10 membered azacycloalkyl;
- said alkyl, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl in the definition of X being optionally substituted independently with up to three halo atoms;
- said azacycloalkyl in the definition of X further optionally being bridged by (C1-C6)alkylenyl;
- said azacycloalkyl in the definition of X being optionally gem-dialkylated or independently substituted with up to three hydroxy, oxo, (C1-C6)alkyl, (C1-C6)alkoxy or —C(O)—Q1—Q2—Q3;
- R is (C1-C6)alkyl;
- (C1-C6)alkenyl;
- 2-pyridyl(C1-C6)alkyl;
- 3-pyridyl(C1-C6)alkyl;
- 4-pyridyl(C1-C6)alkyl, said pyridyls being optionally substituted independently by up to three (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halo or amino;
- or a radical of the formula
- R1 and R2 are taken separately, are different, and are (C1-C6)alkyl, aralkyl, (C3-C10) cycloalkyl or (C3-C10)cycloalkyl-(C1-C6)alkyl;
- or
- R1 and R2 are taken separa ely, are identical and are (C1-C6)alkyl;
- or
- R1 and R2 are taken together, with the nitrogen atom to which they are attached, to form a 3 to 7 membered azacycloalkyl;
- said azacycloalkyl in the definition of R1 and R2 being optionally bridged by (C1-C6)alkylenyl and optionally gem-dialkylated or substituted with up to three hydroxy, oxo, (C1-C6)alkyl, (C1-C6) alkoxy, phenyl-(C1-C6)alkyl or —C(O)—Q1—Q2—Q3
- R3 and R4 are independently hydrogen;
- (C1-C6)alkyl optionally substituted with up to three halo, hydroxy, cyano or (C1-C6)alkoxy;
- R5-carbonyl;
- or (C3-C10) cycloalkyl-(C0-C4) alkylenyl optionally substituted with a hydroxy, (C1-C6)alkoxy, mercapto, (C1-C6) alkylthio, amino, N—(C1-C6)alkylamino, di- N—(C1-C6)alkylamino or (C1-C4)alkyl;
- R5 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy, (C1-C6)alkoxy, mercapto or (C1-C6)alkylthio;
- n is 0 or 1;
- A is independently hydrogen or —C(O)—Q1—Q2—Q3;
- Q1 is independently —O—, —NH—, —N(Q2—Q3)— or
- Q2 is independently (C0-C4)alkylenyl or —(CH2CH2—O)r;
- Q3 is independently hydrogen, hydroxy, methoxy, —O—C(O)—X1, —NHX2 or —N(X1)X2;
- p and p′ are independently , 0, 1, 2 or 3;
- Z is independently —CH— or —N—;
- r is independently 2, 3 or 4;
- X1 and X2 are taken separately and are independently (C1-C6)alkyl;
- or
- X1 and X2 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered azacycloalkyl
- s is 1, 2, 3 or 4;
- Ar is a 5- or 6-membered aryl;
- Y1, Y2 and Y3 are independently hydrogen, hydroxy, mercapto, amino, nitro, halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, —C(O)R6, —C(O)OR6, —C(O)NR6R7,—NR6R7, —(CH2)1CN or —(CH2)1—C(O)—Q1—Q2—Q3;
- said (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl and (C1-C6)alkylsulfonyl being optionally substituted independently with up to three halo atoms;
- t is independently 0, 1 or 2;
- and
- R6 and R7 are taken separately and are independently hydrogen or (C1-C6)alkyl;
- or
- R6 and R7 are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered azacycoalkyl.
39 more elements
A compound of Formula II,
- or a pharmaceutically acceptable salt thereof, wherein:
- X is hydrogen, hydroxy, halo, nitro, mercapto, cyano, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6))alkylsulfinyl, (C1-C6)alkylsulfonyl, —NR3R4, —(N—A)n—C(O)—Q1—Q2—Q3 or a 3 to 10 membered azacycloalkyl;
- said alkyl, alkoxy, alkylthio, alkysulfinyl and alkylsulfonyl in the definition of X being optionally substituted independently with up to three halo;
- said azacycloalkyl in the definition of X further optionally being bridged by (C1-C6)alkylenyl;
- said azacycloalkyl in the definition of X being optionally gem-dialkylated or independently substituted with up to three hydroxy, oxo, (C1-C6)alkyl, (C1-C6)alkoxy or C(O)—Q1—Q2—Q3;
- R1 and R2 are taken separately, are different, and are (C1-C6)alkyl, aralkyl, (C3-C10) cycloalkyl or (C3-C10)cycloalkyl-(C1-C6)alkyl;
- or
- R1 and R2 are taken separately, are identical and are (C1-C6)alkyl;
- or
- R1 and R2 are taken together, with the nitrogen atom to which they are attached, to form a 3 to 7 membered azacycloalkyl;
- said azacycloalkyl in the definition of R1 and R2 being optionally bridged by (C1-C6)alkylenyl and optionally gem-dialkylated or substitut with up to three hydroxy, oxo, (C1-C6)alkyl, (C1-C6) alkoxy, phenyl-(C1-C2)alkyl or —C(O)—Q1—Q2—Q3;
- R3 and R4 are independently hydrogen;
- (C1-C6)alkyl optionally substituted independently with up to three halo, hydroxy, cyano or (C1-C6)alkoxy;
- R5-carbonyl;
- or (C3-C10)cycloalkyl-(C0-C4)alkylenyl optionally substituted independently with a hydroxy, (C1-C6)alkoxy, mercapto, (C1-C6)alkylthio, amino, N—(C1-C6)alkylamino, di- N—(C1-C6)alkylamino or (C1-C6)alkyl;
- R5 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy, (C1-C4)alkoxy, mercapto or (C1-C6)alkylthio;
- n is 0 or 1;
- A is independently hydrogen or —C(O)—Q1—Q2—Q3;
- Q1 is independently —O—, —NH—, —N(Q2—Q3)— or
- Q2 is independently (C0-C4)alkylenyl or —(CH2CH2—O)r;
- Q3 is independently hydrogen, hydroxy, methoxy, —O—C(O)—X1, —NHX2 or —N(X1)X2;
- p and p′ are independently , 0, 1, 2 or 3;
- Z is independently —CH— or —N—;
- r is independently 2, 3 or 4;
- and
- X1 and X2 are taken separately and are independently (C1-C6)alkyl;
- or
- X1 and X2 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered azacycoalkyl.
25 more elements
A compound of the Formula IV
- or a pharmaceutically acceptable salt thereof, wherein:
- X is hydrogen, hydroxy, halo, nitro, mercapto, cyano, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, —NR3R4, —(N—A)n—C(O)—Q1—Q2—Q3or a 3 to 10 membered azacycloalkyl;
- said alkyl, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl in the definition of X being optionally substituted independently with up to three halo;
- said azacycloalkyl in the definition of X further optionally being bridged by (C1-C6)alkylenyl;
- said azacycloalkyl in the definition of X being optionally gem-dialkylated or independently substituted with up to three hydroxy, oxo, (C1-C6)alkyl, (C1-C6)alkoxy or —C(O)—Q1—Q2—Q3;
- R3 and R4 are independently hydrogen;
- (C1-C6)alkyl optionally substituted independently with up to three halo, hydroxy, cyano or (C1-C6)alkoxy;
- R5-carbonyl;
- or (C3-C10)cycloalkyl-(C0-C4)alkylenyl optionally substituted independently with a hydroxy, (C1-C6)alkoxy, mercapto, (C1-C6)alkylthio, amino, N—(C1-C6)alkylamino, di- N—(C1-C6)alkylamino or (C1-C6)alkyl;
- R5 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy, (C1-C4)alkoxy, mercapto or (C1-C6)alkylthio;
- n is 0 or 1;
- A is independently hydrogen or —C(O)—Q1—Q2—Q3;
- Q1 is independently —O—, —NH—, —N(Q2—Q3)— or
- Q2 is independently (C0-C4)alkylenyl or —(CH2CH2—O)r;
- Q3 is independently hydrogen, hydroxy, methoxy, —O—C(O)—X1, —NHX2 or —N(X1)X2;
- p and p′ are independently , 0, 1, 2 or 3;
- Z is independently —CH— or —N—;
- r is independently 2, 3 or 4;
- and
- X1 and X2 are taken separately and are independently (C1-C6)alkyl;
- or
- X1 and X2 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered azacycloalkyl.
19 more elements
A compound of the Formula V
- or a pharmaceutically acceptable salt thereof, wherein:
- X is hydrogen, hydroxy, halo, nitro, mercapto, cyano, carboxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, —NR3R4, —(N—A)n—CO(O)—Q1—Q2—Q3 or a 3 to 10 membered azacycloalkyl;
- said alkyl, alkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl in the definition of X being optionally substituted independently with up to three halo;
- said azacycloalkyl in the definition of X further optionally being bridged by (C1-C6)alkylenyl;
- said azacycloalkyl in the definition of X being optionally gem-dialkylated or independently substituted with up to three hydroxy, oxo, (C1-C6)alkyl, (C1-C6)alkoxy or —C(O)—Q1—Q2—Q3;
- R3 and R4 are independently hydrogen;
- (C1-C6)alkyl optionally substituted independently with up to three halo, hydroxy, cyano or (C1-C6)alkoxy;
- R5-carbonyl;
- or (C3-C10)cycloalkyl-(C0-C4)alkylenyl optionally substituted independently with a hydroxy, (C1-C6)alkoxy, mercapto, (C1-C6)alkylthio, amino, N—(C1-C6)alkylamino, di- N—(C1-C6)alkylamino or (C1-C6)alkyl;
- R6 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy, (C1-C4)alkoxy, mercapto or (C1-C6)alkylthio;
- n is 0 or 1;
- A is independently hydroge or —C(O)—Q1—Q2—Q3;
- Q1 is independently —O—, —N—, —N(Q2—Q3)— or
- Q2 is independently (C0-C4)alkylenyl or —(CH2CH2—O)r;
- Q3 is independently hydrogen, hydroxy, methoxy, —O—C(O)—X1, —NHX2 —N(X1)X2;
- p and p′ are independently , 0, 1, 2 or 3;
- Z is independently —CH— or —N—;
- r is independently 2, 3 or 4;
- and
- X1 and X2 are taken separately and are independently (C1-C6)alkyl;
- or
- X1 and X2 are taken together with the nitrogen atom to which they are attached to form a 3- to 10-membered azacycloalkyl.
19 more elements
Dependencies are inferred from the claim text.