Pyrrolidinyl-alkyl-amide derivatives, their preparation, and their therapeutic application as CCR3 receptor ligands
View Patent ↗The present invention relates to pyrrolidinyl-alkyl-amide derivatives of formula (I) or (IA) wherein the variables are as defined herein, to their preparation and to their therapeutic use as CCR3 receptor ligands.
1. A compound of formula (I) or (IA),
wherein
Ar 1 represents a phenyl or naphthyl group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, halogen atoms, trifluoromethyl groups, cyano groups, nitro groups, hydroxyl groups, C 1-2 alkylenedioxy groups, amino groups, or amino groups substituted with one or two identical or non-identical, straight or branched C 1-4 alkyl groups;
R 1 , represents a hydrogen atom, or a straight or branched C 1-4 alkyl group;
R 4 , R 5 , R 6a , R 6b each represents a hydrogen atom, or
R 4 stands for a straight or branched C 1-4 alkyl group and R 5 , R 6a and R 6b each represents a hydrogen atom, or
R 5 stands for a straight or branched C 1-4 alkyl group and R 4 , R 6a and R 6b each represent a hydrogen atom, or
R 6a stands for a straight or branched C 1-4 alkyl group, R 6b stands for a straight or branched C 1-4 alkyl group or a hydrogen atom, and each of R 5 and R 4 represents a hydrogen atom;
Y, Z each independently represents a straight C 1-4 alkylene group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups;
Ar 2 represents a phenyl, thienyl, or furyl group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, halogen atoms, hydroxyl groups, cyano groups, nitro groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, amino groups, or amino groups substituted with one or two identical or non-identical, straight or branched C 1-4 alkyl groups; or
a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, nitro groups, cyano groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where R 7 and R 8 independently stand for a hydrogen atom or a straight or branched C 1-4 alkyl group, or R 7 and R 8 together with the nitrogen atom form a group of formula (a),
where,
R 2 and R 3 each independently represents a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
A represents a —CHR 12 group, oxygen atom, sulfur atom or —NR 9 group, where R 12 and R 9 each independently stands for a hydrogen atom, a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
m has the value of 1, 2 or 3,
n has the value of 1 or 2,
o has the value of 0 or 1, and
p has the value of 0 or 1;
or
the benzolog of a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more identical or non-identical straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, trifluoromethyl groups, nitro groups, cyano groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where the meanings of R 7 and R 8 are as defined above; or
a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, condensed with a heteroaromatic 6-membered ring containing one or two nitrogen atoms, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, nitro groups, cyano groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where the meanings of R 7 and R 8 are as defined above; and
Q represents an —O − group, or an —N − —H or —N − —CO—R 10 group, where R 10 stands for a hydrogen atom, a straight or branched C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a phenyl-, benzyl- or —NH—R 11 group, where R 11 represents a straight or branched C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a phenyl- or benzyl-group-;
or a salt thereof.
2. A compound according to claim 1 ,
wherein
Ar 1 represents a phenyl or naphthyl group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, halogen atoms, trifluoromethyl groups, cyano groups, nitro groups, hydroxyl groups, C 1-2 alkylenedioxy groups, amino groups, or amino groups substituted with one or two identical or non-identical, straight or branched C 1-4 alkyl groups;
R 1 , represents a hydrogen atom, or a straight or branched C 1-4 alkyl group;
R 4 , R 5 , R 6a , R 6b each represents a hydrogen atom, or
R 4 stands for a straight or branched C 1-4 alkyl group, and R 5 , R 6a and R 6b each represents a hydrogen atom, or
R 5 stands for a straight or branched C 1-4 alkyl group, and R 4 , R 6a and R 6b each represents a hydrogen atom, or
R 6a stands for a straight or branched C 1-4 alkyl group, R 6b stands for a straight or branched C 1-4 alkyl group or a hydrogen atom, and R 5 and R 4 each represents a hydrogen atom;
Y, Z each independently represents a straight C 1-4 alkylene group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups;
Ar 2 represents a phenyl, thienyl, or furyl group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, halogen atoms, hydroxyl groups, cyano groups, nitro groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, amino groups, or amino groups substituted with one or two identical or non-identical, straight or branched C 1-4 alkyl groups; or
a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, nitro groups, cyano groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where R 7 and R 8 each independently stands for a hydrogen atom or a straight or branched C 1-4 alkyl group, or R 7 and R 8 together with the nitrogen atom form a group of formula (a),
where,
R 2 and R 3 each independently represents a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
A represents a —CHR 12 group, oxygen atom, sulfur atom or —NR 9 group, where R 12 and R 9 each independently stands for a hydrogen atom, a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
m has the value of 1, 2 or 3,
n has the value of 1 or 2,
o has the value of 0 or 1, and
p has the value of 0 or 1,
or
the benzolog of a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, trifluoromethyl groups, nitro groups, cyano groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where the meaning of R 7 and R 8 are as defined above; or
a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, condensed with a heteroaromatic 6-membered ring containing one or two nitrogen atoms, optionally substituted with one or more, identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, nitro groups, cyano groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where the meanings of R 7 and R 8 are as defined above; and
Q represents an —N − —H group;
or a salt thereof.
3. A compound according to claim 1 ,
wherein
Ar 1 represents a phenyl or naphthyl group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, or halogen atoms;
R 1 represents a hydrogen atom, or a methyl group;
R 4 , R 5 , K R 6b each represents a hydrogen atom, or
R 4 stands for a methyl group and R 5 , R 6a and R 6b each represents a hydrogen atom, or
R 6a stands for a methyl group, R 6b stands for a methyl group or a hydrogen atom, and R 5 and R 4 each represents a hydrogen atom;
Y, Z each independently represents a straight C 1-4 alkylene group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups;
Ar 2 represents the benzolog of a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, trifluoromethyl groups, nitro groups, cyano groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where R 7 and R 8 each independently stands for a hydrogen atom or a straight or branched C 1-4 alkoxy group, or R 7 and R 8 together with the nitrogen atom form a group of the formula (a),
where,
R 2 and R 3 each independently represents a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
A represents a —CHR 12 group, oxygen atom, sulfur atom or —NR 9 group, where R 12 and R 9 each independently stands for a hydrogen atom, a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
m has the value of 1, 2 or 3,
n has the value of 1 or 2,
o has the value of 0 or 1, and
p has the value of 0 or 1, or
a 5- or 6-membered heterocyclic ring containing one, two, or three nitrogen atoms, or one nitrogen atom and one oxygen atom, or one nitrogen atom and one sulfur atom, condensed with a heteroaromatic 6-membered ring containing one or two nitrogen atoms, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, hydroxyl groups, halogen atoms, nitro groups, cyano groups, trifluoromethyl groups, C 1-2 alkylenedioxy groups, or —NR 7 R 8 , —CONR 7 R 8 or —SO 2 NR 7 R 8 groups, where the meanings of R 7 and R 8 are as defined above; and
Q represents an —O − group, —N − —H or —N − —CO—R 10 group, where R 10 stands for a hydrogen atom, a straight or branched C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a phenyl, benzyl or —NH—R 11 group, where R 11 represents a straight or branched C 1-4 alkyl group, C 3-6 cycloalkyl group, phenyl- or benzyl-group-;
or a salt thereof.
4. A compound according to claim 1 ,
wherein
Ar 1 represents a phenyl group, optionally substituted with one or more identical or non-identical halogen atoms;
R 1 represents a hydrogen atom;
R 4 , R 5 , R 6a , R 6b each represents a hydrogen atom;
Y, Z each independently represents a straight C 1-4 alkylene group, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups;
Ar 2 represents the benzolog of a 5- or 6-membered heterocyclic ring containing one nitrogen atom and one sulfur atom, optionally substituted with one or more, identical or non-identical, straight or branched C 1-4 alkyl groups, or
5- or 6-membered heterocyclic ring containing one nitrogen atom and one sulfur atom, condensed with a heteroaromatic 6-membered ring containing one or two nitrogen atoms, optionally substituted with one or more identical or non-identical, straight or branched C 1-4 alkyl groups, straight or branched C 1-4 alkoxy groups, or a —NR 7 R 8 group, where R 7 and R 8 each independently stands for a hydrogen atom, or a straight or branched C 1-4 alkyl group, or R 7 and R 8 together with the nitrogen atom form a group of the formula (a);
where,
R 2 and R 3 each independently represents a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group,
A represents a —CHR 12 group, oxygen atom, sulfur atom or —NR 9 group, where R 12 and R 9 each independently stands for a hydrogen atom, a straight or branched C 1-4 alkyl group or a C 3-6 cycloalkyl group-,
m has the value of 1, 2 or 3,
n has the value of 1 or 2,
o has the value of 0 or 1, and
p has the value of 0 or 1; and
Q represents a —O − group, or a —N − —H or —N − —CO—R 10 group, where R 10 stands for a hydrogen atom or a straight or branched C 1-4 alkyl group, or a —NH—R 11 group, where R 11 represents a straight or branched C 1-4 alkyl group;
or a salt thereof.
5. A compound according to claim 1 ,
wherein
Ar 1 represents a phenyl group substituted with one or two identical or non-identical halogen atoms,
or a salt thereof.
6. A compound according to claim 1 selected from the group consisting of:
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-methoxy[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-(methylamino) [1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-pyrrolidin-1-yl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-piperidin-1-yl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-morpholin-4-yl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-methyl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-(4-methylpiperazin-1-yl)[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(6-methyl-1,3-benzothiazol-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-(2,6-dimethylmorpholin-4-yl)[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(6-piperidin-1-yl)[1,3]thiazolo[4,5-b]pyrazin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(6-morpholin-4-yl)[1,3]thiazolo[4,5-b]pyrazin-2-yl)propionamide,
N-(3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]-1-methylpropyl)-3-(5-morpholin-4-yl
[1,3]thiazolo[5,4-b]pyridin-2-yl)]propionamide,
N-(3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]-1-methylpropyl)-3-(5-piperidin-1-yl
[1,3]thiazolo[5,4-b]pyridin-2-yl)]propionamide,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-pyrrolidin-1-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino} propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-piperidin-1-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino} propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-morpholin-4-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino} propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino} propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-[3-({3-(5-(2,6-dimethylmorpholin-4-yl)[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium tosylate,
N-{3-[2-(3,4-dichlorophenyl)-1-oxidopyrrolidin-1-yl]propyl}-3-(5-piperidin-1-yl)
[1,3]thiazolo[4,5-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)-1-oxidopyrrolidin-1-yl]propyl}-3-(5-morpholin-4-yl
[1,3]thiazolo[4,5-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)-1-oxidopyrrolidin-1-yl]propyl}-3-(5-pyrrolidin-1-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propionamide, and
1-(Acetylamino)-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-piperidin-1-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium hydrochloride
or a salt thereof.
7. A compound according to claim 6 selected from the group consisting of:
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-(methylamino) [1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-pyrrolidin-1-yl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-piperidin-1-yl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-morpholin-4-yl[1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
N-{3-[2-(3,4-dichlorophenyl)pyrrolidin-1-yl]propyl}-3-(5-(2,6-dimethylmorpholin-4-yl) [1,3]thiazolo[5,4-b]pyridin-2-yl)propionamide,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-pyrrolidin-1-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-piperidin-1-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-morpholin-4-yl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-(3-{[3-(5-methyl[1,3]thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium tosylate,
1-amino-2-(3,4-dichlorophenyl)-1-[3-({3-(5-(2,6-dimethylmorpholin-4-yl) [1,3thiazolo[4,5-b]pyridin-2-yl)propanoyl]amino}propyl)pyrrolidinium tosylate, and
N-{3-[2-(3,4-dichlorophenyl)-1-oxidopyrrolidin-1-yl]propyl}-3-(5-morpholin-4-yl[1,3 thiazolo[4,5-b]pyridin-2-yl)propionamide,
or a salt thereof.
8. A compound of formula (IA) according to claims 3 ,
where,
Q represents an —N − —H group or a salt thereof.
9. A process for preparing a compound of formula (I) or (IA) as set forth in claim 1 , or a salt thereof,
where the meanings of Ar 1 , R 1 , R 4 , R 5 , R 6a , R 6b , Y, Z, Ar 2 and Q are as defined in claim 1 , the process comprising
a.) for preparing a compound of formula (I), reacting a compound of formula (IV),
with a carboxylic acid derivative of formula (V),
where W represents a halogen atom, hydroxyl group, —O(C 1-4 alkyl) group or —OCO—Z—Ar 2 group; or
b.) for preparing a compound of formula (I), reacting an amino compound of the formula (VI)
with a halogen compound of the formula (VII)
where Hal represents halogen atom; or
c.) to prepare the a compound of formula (IA), wherein Q represents —O − group, oxidizing a compound of formula (I) prepared by method a.) or b.) above; or
d.) to prepare a compound of formula (IA), or a salt thereof, where Q represents an —N − —H group, further reacting a compound of formula (I) prepared by method a.) or b.) above with O-tosylhydroxylamine; or
e.) to prepare a compound of formula (IA), or a salt thereof, where Q represents an —N − —CO—R 10 group, where R 10 represents a hydrogen atom, straight or branched C 1-4 alkyl group, C 3-6 cycloalkyl group, phenyl or benzyl group, acylating a compound of formula (IA), prepared by method d.) above, with a group of formula Hlg-CO—R 10 , where Hlg represents a halogen atom; or
f.) to prepare the a compound of formula (IA) where Q represents an —N − —CO—R 10 group, in which R 10 represents an —NH—R 11 group, reacting a compound of formula (IA) prepared by method d.) above with a compound of the formula R 11 NCO.
10. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a salt thereof, and one or more pharmaceutically acceptable excipients.
11. A method for the treatment of asthma, allergic rhinitis, atopic dermatitis, eczema, inflammatory bowel disease, ulcerative colitis, Crohn's disease, allergic conjunctivitis, multiple sclerosis, or HIV infection, the method comprising administering to a patient in need thereof an effective dose of a compound as claimed in claim 1 , or a salt thereof.