Patent Application
20100261758
The present invention relates to organic compounds, e.g. compounds which mediate the activity of a specific G protein coupled receptor.
The G protein coupled receptor GPBAR1, e.g. disclosed in WO03051923 (nucleotide sequence SEQ ID NO:1, protein sequence SEQ ID: NO 2), is a member of the G protein-coupled receptor family of polypeptides. The biological properties of such immunomodulatory polypeptides include monocyte/macrophage migration/activation, regulation of dendritic cell differentiation, regulation of lymphocyte activation, proliferation and differentiation regulation of inflammation, regulation of cytokine production and/or release, regulation of pro-inflammatory mediator production and/or release, regulation of immune reaction, GLP (glucagon-like peptide)-1 secretion, insulin secretion, appetite, pancreatic regeneration, pancreatic β cell differentiation, pancreatic β cell growth, insulin resistance, energy expenditure.
Thus, GPBAR1 is indicated to be of interest in relation to methods of treatment of disorders, wherein such biological properties play a causal or contributory role. Such disorders include but are not limited to (chronic) inflammatory diseases, autoimmune diseases, diseases or syndroms in which a significant pathological component is immune suppression, including viral diseases, transplant rejection crisis and other diseases following transplantation, cancer; neurological disorders, such as neurology CNS disorders, cardiovascular disorders, diabetes (type 2), obesity.
Compounds are herewith provided which surprisingly exert agonistic activity on GPBAR1, e.g. thus activating the GPBAR1 function.
In one aspect the present invention provides a compound of formula
wherein
R1 is aryl, cyclohexyl or heterocyclyl, or (C1-4)alkyl substituted by aryl, cyclohexyl or heterocyclyl,
preferably R1 is aryl, aryl(C1-4)alkyl, or heterocyclyl,
wherein aryl is (C6-18)aryl, such as (C6-12)aryl, e.g. phenyl, naphthalenyl, and wherein aryl may be fused with aliphatic or aromatic heterocyclyl comprising 3 to 12 ring members, e.g. 6, and 1 to 4 heteroatoms selected from N, O, S,
wherein heterocyclyl includes aliphatic or aromatic heterocyclyl, preferably aromatic heterocyclyl, comprising 3 to 12 ring members, such as 5 or 6, and 1 to 4 heteroatoms selected from N, O, S; and wherein heterocycyl may be fused with aryl, such as phenyl or naphthalenyl or may be fused with another heterocyclyl comprising 3 to 12 ring members, such as 5 or 6, and 1 to 4 heteroatoms selected from N, O, S, and
wherein cycloalkyl includes (C3-12)cycloalkyl,
R2 is heterocyclyl selected from the group consisting of
pyridin-4-yl, optionally in the form of an N-oxide, e.g. of formula
pyridin-4-yl optionally in the form of an N-oxide, substituted one or morefold by (C1-4)alkyl, e.g. methyl, halo(C1-4)alkyl, halogen, e.g. including fluoro, chloro, bromo, such as fluoro, chloro, cyano or di(C1-4)alkylamino,
such as substituted one or morefold by (C1-4)alkyl, e.g. methyl, halogen, cyano or di(C1-— 4)alkylamino,
e.g. a group of formula
quinolinyl, oxazolyl, isoxazolyl, imidazo[2,1-b]thiazolyl, imidazolyl, pyrazolyl, and benzoimidazolyl,
wherein quinolinyl, oxazolyl, isoxazolyl, imidazo[2,1-b]thiazolyl, imidazolyl, pyrazolyl, or benzoimidazolyl is optionally in the form of an N-oxide and is unsubstituted or substituted, e.g. unsubstituted or substituted one or morefold by (C1-4alkyl, e.g. methyl, halo(C1-4)alkyl, halogen, cyano or di(C1-4)alkylamino, such as substituted by (C1-4)alkyl, e.g. methyl,
such as a group of formula
optionally in the form of an N-oxide,
R3 is alkyl, aryl, cycloalkyl or heterocyclyl, or (C1-4)alkyl substituted by aryl, cycloalkyl or heterocyclyl,
preferably alkyl, aryl, cyclohexyl, heterocyclyl or (C1-4)alkyl substituted by aryl,
wherein alkyl includes (C1-12)alkyl, e.g. including straight-chain and branched (C3-12)alkyl, wherein aryl includes (C6-18)aryl, such as (C6-12)aryl, e.g. phenyl, naphtalenyl, biphenylyl, and wherein aryl optionally is fused with aliphatic or aromatic heterocyclyl comprising 3 to 12 ring members, e.g. 5 or 6, and 1 to 4 heteroatoms selected from N, O, S, e.g. N, O,
wherein heterocycyl includes aliphatic or aromatic heterocyclyl comprising 3 to 12 ring members, and 1 to 4 heteroatoms selected from N, O, S and wherein heterocyclyl optionally is fused with another ring (system), e.g. with aryl, such as phenyl or naphthalenyl, or is fused with another heterocyclyl, and
wherein cycloalkyl includes (C3-12)cycloalkyl, e.g. (C3-6)cycloalkyl, and
R4 is H or (C1-4)alkyl; or
R3 and R4 together with the carbon atom to which they are attached are cycloalkyl, which cyclyoalkyl is fused with phenyl, such as (C4-8)cycloalkyl fused with phenyl;
wherein aryl, cyclohexyl or heterocyclyl in the meaning of R1 and R3 is unsubstituted or one or morefold substituted, e.g. unsubstituted or substituted by one or more, e.g. one or two,
Preferably in a compound of formula I
R1 is (C6-12)aryl(C1-4)alkyl, such as phenylethyl,
(C6-12)aryl, such as phenyl, naphthalenyl, e.g. naphthalen-1-yl, naphthalen-2-yl,
(C6-12)aryl substituted by (C6-12)aryl, e.g. biphenylyl,
(C1-4)alkylphenyl, such as (C1-4)alkylphenyl, e.g. tolyl, such as o-tolyl, m-tolyl, p-tolyl, ethylphenyl, e.g. 2-ethylphenyl, propylphenyl, e.g. n-propylphenyl, such as 2-n-propylphenyl, butylphenyl, e.g. tert-butylphenyl, such as 4-tert-butylphenyl,
di(C1-4)alkylphenyl, such as dimethylphenyl, e.g. 2,3-dimethylphenyl, 2,6-dimethylphenyl, (C1-4)alkoxyphenyl, e.g. methoxyphenyl, e.g. 2-methoxyphenyl, 3-methoxyphenyl, phenoxyphenyl, e.g. 4-phenoxyphenyl,
halo(C1-4)alkyl-phenyl, such as halomethylphenyl, e.g. trifluoromethylphenyl, such as 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl,
bis-halo(C1-4)alkyl-phenyl, e.g. bis-trifluoromethylphenyl, such as 3,5-bis-trifloromethylphenyl, (halo)((C1-4)alkyl)-phenyl, e.g. (halo)(methyl)-phenyl, such as 2-methyl-4-fluorophenyl, 3-methyl-4-fluorophenyl,
(halo)(halo(C1-4)alkyl)phenyl, such as (halo)(trifluoromethyl)-phenyl, e.g. 3-trifluoromethyl-4-chloro-phenyl, 3-trifluoromethyl-4-fluoro-phenyl, 2-trifluoromethyl-4-fluoro-phenyl, halo(C1-4)alkoxyphenyl, such as halomethoxyphenyl, e.g. trifloromethoxyphenyl, e.g. 2-trifluoromethoxyphenyl,
(halo)(cyano)phenyl, e.g. 2-cyano-4-fluoro-phenyl, 3-cyano-4-fluoro-phenyl, halophenyl, e.g. fluorophenyl, such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, chlorophenyl, such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, dihalophenyl, such as dichlorophenyl, e.g. 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, (chloro)(fluoro)phenyl, e.g. 2-chloro-4-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, dibromophenyl, e.g. 2,4-dibromophenyl,
cyaonphenyl, such as 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,
nitrophenyl, e.g. 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl,
aminocarbonylphenyl, e.g. 2-aminocarbonylphenyl,
5 or 6-membered, e.g. 5 or 6-membered, aromatic or aliphatic, e.g. aromatic, heterocyclyl comprising 1 to 4 heteroatoms, e.g. one or two, selected from N, O, S, e.g. N, such as pyrazolyl, e.g. 1H-pyrazol-3-yl, such as 1-methyl-1H-pyrazol-3-yl, pyridinyl, e.g. pyridine-3-yl, e.g. including cyanopyridinyl, such as 4-cyano-pyridinyl-3-yl, aminocarbonylpyridinyl, such as 4-aminocarbonyl-pyridinyl-3-yl,
or 5 or 6-membered, aromatic or aliphatic, e.g. aromatic, heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, S, such as 6-membered aromatic heterocyclyl comprising 1 or 2 heteroatoms selected from N, O, S, e.g. N, which heterocyclyl is fused with another ring system, e.g. fused with phenyl, such as isoquinolinyl, e.g. isoquinolin-1-yl.
Preferably in a compound of formula I
R2 is selected from the group consisting of
pyridin-4-yl,
2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl,
2,5-dimethyl-pyridin-4-yl, 2,3-dimethyl-pyridin-4-yl, 2,5-dimethyl-pyridin-4-yl,
2-fluoro-pyridin-4-yl, 2-chloro-pyridin-4-yl, 3-chloro-pyridin-4-yl,
2-cyano-pyridin-4-yl,
3,5-dichloro-pyridin-4-yl,
2-chloro-6-methyl-pyridin-4-yl, 2-chloro-3-methyl-pyridin-4-yl, 2-chloro-5-methyl-pyridin-4-yl,
2-fluoro-3-methyl-pyridin-4-yl, 2-fluoro-5-methyl-pyridin-4-yl,
2-amino-pyridin-4-yl, 2-amino-5-methyl-pyridin e.g. including 2-dimethylamino-pyridin-4-yl, and 2-dimethylamino-5-methyl-pyridin,
wherein pyridinyl is optionally in the form of an N-oxide,
quinolinyl, e.g. quinolin-4-yl, e.g. optionally in the form of an N-oxide,
oxazolyl, such as oxazol-5-yl, e.g. including 4-methyl-oxazol-5-yl, e.g. optionally in the form of an N-oxide,
isoxazolyl, such as isoxazol-4-yl, e.g. including 5-methyl-isoxazol-4-yl, 3,5-dimethyl-isoxazol-4-yl, e.g. optionally in the form of an N-oxide,
imidazo[2,1-b]thiazolyl, such as imidazo[2,1-b]thiazol-5-yl, e.g. including 6-methyl-imidazo[2,1-b]thiazol-5-yl), e.g. optionally in the form of an N-oxide,
imidazolyl, such as 3H-imidazol-4-yl, e.g. including 3,5-dimethyl-3H-imidazol-4-yl, e.g. optionally in the form of an N-oxide,
1H-pyrazolyl, such as 1H-pyrazol-4-yl, e.g. including 3,5-dimethyl-1H-pyrazol-4-yl, e.g. optionally in the form of an N-oxide, and
benzoimidazolyl, such as 3H-benzoimidazol-5-yl, e.g. optionally in the form of an N-oxide,
In one preferred aspect of the present invention R2 is 3-methyl-pyridin-4-yl.
Preferably in a compound of formula I
R3 is
substituted or unsubstituted (C1-12)alkyl, such as (C1-8)alkyl, e.g.
unsubstituted alkyl, such as methyl, isopropyl, 2-methyl-butyl, tert-butyl, 2-ethyl-butyl, 2-methyl-pentyl, or alkyl substituted by aryl, e.g. (C6-12)aryl(C1-4)alkyl, e.g. benzyl, (C3-12)cycloalkyl, e.g. (C3-8)cycloalkyl, such as cyclopropyl, cyclopentyl, cylohexyl, substituted or unsubstituted (C6-12)aryl, such as phenyl,
(C1-6)alkylphenyl, e.g. tolyl, such as o-tolyl, m-tolyl, p-tolyl, ethylphenyl, such as 2-ethylphenyl, isopropylphenyl, such as 4-isopropylphenyl, n-butylphenyl, such as 2-n-butylphenyl,
(C6-12)aryl substituted by (C6-12)aryl, e.g. biphenylyl,
di(C1-4)alkylphenyl, e.g. dimethylphenyl, such as 2,3-dimethylphenyl, 2,6-dimethylphenyl, halo(C1-4)alkylphenyl, such as trifluoromethylphenyl, e.g. 2-trifluoromethylphenyl, 4-trifluoromethylphenyl,
(C1-4)alkoxyphenyl, such as methoxyphenyl, e.g. 2-methoxyphenyl, isobutoxyphenyl, e.g. 2-isobutoxyphenyl, aminocarbonyl(C1-4alkoxyphenyl, such as aminocarbonylmethoxyphenyl, e.g. 2-aminocarbonylmethoxyphenyl,
(C1-4)alkoxy(C1-4)alkoxyphenyl, such as 2-(ethoxy)-ethoxyphenyl, e.g. 2-[2-(ethoxy)-ethoxy]-phenyl,
di(C1-4alkoxyphenyl, such as dimethoxyphenyl, e.g. 2,6-dimethoxyphenyl,
(C6-12)aryloxyphenyl, such as phenoxyphenyl, e.g. 4-phenoxyphenyl,
halo(C1-4alkoxyphenyl, such as trifluoromethoxyphenyl, e.g. 2-trifluoromethoxyphenyl,
(halo)(halo(C1-4)alkyl)phenyl, such as (halo)(trifluoromethyl)-phenyl, e.g. 3-trifluoromethyl-4-chloro-phenyl,
(halo)((C1-4)alkoxy)phenyl, such as (halo)(methoxy)phenyl, e.g. fluoro-methoxy-phenyl, such as difluoro-methoxy-phenyl, e.g. 2,4-difluoro-6-methoxy-phenyl, cyanophenyl, e.g. 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, hydroxyphenyl, e.g. 2-hydroxyphenyl,
(C1-4)alkylcarbonyloxyphenyl, such as methylcarbonyloxyphenyl, aminocarbonylphenyl, halophenyl, e.g. fluorophenyl, such as 3-fluorophenyl, 4-fluorophenyl, chlorophenyl, such as 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, bromophenyl, such as 4-bromophenyl, dihalophenyl, e.g. dichlorophenyl, such as 2,4-dichlorophenyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl,
aminophenyl, such as di(C1-4)alkylaminophenyl, e.g. dimethylaminophenyl, such as 2-dimethylaminocarbonylphenyl,
nitrophenyl, e.g. 3-nitrophenyl, 4-nitrophenyl,
heterocyclylphenyl, wherein heterocyclyl comprises aromatic and aliphatic heterocyclyl,
having 5 to 6 ring members and one to 4 heteroatoms selected from N, O, S, e.g. N, O, such as pyridinylphenyl, e.g. 2-(pyridin-3-yl)-phenyl, 2-(pyridin-4-yl)-phenyl, morpholinophenyl, such as morpholin-4-yl-phenyl, e.g. 2-(morpholin-4-yl)-phenyl, tetrazolyl-phenyl, such as methyl-tetrazolyl-phenyl, e.g. 1-methyl-1H-tetrazol-5-yl-phenyl, such as 3-(1-methyl-1H-tetrazol-5-yl)-phenyl, 2-methyl-2H-tetrazol-5-yl-phenyl, such as 3-(2-methyl-2H-tetrazol-5-yl)-phenyl,
phenyl fused with heterocycyl, wherein heterocyclyl comprises 5 or 6 ring members and 1 to 4 heteroatoms, e.g. 2, selected from N, O, S, e.g. N.O, such as indolyl, e.g. 1H-indol-4-yl, 1H-indol-6-yl, methylindolyl, such as 2-methyl-1H-indol-4-yl, 2,3-dihydro-1H-indolyl, e.g. methyl-2,3-dihydro-1H-indolyl, such as 2,3-dihydro-1H-indol-4-yl, 2-methyl-2,3-dihydro-1H-indol-4-yl, pyridin-carbonyl-2,3-dihydro-1H-indolyl, such as methylpyridine-carbonyl-2,3-dihydro-1H-indolyl, e.g. 3-methyl-pyridine-4-carbonyl)-2,3-dihydro-1H-indol-4-yl, benzo[1,3]dioxolyl, e.g. benzo[1,3]dioxol-4-yl, e.g. including 2,2-difluoro-benzo[1,3]dioxol-4-yl, 2,3-dihydro-benzo[1,4]dioxinyl, such as 2,3-dihydro-benzo[1,4]dioxin-6-yl, 1H-indazol-7-yl, such as 1-methyl-1H-indazol-7-yl, benzo[1,2,5]thiadiazolyl, such as benzo[1,2,5]thiadiazol-4-yl, benzofuranyl, benzofuran-7-yl, methyl-benzofuranyl, e.g. 2-methyl-benzofuran-7-yl, N-quinolin-8-yl, 2-oxo-1,2-dihydro-quinolinyl, such as 2-oxo-1,2-dihydro-quinolin-4-yl, naphthalenyl, e.g. including naphthalen-1-yl, naphthalen-2-yl, (C1-4)alkoxynaphthalenyl, e.g. methoxy-naphthalenyl, such as 3-methoxy-naphthalen-2-yl,
heterocyclyl comprising 5 or 6 ring members and 1 to 4 heteroatoms selected from N, O, S, e.g. arylic hetrocyclyl, e.g. including pyridinyl, e.g. pyridin-2-yl, pyridin-3-yl, methyl-pyridinyl, such as methyl-pyridin-2-yl, e.g. 6-methyl-pyridin-2-yl, morphotinyl-pyridinyl, such as 2-morpholin-4-yl-pyridin-3-yl, furanyl, e.g. furan-2-yl, furan-3-yl, thiophenyl, e.g. thiophen-2-yl, triazolyl, e.g. 2H-[1,2,3]triazol-4-yl), phenyltriazolyl, such as cyanophenyl-triazolyl, e.g. 2-phenyl-2H-[1,2,3]triazol-4-yl, 2-(4-cyano-phenyl)-2H-[1,2,3]triazol-4-yl, oxazolyl, eg. phenyloxyzolyl, chlorophenyloxazolyl, such as oxazol-5-yl, 2-phenyl-oxazol-5-yl, 2-(2-chloro-phenyl)-oxazol-5-yl, thiazolyl, such as thiazol-5-yl, thiazolyl substituted by thiazolyl, such as [2,4′]bithiazolyl-5-yl, methyl-[2,4′]bithiazolyl-5-yl, e.g. 5′-methyl-[2,4′]bithiazolyl-5-yl, pyrrolyl, such as pyrrol-3-yl, phenylpyrrolyl, e.g. 1-phenyl-1H-pyrrol-3-yl,
heterocyclyl comprising 5 or 6 ring members and 1 to 4 heteroatoms selected from N, O, S, which heterocycyl is fused with another ring system,
such as fused with (C6-12)aryl, e.g. phenyl, such as quinolinyl, e.g. quinolin-3-yl, aminoquinolinyl, di(C1-4alkylamino-quinolinyl, e.g. dimethylamino-quinolinyl, such as 2-dimethylamino-quinolin-3-yl, 1,2-dihydro-isoquinolinyl, such as 2-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl, 1H-indol-3-yl, such as cyano-1H-indol-3-yl, e.g. 5-cyano-1H-indol-3-yl, benzothiazolyl, such as benzothiazol-2-yl, oxazolyl, phenyl-oxazolyl, oxochromenyl, such as 4-oxo-4H-chromen-3-yl,
or
such as heterocyclyl fused with another heterocyclyl, e.g. aliphatic or aromatic heterocyclyl, such as aromatic heterocyclyl, wherein heterocyclyl comprising 5 to 6 ring members and 1 to 4 heteroatoms selected from N, O, S, such as Imidazo[2,1-b]thiazolyl, methyl-Imidazo[2,1-b]thiazolyl, e.g. Imidazo[2,1-b]thiazol-5-yl, 6-methyl-imidazo[2,1-b]thiazol-5-yl), imidazo[1,2-a]pyridinyl, e.g. including methyl-imidazo[1,2-a]pyridinyl, such as 2-methyl-imidazo[1,2-a]pyridin-3-yl, or
R3 and R4 together with the carbon atom to which they are attached are (C5-8)cycloalkyl which cycloalkyl is fused with phenyl, such as indanyl, e.g. indan-1-yl, tetrahydronaphthalenyl, e.g. (1,2,3,4-tetrahydro-naphthalen-1-yl, tetrahydro-benzocycloheptenyl, such as 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl.
Preferably in a compound of formula I R4 is hydrogen or methyl.
In one preferred embodiment of the present invention R4 is hydrogen.
In another aspect the present invention provides a compound of formula I, wherein
R1 is
(C6-12)aryl(C1-4)alkyl, phenyl, naphthalenyl, (C6-12)aryl substituted by (C6-12)aryl,
(C1-8)alkylphenyl, di(C1-4)alkylphenyl, (C1-4alkoxyphenyl, halo(C1-4alkyl-phenyl, bis-halo(C1-4)alkyl-phenyl, (halo)(halo(C1-4)alkyl)phenyl, halo(C1-4)alkoxyphenyl, (halo)(cyano)phenyl halophenyl, dihalophenyl, cyaonphenyl, nitrophenyl, aminocarbonylphenyl, 5 or 6-membered heterocyclyl comprising 1 to 4 heteroatoms, selected from N, O, S, or 5 or 6-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, S, which heterocyclyl is fused with another ring system;
R2 is selected from the group consisting of
pyridin-4-yl, 2-methyl-pyridin-4-yl, 3-methyl-pyridin-4-yl, 2,5-dimethyl-pyridin-4-yl, 2,3-dimethyl-pyridin-4-yl, 2,5-dimethyl-pyridin-4-yl, 2-fluoro-pyridin-4-yl, 2-chloro-pyridin-4-yl, 3-chloro-pyridin-4-yl, 2-cyano-pyridin-4-yl, 3,5-dichloro-pyridin-4-yl, 2-chloro-6-methyl-pyridin-4-yl, 2-chloro-3-methyl-pyridin-4-yl, 2-chloro-5-methyl-pyridin-4-yl, 2-fluoro-3-methyl-pyridin-4-yl, 2-fluoro-5-methyl-pyridin-4-yl, 2-amino-pyridin-4-yl, 2-amino-5-methyl-pyridin, 2-dimethylamino-pyridin-4-yl, 2-dimethylamino-5-methyl-pyridin,
wherein pyridinyl is optionally in the form of an N-oxide,
quinolinyl, oxazolyl, isoxazolyl, imidazo[2,1-b]thiazolyl, imidazolyl, 1H-pyrazolyl, and
benzoimidazolyl,
optionally in the form of an N-oxide,
R3 is
unsubstituted (C1-12)alkyl, alkyl substituted by (C6-12)aryl, (C3-12)cycloalkyl, unsubstituted (C6-12)aryl, (C1-4)alkylphenyl, (C6-12)aryl substituted by (C6-12)aryl, di(C1-4)alkylphenyl, halo(C1-4)alkylphenyl, (C1-4)alkoxyphenyl, aminocarbonyl(C1-4)alkoxyphenyl, (C1-4)alkoxy(C1-4)alkoxyphenyl, di(C1-4)alkoxyphenyl, (C6-12)aryloxyphenyl, halo(C1-4)alkoxyphenyl, (halo)(halo(C1-4)alkyl)phenyl, (halo)((C1-4)alkoxy)phenyl, cyanophenyl, hydroxyphenyl, (C1-4)alkylcarbonyloxyphenyl, aminocarbonylphenyl, halophenyl, dihalophenyl, aminophenyl, di(C1-4)alkylaminophenyl, nitrophenyl, heterocyclylphenyl, wherein heterocyclyl comprises aromatic and aliphatic heterocyclyl, having 5 to 6 ring members and one to 4 heteroatoms selected from N, O, S, phenyl fused with heterocycyl, wherein heterocyclyl comprises 5 or 6 ring members and 1 to 4 heteroatoms, selected from N, O, S, naphthalenyl, heterocyclyl comprising 5 or 6 ring members and 1 to 4 heteroatoms selected from N, O, S, heterocyclyl comprising 5 or 6 ring members and 1 to 4 heteroatoms selected from N, O, S, which heterocycyl is fused with another ring system,
or R3 and R4 together with the carbon atom to which they are attached are (C5-8)cycloalkyl which cycloalkyl is fused with phenyl, and
R4 is hydrogen or methyl, with the proviso as indicated above.
In a compound of formula I each single defined substituent may be a preferred substituent, e.g. independently of each other substituent defined and each single compound or compound group defined above or below may be a preferred compound group.
In another aspect the present invention provides a compound of formula I, which is selected from the group consisting of
N-(2,4-Dichloro-phenyl)-3-methyl-N-(2-methyl-1H-indol-4-ylmethyl)-isonicotinamide,
Any group indicated or defined herein may be unsubstituted or substituted, e.g. one or morefold, e.g. such as indicated herein. Substituents include groups which are conventional in organic chemistry, e.g. such as indicated herein.
Compounds provided by the present invention are hereinafter designated as “compound(s) of (according to) the present invention”. A compound of the present invention includes a compound in any form, e.g. in free form, in the form of a salt, in the form of a solvate and in the form of a salt and a solvate.
In another aspect the present invention provides a compound of the present invention in the form of a salt.
Such salts include preferably pharmaceutically acceptable salts, although pharmaceutically unacceptable salts are included, e.g. for preparation/isolation/purification purposes.
A compound of the present invention in free form may be converted into a corresponding compound in the form of a salt; and vice versa. A compound of the present invention in free form or in the form of a salt and in the form of a solvate may be converted into a corresponding compound in free form or in the form of a salt in non-solvated form; and vice versa.
A compound of the present invention may exist in the form of isomers and mixtures thereof; e.g. optical isomers, diastereoisomers, cis/trans conformers. A compound of the present invention may e.g. contain asymmetric carbon atoms and may thus exist in the form of enantiomers or diastereoisomers and mixtures thereof, e.g. in the form of a racemat. A compound of the present invention may be present in the (R)-, (S)- or (R,S)-configuration preferably in the (R)- or (S)-configuration regarding specified positions in the compound. E.g. in a compound of formula I, wherein R3 is branched (C3-8)alkyl or substituted alkyl, or substituted cycloalkyl, e.g. or in a compound of formula I, wherein R4 is alkyl, asymmetric carbon atoms may exist, e.g. the carbon atom to which R3 and R4 are attached may be asymmetric, and compounds comprising an asymmetric carbon atom may be in the (R)-, -(S)- or (R/S)-form regarding the position of an asymmetric carbon atom.
Isomeric mixtures may be separated as appropriate, e.g. according, e.g. analogously, to a method as conventional, to obtain pure isomers. The present invention includes a compound of the present invention in any isomeric form and in any isomeric mixture.
The present invention also includes tautomers of a compound of the present invention, where tautomers can exist.
In another aspect the present invention provides a process for the production of a compound of the present invention, e.g. of formula I, comprising reacting a compound of formula
wherein R1, R3 and R4 are as defined above, with a compound of formula
HOOC—R2 III
wherein R2 is as defined above, e.g. wherein a compound of formula III is in an activated form, e.g. reacted with 1-chloro-N,N,2-trimethyl-1-propenylamine,
in the presence of an amine, e.g. triethylamine, and isolating a compound of formula I obtained from the reaction mixture.
A compound of formula II wherein R4 is hydrogen may be e.g. obtained by reacting a compound of formula
R3CHO IV
wherein R3 is as defined above, with a compound of formula
R1—NH2 V
wherein R1 is as defined above, in the presence of a reducing agent, such as sodium triacetoxyborohydride, and isolating a compound of formula II obtained from the reaction mixture.
A compound of formula II wherein R4 is alkyl may be e.g. obtained by reacting a compound of formula
R1—NH2 V
wherein R1 is as defined above, with a compound of formula
wherein R3 is as defined above and R4 is alkyl, in the presence of an amine, e.g. triethylamine, followed by treating the reaction mixture obtained with titanium tetrachloride and sodium cyanoborohydride; and isolating a compound of formula II wherein R4 is alkyl, obtained from the reaction mixture.
In an intermediate of formula II, III, IV, V or VI (starting materials), functional groups, if present, optionally may be in protected form or in the form of a salt, if a salt-forming group is present. Protecting groups, optionally present, may be removed at an appropriate stage, e.g. according, e.g. analogously, to a method as conventional
A compound of formula I thus obtained may be converted into another compound of formula I, e.g. or a compound of formula I obtained in free form may be converted into a salt of a compound of formula I and vice versa.
The above reaction between a compound of formula II and a compound of formula III is an acylation reaction rand may be carried out as appropriate, e.g. according, e.g. analogously, to a method as conventional.
Intermediates (starting materials) of formula II, III, IV, V and VI are known or may be prepared according, e.g. analogously, to a method as conventional or as described herein. Any compound described herein, e.g. a compound of the present invention and a compound for the treatment of disorders which are mediated by GPBAR1 or for the manufacture of a medicament thereof, and intermediates of formula II, III, IV, V and VI may be prepared as appropriate, e.g. according, e.g. analogously, to a method as conventional, e.g. or as specified herein.
The compounds of the present invention and compounds of formula I, wherein R3 is as defined above and additionally denotes (C2-4)alkynyl-phenyl, e.g. including the compounds N-(2-ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide (compound of example 158 in TABLE 1) and N-(4-ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide (compound of example 159 in TABLE 1), e.g. in free form or in the form of a salt, e.g. optionally in the form of a solvate, exhibit pharmacological activity and are therefore useful as pharmaceuticals.
The compounds of the present invention and compounds of formula I, wherein R3 is as defined above and additionally denotes (C2-4)alkynyl-phenyl, e.g. including the compounds N-(2-ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide (compound of example 158 in TABLE 1) and N-(4-ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide (compound of example 159 in TABLE 1), e.g. in free form or in the form of a salt, e.g. optionally in the form of a solvate, are herein also designated as “specific GPBAR1 compound(s) of (according to) the present invention”.
The specific GPBAR1 compounds of the present invention show agonistic activity on GPBAR1, and are prone for the treatment of disorders which are mediated by, e.g. dysfunctional, e.g. insufficient, GPBAR1 activity.
Pharmaceutical activity of the specific GPBAR1 compounds of the present invention e.g. may be shown in the cAMP Assay, e.g. GPBAR1 is a Gαs-coupled GPCR and ligands induce the formation of cAMP in cells expressing GPBAR1.
cAMP Cyclic adenosine 3′,5′-monophosphate
EC50 Agonist concentration that produces 50% of the maximal effect
GPCR G protein-coupled receptor
Gαs Adenylate cyclase-stimulating G protein
GFP Green fluorescent protein
HBSS Hanks' Balanced Salt Solution
HTRF Homogeneous Time-Resolved Fluorescence
FRET Fluorescence Resonance Energy Transfer
IBMX 3-isobutyl-1-methylxanthine
RT Room Temperature
The human lymphoblastoid cell line Jurkat is transduced with a murine leukaemia based replication-defective retroviral vector construct to mediate stable expression of the ORP9651 cDNA. Briefly, the cDNA of the human GPBAR1 gene is cloned into the retroviral expression vector pMXpie, which contains an IRES (internal ribosomal entry site)-GFP expression cassette and a puromycin resistance gene. Phoenix™-Ampho packaging cells are transfected using LipofectAMINE (Invitrogen) as described by the manufacturer. At 24 h after transfection, supernatants containing retrovirus are harvested and filtered (0.2 μm). For retroviral infection of Jurkat cell lines, 2×106 cells are incubated with virus-containing supernatants supplemented with 10 μg/ml of Polybrene (Sigma). After 48 h of culture, Jurkat cells expressing high levels of GFP are collected by fluorescence-activated cell sorting and subsequently cultured in AIM-V serum-free medium (GIBCO BRL) containing 1 μg/ml puromycin, 1 IE/ml penicillin and 1 μg/ml streptomycin. Expression of the GPBAR1 gene is verified by RT-PCR.
Experiments to determine changes in cAMP after compound addition to Jurkat cells expressing GPBAR1 are performed with the HTRF kit from CIS Bio International (Bagnols sur Ceze, France). The method is based on a competitive immunoassay between native CAMP produced by cells and added cAMP labeled with XL665 and is performed according to instructions by the manufacturer in 384 well black FIA plates (Greiner) and a final volume of 20 μl per well. Briefly, assay plates containing 5 μl of cell suspension, adjusted to 1×106 cells per ml HBSS (GIBCO BRL) containing 1 mM IBMX (Sigma), and 5 μl of compound dilution are incubated at RT for 30 minutes in a humidified box to stimulate cAMP production. The total cAMP concentration in cells is analyzed by adding 5 μl cAMP-XL655 and 5 μl of anti-cAMP-Cryptate antibody solution, both pre-diluted 1:20 in conjugation/lysis buffer, as supplied by the manufacturer. After another incubation for 1 hour in a humidified box FRET, measurements are performed with the PHERAstar (BMT Labtech) plate reader (excitation 337 nm, emission 620 and 665 nm). Data are calculated from intensities of emitted light filtered at two wavelengths L1 (665 nM) and L2 (620 nM) as the ratio L1/L2 and normalised by ΔF=[(sample ratio−negative ratio)/negative ratio]×100.
The selectivity of compounds for GPBAR1 is determined in cAMP assays using a Jurkat control cell line generated by transduction of empty pMXpie vector following exactly the same protocol as described above. All compounds are inactive up to a concentration of 20 μM in that cell line.
The specific GPBAR1 compounds of the present invention exhibit EC50 values in the cAMP Assay as described above, from the low nanomolar range up to low micromolar range, e.g. 0.3 nM up to 5 μM. The compounds of the present are therefore prone to be useful for the treatment of disorders mediated by GPBAR1 activity, e.g. insufficient GPBAR1 activity.
Disorders as used herein include diseases.
Disorders mediated by GPBAR1 activity which are prone to be successfully treated with GPBAR1 agonists, e.g. with a specific GBPAR1 activating compound of the present invention, include disorders, wherein the activity of GPBAR1 play a causal or contributory role, such as immune responses initiated by dendritic cells (DCs), monocytes or lymphocytes.
Such disorders e.g. include, but are nit limited to
Disorders mediated by, e.g. insufficient, GPBAR1 activity which are prone to be successfully treated with GPBAR1 agonists, such as specific GBPAR1 activating compounds of the present invention, preferably include inflammatory, immune, e.g. autoimmune and allergic disorders, such as rheumatoid arthritis, inflammatory bowel disease, systemic lupus erytomatosis, multiple sclerosis, transplant rejection crisis, psoriasis, cancer, AIDS, diabetes (diabetes type II), obesity; more preferably rheumatoid arthritis, systemic lupus erytomatosis, multiple sclerosis, psoriasis, diabetes (diabetes type II), obesity; e.g. psoriasis.
In another aspect the present invention provides
In another aspect the present invention provides the compounds
N-(2-Ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide, and
N-(4-Ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide,
e.g. in free form or in the form of a salt, e.g. wherein salts preferably include pharmaceutically acceptable salts, although other salts, e.g. for production/purifaction/isolation processes, are included, e.g. and wherein solvates, e.g. of a free form or of a salt form are included.
For pharmaceutical use one or more compounds of the present invention may be used, e.g. one, or a combination of two or more compounds of the present invention, or specific GPBAR1-compound(s) of the present invention, preferably one compound of the present invention or specific GPBAR1-compound of the present invention is used.
A compound of the present invention or a specific GBPAR1 activating compound of the present invention may be used as a pharmaceutical in the form of a pharmaceutical composition.
In another aspect the present invention provides a pharmaceutical composition comprising a compound of the present invention in association with at least one pharmaceutically acceptable excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars or sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
In another aspect the present invention provides a pharmaceutical composition comprising the compound N-(2-ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide or N-(4-ethynyl-benzyl)-3-methyl-N-phenyl-isonicotinamide, e.g. in free form or in the form of a salt, in association with at least one pharmaceutically acceptable excipient, e.g. appropriate carrier and/or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars or sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.
A pharmaceutical composition provided by the present invention is herein also designated as “pharmaceutical composition of (according to) the present invention”.
In another aspect the present invention provides
In a further aspect the present invention provides a method of treating disorders which are mediated by, e.g. insufficient, GPBAR1 activity, e.g. including disorders as specified above, which treatment comprises administering to a subject in need of such treatment a therapeutically effective amount of a specific GBPAR1 activating compound of the present invention; e.g. in the form of a pharmaceutical composition.
In another aspect the present invention provides
Treatment includes treatment and prophylaxis (prevention).
For such treatment, the appropriate dosage will, of course, vary depending upon, for example, the chemical nature and the pharmacokinetic data of a compound of the present invention used, the individual host, the mode of administration and the nature and severity of the conditions being treated. However, in general, for satisfactory results in larger mammals, for example humans, an indicated daily dosage includes a range
A compound of the present invention may be administered to larger mammals, for example humans, by similar modes of administration, e.g. at similar dosages, than conventionally used or indicated for other mediators, e.g. low molecular weight activators, of GPBAR1 activity.
A compound of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral, administration; parenterally, e.g. including intravenous, intramuscular, subcutanous administration; or topically; e.g. including epicutaneous, intranasal, intratracheal administration;
e.g. in form of coated or uncoated tablets, capsules, (injectable) solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, vials, in the form of creams, gels, pastes, inhaler powder, foams, tinctures, lip sticks, drops, sprays, or in the form of suppositories.
The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt, or in free form; optionally in the form of a solvate. A compound of the present invention in the form of a salt and/or in the form of a solvate exhibit the same order of activity as a compound of the present invention in free form.
A compound of the present invention may be administered by any conventional route, for example enterally, e.g. including nasal, buccal, rectal, oral administration; parenterally, e.g. including intravenous, intraarterial, intramuscular, intracardiac, subcutanous, intraosseous infusion, transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucous membrane), inhalational administration; topically; e.g. including epicutaneous, intranasal, intratracheal administration; intraperitoneal (infusion or injection into the peritoneal cavity); epidural (peridural) (injection or infusion into the epidural space); intrathecal (injection or infusion into the cerebrospinal fluid); intravitreal (administration via the eye); or via medical devices, e.g. for local delivery, e.g. stents.
For topical use, e.g. including administration to the eye, satisfactory results may be obtained with local administration of a 0.5-10%, such as 1-3% concentration of active substance several times daily, e.g. 2 to 5 times daily.
A compound of the present invention may be used for any method or use as described herein alone or in combination with one or more, at least one, other, second drug substance.
In another aspect the present invention provides
Combinations include fixed combinations, in which a compound of the present invention or a specific GBPAR1 activating compound of the present invention and at least one second drug substance are in the same formulation; kits, in which a compound of the present invention or a specific GBPAR1 activating compound of the present invention and at least one second drug substance in separate formulations are provided in the same package, e.g. with instruction for co-administration; and free combinations in which a compound of the present or a specific GBPAR1 activating compound of the present invention and at least one second drug substance are packaged separately, but instruction for concomitant or sequential administration are given.
In another aspect the present invention provides
Treatment with combinations according to the present invention may provide improvements compared with single treatment.
In another aspect the present invention provides
A combination of the present invention and a second drug substance as a combination partner may be administered by any conventional route, for example as set out above for a compound of the present invention. A second drug may be administered in dosages as appropriate, e.g. in dosage ranges which are similar to those used for single treatment, or, e.g. in case of synergy, even below conventional dosage ranges.
Pharmaceutical compositions according to the present invention may be manufactured according, e.g. analogously, to a method as conventional, e.g. by mixing, granulating, coating, dissolving or lyophilizing processes. Unit dosage forms may contain, for example, from about 0.1 mg to about 1500 mg, such as 1 mg to about 1000 mg.
Pharmaceutical compositions comprising a combination of the present invention and pharmaceutical compositions comprising a second drug as described herein, may be provided as appropriate, e.g. according, e.g. analogously, to a method as conventional, or as described herein for a pharmaceutical composition of the present invention.
By the term “second drug substance” is meant a chemotherapeutic drug, especially any chemotherapeutic agent other than a specific GBPAR1 activating compound of the present invention.
For example, a second drug substance as used herein includes anti-inflammatory and/or immunomodulatory and/or anticancer drugs, e.g. including antiviral drugs, e.g. and/or anesthetics.
Anti-inflammatory and/or immunomodulatory drugs which are prone to be useful in combination with a specific GBPAR1 activating compound of the present invention e.g include
Anti-inflammatory drugs which are prone to be useful in combination with a specific GBPAR1 activating compound of the present invention include e.g. non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); cyclooxygenase-2 (COX-2) inhibitors such as celecoxib; inhibitors of phosphodiesterase type IV (PDE-IV); antagonists of the chemokine receptors, especially CCR1, CCR2, and CCR3; cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), and probucol; anticholinergic agents such as muscarinic antagonists (ipratropium bromide); other compounds such as theophylline, sulfasalazine and aminosalicylates, e.g. 5-aminosalicylic acid and prodrugs thereof, antirheumatics, IgE antibodies, e.g. omalizumab (Xolair®.
Antiallergic drugs which are prone to be useful in combination with a specific GBPAR1 activating compound of the present invention include e.g. antihistamines (H1-histamine antagonists), e.g. bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and non-steroidal anti-asthmatics such as β2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, salmeterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); bronchodilators, antiasthmatics (mast cell stabilizers).
Anesthetics which are prone to be useful as a combination partner with a specific GBPAR1 activating compound of the present invention e.g. include ethanol, bupivacaine, chloroprocaine, levobupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, tetracaine, desflurane, isoflurane, ketamine, propofol, sevoflurane, codeine, fentanyl, hydromorphone, marcaine, meperidine, methadone, morphine, oxycodone, remifentanil, sufentanil, butorphanol, nalbuphine, tramadol, benzocaine, dibucaine, ethyl chloride, xylocaine, and phenazopyridine.
Anticancer drugs which are prone to be useful as a combination partner with which are prone to be useful in combination with a specific GBPAR1 activating compound of the present invention, e.g. prone to be useful according to the present invention, e.g. include
Cancer treatment optionally in combination with an anticancer drug may be associated with radiotherapy, e.g. including DOTATATE therapy, such as Y90-DOTATATE therapy.
Cancer treatment may also be associated with vitamin or vitamin derivative (e.g. Leucovorin®) treatment.
Anti-cancer drugs, e.g. for the treatment of breast cancer, e.g. may be used in combination with Abraxane® which may improve the release of drugs, and even may enhance the drug benefit, e.g. such as in case of administration of paclitaxel in combination with Abraxane®. (wherein Abraxane® combines the drug paclitaxel with the protein albumin, which turns into a nanoparticle when injected into the bloodstream allowing a greater concentration of the drug in the tumor and starving the malignant cells of the nutrients they need to grow).
If the compounds of the present invention are administered in combination with other drugs dosages of the co-administered second drug will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated, as in case of a compound of the present invention. In general dosages similar than those as provided by the second drug supplier may be appropriate
The chemical names of the compounds of the present invention as indicated herein are copied from ISIS, version 2.5 (AutoNom 2000 Name). Chemical names of second drug substances and other substances may be derived from the Internet, e.g. via a search program such as the SCI FINDER.
In another aspect the present invention provides a compound of formula
wherein
R1 is aryl, cyclohexyl or heterocyclyl, or (C1-4)alkyl substituted by aryl, cyclohexyl or heterocyclyl,
R2 is heterocyclyl,
R3 is branched (C3-12)alkyl, aryl, cyclohexyl or heterocyclyl, or (C1-4)alkyl substituted by aryl, cyclohexyl or heterocydyl, and
R4 is H or alkyl.
In another aspect the present invention provides a compound of formula
wherein
R1 is aryl, cyclohexyl or heterocyclyl, or (C1-4)alkyl substituted by aryl, cyclohexyl or heterocyclyl,
R2 is heterocyclyl,
R3 is alkyl, aryl, cyclohexyl or heterocyclyl, or (C1-4)alkyl substituted by aryl, cyclohexyl or heterocyclyl,
R4 is H or alkyl, or
R3 and R4 together with the carbon atom to which they are attached are cycloalkyl fused with phenyl.
In the following examples all temperatures indicated are in degree Celsius (° C.).
The following abbreviations are used
EtOAc ethyl acetate
RT room temperature
2.25 g of 2-methoxybenzaldehyde in 10 ml of dry CH2Cl2 are treated with 3.18 g of 3,5-dichloroaniline and 6.93 g of sodium triacetoxyborohydride and the mixture obtained is stirred at RT until TLC analysis shows consumption of starting material. To the mixture obtained a saturated aqueous solution of NaHCO3 is slowly added until no further gas evolution occurs. A two phase system is formed and the aqueous layer is separated and washed with EtOAc. The combined organic layers are dried, solvent is removed under reduced pressure and (3,5-dichloro-phenyl)-(2-methoxy-benzyl)-amine is obtained. 150 mg of 3-methyl-isonicotinic acid in 10 ml of dry CH2Cl2 are treated with 217 μl of 1-chloro-N,N,2-trimethyl-1-propenylamine and the mixture obtained is stirred at RT until TLC analysis shows consumption of starting material. To the mixture obtained 339 mg of (3,5-dichloro-phenyl)-(2-methoxy-benzyl)-amine and 460 μl of triethylamine are added and the mixture obtained is stirred at RT until TLC analysis shows no further reaction progress. The mixture obtained is diluted with EtOAc and treated with a saturated aqueous solution of NaHCO3. The aqueous layer is separated and washed with EtOAc. A two phase system is formed and the aqueous layer is separated and washed with EtOAc. The combined organic layers are dried, solvent is removed under reduced pressure and N-(3,5-dichloro-phenyl)-N-(2-methoxy-benzyl)-3-methyl-isonicotinamide is obtained.
Under an atmosphere of argon, 2.11 g Of 3,5-dichloroaniline in 50 ml of dry CH2Cl2 are treated with 1.96 g of 2-methoxyacetophenone and 3.96 g of triethylamine. To the mixture obtained 6.5 ml of a solution of titanium tetrachloride (1.0 M in CH2Cl2) is added dropwise and the mixture obtained is stirred at RT overnight. To the mixture obtained 39 ml of a solution of sodium cyanoborohydride (1.0 M in methanol) is added and the mixture is stirred for 1 hour. The pH of the mixture is adjusted to ca. 13 by addition of NaOH (1.0 M in water) and EtOAc is added. A two phase system is formed and the aqueous layer is separated and washed with EtOAc. The combined organic layers are dried and solvent is removed under reduced pressure. (3,5-dichloro-phenyl)-[1-(2-methoxy-phenyl)-ethyl]-amine is obtained. 136 mg of 3-methyl-isonicotinic acid in 3 ml of dry CH2Cl2 are treated with 140 μl of 1-chloro-N,N,2-trimethyl-1-propenylamine and the mixture obtained is stirred at RT until TLC analysis shows consumption of starting material. To the mixture obtained 95 mg of (3,5-dichloro-phenyl)-[1-(2-methoxy-phenyl)-ethyl]-amine, 40 mg of N,N-dimethyl-4-aminopyridine and 97 mg of triethylamine are added. The mixture obtained is stirred at RT until TLC analysis shows no further reaction progress. The mixture obtained is diluted with EtOAc and treated with a saturated aqueous solution of NaHCO3. A two phase system is formed and the aqueous layer is separated and washed with EtOAc. The combined organic layers are dried, solvent is removed under reduced pressure and N-(3,5-dichloro-phenyl)-N-[1-(2-methoxy-phenyl)-ethyl]-3-methyl-isonicotinamide is obtained.
Analogously to a method as described in Examples 1 and 2, but using appropriate starting materials (intermediates) compounds of formula
wherein R1, R2, R3 and R4 are as set out in TABLE I below, are obtained:
In TABLE 1 “EX” is the Example number and “MS” is the M+ peak determined in mass spectroscopy analysis. In examples 1, 2, 3, 4, 8, 140, 141, 143, 144, 145, 146, 148, 149, 150, 151, 153, 154, 156, 158, 159, 160, 161, 165, 166, 171, 173, 176, 177, 178, 179, 180, 182, 183, 185, 186, 190, 191, 197 to 202, 233, 237 to 240, 243, 245 to 254 and 258 to 265 the data set out in the column “MS” refers to the [M+Na]+-peak, in all other Examples to the [M+H]+-peak with the exception of example 224 ([M+K]+ peak).
The compound structures of the compounds indicated in TABLE 1 are confirmed by NMR spectroscopy.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0606202.0 | Mar 2006 | GB | national |
| 06120553.0 | Sep 2006 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2007/002764 | 3/28/2007 | WO | 00 | 9/26/2008 |
