CN100378096C - Diazepanes derivatives useful as LFA inhibitors - Google Patents
Diazepanes derivatives useful as LFA inhibitors Download PDFInfo
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- CN100378096C CN100378096C CNB2004800021638A CN200480002163A CN100378096C CN 100378096 C CN100378096 C CN 100378096C CN B2004800021638 A CNB2004800021638 A CN B2004800021638A CN 200480002163 A CN200480002163 A CN 200480002163A CN 100378096 C CN100378096 C CN 100378096C
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Abstract
Pharmaceutically active diazepanes, e.g. useful for treating disorders or diseases mediated by LFA-1/ICAM-1, LFA-1/ICAM-2, LFA-1/ICAM-3 or LFA-1/JAM-1 interactions.
Description
The present invention relates to the Diazesuberane (diazepane) of pharmaceutical active.
On the one hand, the invention provides the compound of formula I:
For example, comprise formula I
ACompound:
Wherein:
R
1Be (C
1-4) alkyl, methyl for example,
R
2Be unsubstituted (C
1-4) alkyl for example methyl or the (C that replaced by following group
1-4) alkyl:
Unsubstituted or replacement
-(C
6-18) aryl for example phenyl or
-with have 5 or 6 ring memberses and 1 to 4 heteroatomic heterocyclic radical condensed (C that is selected from N, O, S
6-18) aryl phenyl for example,
For example described aryl or replaced by following group list with heterocyclic radical condensed aryl or polysubstituted:
-halogen,
-halo (C
1-6) alkyl,
-(C
1-6) alkoxyl group,
-cyano group,
-amino,
R
3Replaced or polysubstituted (C by following group list
6-18) aryl phenyl for example:
-halogen,
-halo (C
1-6) alkyl,
-halo (C
1-6) alkoxyl group,
-cyano group,
-phenyl,
-having 5 to 6 ring memberses and 1 to 4 heteroatomic heterocyclic radical that is selected from N, O, S, aromatic heterocyclic radical for example is as pyrimidyl.
Preferably, in formula I compound
-R
1Be methyl,
-R
2Be methyl or
The methyl that is replaced by following group:
-quinolyl,
-benzo [1,3] dioxolyl,
-phenyl,
-replaced or polysubstituted phenyl by following group list: halogen, halo (C
1-4) alkyl, (C
1-4) alkoxyl group, cyano group, amino, dimethylamino, carboxyl (C
1-2) alkyl carbon acylamino, amino (C
1-2) alkyl carbon acylamino, (C
2-4) thiazolinyl carbon acylamino, heterocyclic radical carbonyl (C
1-2) the alkyl carbon acylamino, wherein heterocyclic radical has 6 ring memberses and 2 heteroatomss that are selected from N, O, as piperazinyl, morpholinyl,
-R
3Replaced or phenyl polysubstituted, that for example 1-replaces to 3-by following group list:
-halogen,
-halo (C
1-2) alkyl, for example CF
3,
-halo (C
1-2) alkoxyl group, for example OCF
3,
-cyano group,
-phenyl,
-heterocyclic radical comprises aromatic heterocyclic radical, and it has 6 ring memberses and 2 nitrogen heteroatoms, as pyrimidyl.
On the other hand, the invention provides the compound of formula I, wherein:
-R
1Be methyl,
-R
2By the methyl that quinoline-the 6-base replaces,
-R
3Replaced by following group list or phenyl that polysubstituted, for example 1-or 2-replace:
-halogen, for example fluorine, chlorine, bromine,
-halo (C
1-2) alkyl, for example CF
3,
-halo (C
1-2) alkoxyl group, for example OCF
3,
-phenyl,
-have the aromatic heterocyclic radical of 6 ring memberses and 2 nitrogen heteroatoms, for example a pyrimidine-5-base.
On the other hand, the invention provides the compound of formula I, wherein:
-R
1Be methyl,
-R
2By the methyl that benzo [1,3] dioxole-the 5-base replaces,
-R
3Replaced by following group list or phenyl that polysubstituted, for example 1-or 2-replace:
-halogen, fluorine or chlorine for example,
-halo (C
1-2) alkyl, for example CF
3,
-halo (C
1-2) alkoxyl group, for example OCF
3,
-cyano group.
On the other hand, the invention provides the compound of formula I, wherein:
-R
1Be methyl,
-R
2The methyl that is replaced by phenyl or
By the methyl that such phenyl replaces, this phenyl is replaced by following group list or polysubstituted, for example 1-replaces to 3-:
-halogen, chlorine for example,
-halo (C
1-2) alkyl, for example CF
3,
-(C
1-2) alkoxyl group, methoxyl group for example,
-cyano group,
-amino,
-dimethylamino,
-carboxyl (C
1-2) the alkyl carbon acylamino,
-amino (C
1-2) the alkyl carbon acylamino,
-vinyl carbon acylamino,
-heterocyclic radical carbonyl-(C
1-2) the alkyl carbon acylamino, wherein heterocyclic radical has 6 ring memberses and 2 heteroatomss that are selected from N, O, S, are preferably selected from N or O, piperazine 1-base or morpholine-4-base for example,
-R
3Replaced or polysubstituted phenyl by following group list:
-halogen, for example chlorine or fluorine,
-halo (C
1-2) alkyl, for example CF
3,
-halo (C
1-2) alkoxyl group, for example OCF
3,
-cyano group.
On the other hand, the invention provides the compound of formula I, wherein:
-R
1Be methyl,
-R
2Be methyl,
-R
3By the phenyl of halogen, the replacement of for example chlorine.
On the other hand, the invention provides and be selected from following compound:
-2-[3-(3-fluoro-phenyl)-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[3 for example; 5-cis-3-(3-fluoro-phenyl)-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[3 for example; 5-cis-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(4-fluoro-phenyl)-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[3 for example; 5-cis-3-(4-fluoro-phenyl)-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(2-fluoro-phenyl)-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[3 for example; 5-cis-3-(2-fluoro-phenyl)-5-methyl-2-oxo-4-(quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-base-3-naphthalene-1-base-propionic acid amide
-2-[3-(3-bromo-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; 2-[3 for example; 5-cis-3-(3-bromo-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-base-3-naphthalene-1-base-propionic acid amide
-2-[3-biphenyl-3-base-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide,
-2-[3-(3-chloro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3-chloro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(3; 5-two chloro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3; 5-two chloro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(4-chloro-3-trifluoromethyl-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(4-chloro-3-trifluoromethyl-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(3-chloro-4-fluoro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3-chloro-4-fluoro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-3-(2-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R) 5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-3-(2-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(3; 4-two fluoro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3; 4-two fluoro-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(3-cyano group-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3-cyano group-phenyl)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[5-methyl-2-oxo-3-(3-pyrimidine-5-base-phenyl)-4-(2-quinoline-6-base-ethanoyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[5-methyl-2-oxo-3-(3-pyrimidine-5-base-phenyl)-4-(2-quinoline-6-base-ethanoyl)-[1 for example; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-3-(3-trifluoromethoxy-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-5-methyl-2-oxo-4-(2-quinoline-6-base-ethanoyl)-3-(3-trifluoromethoxy-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-fluoro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[4-(2-benzo [1 for example; 3] dioxole-5-base-ethanoyl)-3; 5-cis-3-(3-fluoro-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-5-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-5-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-chloro-4-fluoro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-chloro-4-fluoro-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-cyano group-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-3-(3-cyano group-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-5-methyl-2-oxo-3-(3-trifluoromethoxy-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-(2-benzo [1; 3] dioxole-5-base-ethanoyl)-5-methyl-2-oxo-3-(3-trifluoromethoxy-phenyl)-[1,4] Diazesuberane-1-yl]-3-naphthalene 1-base-propionic acid amide
-2-[3-(3-chloro-phenyl)-5-methyl-2-oxo-4-phenyl acetyl-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3-chloro-phenyl)-5-methyl-2-oxo-4-phenyl acetyl-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(3-fluoro-phenyl)-5-methyl-2-oxo-4-[(3-trifluoromethyl-phenyl)-and ethanoyl]-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-{3 for example; 5-cis-3-(3-fluoro-phenyl)-5-methyl-2-oxo-4-[(3-trifluoromethyl-phenyl)-and ethanoyl]-[1; 4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide
-2-{3-biphenyl-4-base-5-methyl-2-oxo-4-[2-(2; 3; 6-three chloro-phenyl)-and ethanoyl]-[1; 4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide, for example 3,5-cis-2-{3-biphenyl-4-base-5-methyl-2-oxo-4-[2-(2; 3; 6-three chloro-phenyl)-ethanoyl]-[1,4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide
-2-[4-[2-(4-cyano group-phenyl)-ethanoyl]-3-(3; 4-two fluoro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-[2-cyano group-phenyl)-ethanoyl]-3-(3; 4-two fluoro-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[3-(3-chloro-phenyl)-4-[2-(4-cyano group-phenyl)-ethanoyl]-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-3-(3-chloro-phenyl)-4-[2-(4-cyano group-phenyl)-ethanoyl]-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-[2-(4-amino-phenyl)-ethanoyl]-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-[2-(4-amino-phenyl)-ethanoyl]-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-[2-(4-amino-phenyl)-ethanoyl]-5-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-[2-(4-amino-phenyl)-ethanoyl]-5-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-[2-(4-dimethylamino-phenyl)-ethanoyl]-5-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-[2-(4-dimethylamino-phenyl)-ethanoyl]-5-methyl-2-oxo-3-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-[2-(3-amino-phenyl)-ethanoyl]-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-[2-(3-amino-phenyl)-ethanoyl]-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-N-(4-{2-[4-(1-formamyl-2-naphthalene-1-base-ethyl)-7-methyl-3-oxo-2-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-succinamic acid; N-(4-{2-[(2S for example; 7R)-4-((R)-1-formamyl-2-naphthalene-1-base-ethyl)-7-methyl-3-oxo-2-(3-trifluoromethyl-phenyl)-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-succinamic acid
-N-(4-{2-[4-(1-formamyl-2-naphthalene-1-base-ethyl)-2-(3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-succinamic acid; N-(4-{2-[(2S for example; 7R)-4-((R)-1-formamyl-2-naphthalene-1-base-ethyl)-2-(3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-succinamic acid
-N-(3-{2-[4-(1-formamyl-2-naphthalene-1-base-ethyl)-2-(3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-succinamic acid; N-(3-{2-[(2S for example; 7R)-4-((R)-1-formamyl-2-naphthalene-1-base-ethyl)-2-(3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-succinamic acid
-2-[4-{2-[4-(2-amino-acetylamino)-phenyl]-ethanoyl }-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-{2-[4-(2-amino-acetylamino)-phenyl]-ethanoyl }-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-{2-[3-(2-amino-acetylamino)-phenyl]-ethanoyl }-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-{2-[3-(2-amino-acetylamino)-phenyl]-ethanoyl }-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-2-[4-{2-[4-(3-amino-propionyl amino)-phenyl]-ethanoyl }-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-{2-[4-(3-amino-propionyl amino)-phenyl]-ethanoyl }-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide
-N-(4-{2-[4-(1-formamyl-2-naphthalene-1-base-ethyl)-2-(3-chloro-phenyl) 7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-acrylamide; N-(4-{2-[4-((R)-1-formamyl-2-naphthalene-1-base-ethyl)-2-(3-chloro-phenyl)-7-methyl-3-oxo-[1 for example; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-acrylamide
-N-; (4-{2-[4-; (1-formamyl-2-naphthalene-1-base-ethyl)-2-; (3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-4-morpholine-4-base-4-oxo-butyramide; N-for example; (4-{2-[; (2S; 7R)-4-; (; (R)-1-formamyl-2-naphthalene-1-base-ethyl)-2-; (3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-4-morpholine-4-base-4-oxo-butyramide
-N-; (4-{2-[4-; (1-formamyl-2-naphthalene-1-base-ethyl)-2-; (3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-4-oxo-4-piperazine-1-base-butyramide; N-for example; (4-{2-[; (2S; 7R)-4-; (; (R)-1-formamyl-2-naphthalene-1-base-ethyl)-2-; (3-chloro-phenyl)-7-methyl-3-oxo-[1; 4] Diazesuberane-1-yl]-2-oxo-ethyl }-phenyl)-4-oxo-4-piperazine-1-base-butyramide
-2-{3-(3-chloro-phenyl)-4-[2-(2-methoxyl group-phenyl)-ethanoyl]-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide; (R)-2-{ (3S for example; 5R)-3-(3-chloro-phenyl)-4-[2-(2-methoxyl group-phenyl)-ethanoyl]-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide
-2-{3-(3-chloro-phenyl)-4-[2-(4-methoxyl group-phenyl)-ethanoyl]-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide; (R)-2-{ (3S for example; 5R)-3-(3-chloro-phenyl)-4-[2-(4-methoxyl group-phenyl)-ethanoyl]-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl }-3-naphthalene-1-base-propionic acid amide
-2-[4-[2-(3-chloro-4-methoxyl group-phenyl)-ethanoyl]-(3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl)-3-naphthalene-1-base-propionic acid amide; (R)-2-[(3S for example; 5R)-4-[2-(3-chloro-4-methoxyl group-phenyl)-ethanoyl]-(3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl)-3-naphthalene-1-base-propionic acid amide
-2-[4-ethanoyl-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1; 4] Diazesuberane-1-yl]-3-naphthalene 1-base propionic acid amide; (R)-2-[(3S for example; 5R)-4-ethanoyl-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base propionic acid amide.
On the other hand, the invention provides and be formula I
PREFThe formula I compound of compound:
For example comprise formula I '
PREFCompound:
On the other hand, the invention provides (R)-2[(3S, 5R)-4-(2-benzo [1,3] dioxole-5-base-ethanoyl)-3-(3-chloro-phenyl)-5-methyl-2-oxo-[1,4] Diazesuberane-1-yl]-3-naphthalene-1-base-propionic acid amide.
If do not define in addition, then in this article:
-alkyl comprises straight or branched (C
1-6) alkyl, as (C
1-4) alkyl, for example (C
1-2) alkyl, comprise alkyl unsubstituted or that replace, for example by the conventional group in the organic chemistry for example halogen, OH, NH
2Or halo (C
1-6) alkyl that replaces of alkyl;
-haloalkyl comprises halo (C
1-6) alkyl, as halo (C
1-4) alkyl, for example halo (C
1-2) alkyl, wherein in alkyl, there are one or more halogens, preferred-CF
3
-halogen comprises fluorine, chlorine, bromine, iodine, for example fluorine, chlorine, bromine, preferably fluorine or chlorine;
-amino comprises amino unsubstituted and that replace, for example (C
1-4) alkylamino, two (C
1-4) alkylamino and by the amino of acyl substituted;
-acyl group comprises the acyl group that has 1 to 12 carbon atom altogether, for example carboxyl (C
1-4) alkyl-carbonyl such as carboxyl (C
1-3) alkyl-carbonyl, amino (C
1-4) alkyl-carbonyl is as amino (C
1-3) alkyl-carbonyl, (C
2-4) alkenyl carbonyl or heterocyclic radical carbonyl (C
1-4) alkyl-carbonyl, wherein heterocyclic radical has 5 or 6 ring memberses and 1 to 4, preferred 1 or 2 heteroatoms that is selected from N, O, S, preferred N, O, for example piperazinyl or morpholinyl;
-heterocyclic radical comprises having 5 or 6 ring memberses and 1 to 4 heteroatomic heterocyclic radical that is selected from N, O, S, preferred N, O, as alicyclic and aromatic heterocyclic radical, for example have 6 ring memberses and 1 to 2 the heteroatomic heterocyclic radical that is selected from N, O, for example piperazinyl, morpholinyl, pyrimidyl;
-aryl comprises (C
6-18) aryl for example phenyl and with have 5 or 6 ring memberses and 1 to 4 and be selected from the heteroatomic heterocyclic radical condensed (C of N, O, S, preferred N, O
6-18) aryl phenyl for example, for example have 5 ring memberses and 2 heteroatomic heterocyclic radicals that are selected from N, O, preferred benzo (1,3) dioxole-4-base, benzo (1,3) dioxole-5-base, quinoline-5-base, quinoline-6-base, quinoline-7-base, quinoline-8-base.
Compound provided by the invention for example comprises formula I, I
A, I
PREFAnd I '
PREFCompound, be called " compound of the present invention " hereinafter.Each independent substituting group defined above can itself be a preferred substituted in the compound of the present invention, and is independently of one another with defined other substituting group.
Compound of the present invention comprises any type of compound, for example free form, salt form, solvate form thereof and salt form and be the compound of solvate form thereof.The compound of the present invention of free form can be transformed into the compound of corresponding salt form, vice versa.Can with free form or salt form and be the free form of non-solvent compound form or the compound of salt form accordingly for the compound of the present invention of solvate form thereof is transformed into, vice versa.
On the other hand, the invention provides the compound of the present invention of salt form.
The salt of compound of the present invention comprises pharmaceutically useful salt, for example comprises metal-salt or acid salt.Metal-salt comprises for example basic metal or alkaline earth salt; Acid salt comprises formula I compound and the sour for example salt of acetate, trifluoroacetic acid, hydrochloric acid.
Compound of the present invention can exist with isomeric forms and its form of mixtures; For example optically active isomer, diastereomer, cis/trans isomer.Compound of the present invention can for example contain unsymmetrical carbon, therefore can with diastereomer and its mixture or enantiomorph and its mixture for example the form of racemoid exist.Radicals R for example
1, R
3With the menaphthyl of * position in the formula I compound can be (R)-or (S)-configuration, for example comprise its mixture.Preferably, menaphthyl and the R in the formula I compound
1All are (R)-configurations, R
3It is (S)-configuration.Isomer mixture can be separated suitably, for example according to as separate with the similar method of ordinary method and to obtain pure isomer.The present invention includes the compound of the present invention of any isomeric forms and any isomer mixture form.
Similar consideration also is applicable to the starting raw material that shows the isomer characteristic, for example to described above similar.
Described herein any compound, for example compound of the present invention can adopt the preparation of suitable method, for example according to for example with the similar method of ordinary method for example or given herein method prepare.Starting raw material be known or can according to for example with similar method of ordinary method or the preparation of described herein method.
On the other hand, the invention provides the method for preparation compound of the present invention, it comprises:
A) make the compound of formula II:
R wherein
1And R
3As defined above,
Compound reaction with formula III:
For example react with protected form,
For example under existing, following material reacts:
-condensing agent, for example carbodiimide
-alkali, amine for example, as diisopropyl ethyl amine or Dimethylamino pyridine,
In organic solvent, react, polar organic solvent for example, as N, dinethylformamide randomly goes protection, and randomly further reaction and isolate the compound of formula I obtaining the compound of formula I,
Perhaps
B) make the compound of formula IV
R wherein
1And R
2As defined above,
With the optional formula V that replaces
AOr V
BCompound reaction:
Wherein A represents to have 5 (n=1) or the individual ring members of 6 (n=2) and 1 to 4 heteroatomic aromatic heterocyclic radical that is selected from N, O, S,
For example in catalyzer such as Pd (PPh
3)
4React under existing,
Obtain formula I compound, wherein R
3Be the phenyl that is optionally substituted or have 5 or 6 ring memberses and phenyl that heteroatomic aromatic heterocyclic radical that 1 to 4 is selected from N, O, S replaces, and from reaction mixture, isolate the formula I compound of gained.
The randomly protected radicals R of formula III
2For example comprise the phenyl that is replaced by amine.Described amine can be protected by suitable protecting group, and described suitable protecting group for example comprises tertbutyloxycarbonyl (Boc), after formula II compound and the reaction of formula III compound, protecting group can be removed to obtain the free amine groups.Further reaction for example comprises as one sees fit described amine groups alkylation or acidylate, for example according to for example carrying out with the similar method of ordinary method.
In the intermediate (starting raw material) of formula II or formula IV, if there is functional group, then it can randomly be protected form or salt form (if having salt forming group).The optional protecting group that exists can be removed in the suitable stage, for example according to for example removing with the similar method of ordinary method.
Thus obtained formula I compound can be transformed into another kind of formula I compound, for example or the formula I compound of the free form that obtains can be transformed into the formula I compound of salt form, vice versa.
On the other hand, the invention provides:
The compound of-Shi II, wherein R
1And R
3As defined above and
The compound of-Shi IV, wherein R
1And R
2As defined above,
For example it can be used as the intermediate for preparing compound of the present invention.
Above-mentioned reaction A) is the acylation reaction of amine, can under appropriate condition, carries out, for example according to for example carrying out with similar method or the described herein method of ordinary method.Above-mentioned reaction B) is cross-coupling reaction, can under appropriate condition, carries out, for example according to for example carrying out with similar method or the described herein method of ordinary method.
Described herein any compound, the intermediate of compound for example of the present invention and formula II and IV can prepare under appropriate condition, for example according to for example with similar method of ordinary method or given herein method preparation.
Compound of the present invention shows the valuable pharmacological characteristic, for example by mediation as the active pharmacological characteristics that shows of inhibition LFA-1/ICAM-1, LFA-1/ICAM-2, LFA-1/ICAM-3 or LFA-1/JAM-1 interaction, therefore can mediate for example inflammation-inhibiting, for example shown in external and body built-in test system herein like that, thereby be applicable to treatment.
A. vitro test system: (cell free analysis)
This analysis mensuration soluble human ICAM-1 combines with fixed people LFA-1's, LFA-1 by with Dustin etc., J.Immunol.148,2654-2663, the similar immunoaffinity chromatography of 1992 described methods is obtained by JY cell (a kind of people's lymphoblastoid B clone) purifying.ICAM-1 mouse C κ fusion rotein (ICAM-1) is with Weitz-Schmidt etc., Anal.Biochem.238,184-190,1996 described rhabdovirus systems preparations.
With the LFA-1 of purifying with containing 2mM MgCl
2, pH 7.4 phosphate buffered saline buffer (PBS) diluted by 1: 20 and reach 3 hours in being applied under 37 ℃ on the microtiter plate (Nunc).Each plate was blocked 2 hours with 1% the heat treated bovine serum albumin in PBS down in 37 ℃, used PBS, 2mM MgCl subsequently
2, 1% foetal calf serum, pH 7.4 (analysis buffer) washing.With compound of the present invention (solution of 10mM in DMSO) with analysis buffer dilution and add in the plate.Be added in the biotinylated reorganization ICAM-1 (6 μ g/ml) in the analysis buffer and make its under 37 ℃ in conjunction with 1 hour.Behind the incubation, wash each hole with analysis buffer.Add with the streptavidin-peroxidase of analysis buffer dilution in 1: 5000 and 37 ℃ of following incubations 45 minutes.Plate is washed with analysis buffer, and in each hole, add 2,2 '-azino-two (3-ethyl benzo thiazole phenanthroline-6-sulfonic acid) di-ammonium salts substrate solution.Stop this reaction after 20 minutes, by in microplate reader, measuring bonded ICAM-1 in 405nm place measuring light density.
In this was analyzed, compound of the present invention showed activity, and compound for example of the present invention suppresses the adhesion of LFA-1 to ICAM-1, IC
50≤ 50 μ M, preferred 0.05 to 50 μ M.Embodiment 13 and 14 compound are preferred compounds of the present invention, demonstrate the IC that is respectively 0.43 or 0.09 μ M in this analysis
50Value.We are surprised to find: in described LFA-1 vitro test system, and R wherein
3The formula I compound that is the phenyl of replacement compares wherein R
3The formula I compound exhibits that is unsubstituted phenyl goes out higher IC
50Value.
B. body built-in test system: contact dermatitis (ACD)
With every group of 8 female NMRI mouse organize the belly of mouse after shaving hair with 50 μ l oxazolone (2% in acetone) sensitization, after 7 days, excite in the auris dextra internal surface of mouse oxazolone with 10 μ l 0.2%.The left ear that excites is estimated dermatitis with each ear weight difference as normal control, with it as exciting measuring of back 24 hours inflammatory swellings.In test group and control group dermatitis is estimated, test group is with the oral processing of test compound (exciting back 2 hours), and control group only carries out similar processing with carrier.For Orally administered, these compounds are used with oil-in-water emulsion.With the data of the control group of test group and vehicle treated with ANOVA, then with Dunnet T-check (normal distribution or data) or check with H-check and U-respectively and carry out statistical analysis.When using with the oral dose of 0.03mg/kg to 30mg/kg, compound of the present invention suppresses the inductive phase of contact dermatitis.For example, in this analysis, the compound of embodiment 14 has＞30% restraining effect when using with the oral dose of 0.03mg/kg.
Therefore, estimate that compound of the present invention can be used for treating disease or the illness by the interaction mediation of the LFA-1 relevant with cell adhesion, migration and activation and its part.These compounds preferably can be used for treating inflammatory conditions, allergic disease or autoimmune disorder.Example has the inflammatory damage (psoriatic of skin, eczema, urticaria, acne, pyoderma gangraenosum, sunburn or toxic epidermal necrolysis), the inflammatory damage of lung (adult respiratory distress syndrome, COPD), the inflammatory damage of kidney (acute/chronic between matter/glomerulonephritis), the inflammatory damage of liver is (acute/chronic hepatitis, granulomatous disease), inflammatory damage (the ischemia/reperfusion injury of cardiovascular systems, shock, arteriosclerosis, vasculitis), inflammatory damage (the conjunctivitis of eye, keratitis) or GI inflammatory damage (regional ileitis, ulcerative colitis).The example of allergic conditions has contact dermatitis, atopic dermatitis or asthma.Rheumatoid arthritis, multiple sclerosis, (systematicness) lupus erythematosus, sjogren syndrome, alopecia areata, uveitis, lichen planus, day kitchen sore, bullous pemphigoid, epidermolysis bullosa or myasthenia gravis are the examples of the illness of autoimmunization mediation.
Compound of the present invention also can be used for preventing acute and chronic rejection, host versus graft or the graft versus host disease (GVH disease) of homotransplant or heterograft transplanting, also can be used for treating the neoplastic disease, AIDS and the infectious diseases that comprise tumprigenicity or carcinous long transfer or cancer.
Described treatment comprises prevention.
Compound of the present invention can be preferred for treating rejection and the graft versus host disease (GVH disease) after psoriatic, rheumatoid arthritis, inflammatory bowel (regional ileitis, ulcerative colitis), (systematicness) lupus erythematosus, atopic dermatitis, sjogren syndrome, the transplanting.
One preferred aspect, compound of the present invention can be used for treating for example for example psoriatic or atopic dermatitis of rheumatoid arthritis or inflammatory conditions of autoimmune disorder, as rheumatoid arthritis.
For such use, required dosage will change according to method of application, concrete illness to be treated and required effect certainly.Generally speaking, show that using compound of the present invention with about 0.1mg/kg to the per daily dose general of about 100mg/kg body weight can obtain gratifying result.Bigger Mammals for example the per daily dose that is suitable for of people for about 0.5mg to about 500mg (for example about 0.00625mg/kg is about 6.25mg/kg extremely), this per daily dose can be for example to be no more than 4 times divided dose every day or to be used easily with the slowly-releasing form.
Compound of the present invention can general be used or topical application, can use by any conventional route, particularly for example Orally administered through intestines, for example Orally administered with tablet or Capsule form, topical application, for example with lotion, gelifying agent, ointment or the topical application of ointment form, perhaps via intranasal application or use with suppository form.Applied dermally by patch or other delivery system also can be prevention or a kind of possibility approach for the treatment of above-mentioned disease.
Use for the part, for example comprise being applied to eye, every day for several times, for example every day 2 to 5 topical application concentration be 0.5-10%, can obtain gratifying result as the active substance of 1-3%.
On the other hand, the invention provides the compound of the present invention that as medicine, for example is used as the medicine of above-mentioned disease of antagonism such as rheumatoid arthritis.
For pharmaceutical use, compound of the present invention comprise one or more, preferred a kind of compound of the present invention, for example combination of two or more The compounds of this invention.
On the other hand, the invention provides the purposes of compound of the present invention in preparation medicine, for example pharmaceutical composition, described medicine is used for the treatment of above-mentioned disease, for example by the interact disease of mediation of LFA-1/ICAM-1, LFA-1/ICAM-2, LFA-1/ICAM-3 or LFA-1/JAM-1, for example resist inflammatory diseases, allergic conditions or autoimmune disorder, as autoimmune disorder, for example psoriatic, asthma or rheumatoid arthritis.
On the other hand, the invention provides a kind of pharmaceutical composition, it comprises compound of the present invention and at least a pharmaceutically useful vehicle, for example comprise carrier and/or thinner, for example comprise the salt and/or the buffer reagent of weighting agent, tackiness agent, disintegrating agent, glidant, lubricant, sugar and sweeting agent, perfume compound, sanitas, stablizer, wetting agent and/or emulsifying agent, solubilizing agent, adjusting osmotic pressure.
Described composition can according to for example with the preparation of the similar method of ordinary method, for example by compound of the present invention and pharmaceutically useful vehicle such as carrier and/or mixing diluents are prepared.Be used for Orally administered unit dosage form and contain for example about 0.1mg to about 1000mg (for example about 0.00125mg/kg extremely about 12.5mg/kg), for example 0.5mg to 500mg, as the about 125mg compound of the present invention extremely of 1mg for example.
Compound of the present invention can be applied with pharmacologically acceptable salt, for example acid salt or metallic salt form; Perhaps be applied with free shape; Randomly be applied with solvate form thereof.The compound exhibits of the present invention of salt form goes out the activity with the compound same levels of the present invention of free form, randomly is solvate form thereof.
On the other hand, the invention provides:
-treatment is by LFA-1/ICAM-1, LFA-1/ICAM-2, LFA-1/ICAM-3 or LFA-1/JAM-1A the interact illness of mediation or disease, the method for above-mentioned disease for example in the individuality of the described treatment of needs, and this method comprises the compound of the present invention of described individuality being used significant quantity; With
-treatment above-mentioned disease, for example inflammatory, allergy or autoimmune disorder, the method for above-mentioned such disease, for example psoriatic, asthma, rheumatoid arthritis for example in the individuality of the described treatment of needs, this method comprises the compound of the present invention of described individuality being used significant quantity.
For this treatment, proper dosage will depend on certainly that the chemical property of for example used compound of the present invention and pharmacokinetic data, discrete are subjected to alms giver's body, method of application and the character of the illness of being treated and seriousness and change.Yet, generally speaking,, obtain satisfied result for bigger Mammals people for example, suitable per daily dose is that about 0.01g is to about 1.0g (for example about 0.125mg/kg is about 12.5mg/kg extremely) compound of the present invention; This per daily dose can be for example be applied easily with the divided dose that is no more than 4 every day.
Compound of the present invention can be applied by any conventional route, for example uses through intestines, for example comprises nasal cavity, oral cavity, rectum, Orally administered; Use through parenteral, for example comprise intravenously, intramuscular, subcutaneous administration; Or topical application, for example comprise in epidermis, the nose, use in the tracheae; For example with dressing or uncoated tablets, capsule, injection solution agent or suspensoid form, for example with the form of ampulla, bottle, use with ointment, gelifying agent, paste, suction powder, foam, tincture, lipstick, drops, spray form or with suppository form.
Compound of the present invention can be separately or with at least a, for example one or more other forms of pharmacologically active agents combinations are used for pharmacological agent of the present invention.Described other forms of pharmacologically active agents for example is included in has active compound or other anti-inflammatory agent in the immunomodulatory field, for example be used for the treatment of or prevent the acute or chronic rejection of inflammatory or allergic conditions, autoimmune conditions or homotransplant or heterograft.For example, compound of the present invention can use with following drug regimen: the ciclosporin class, rapamycins or ascosin class or their immunosuppression analogue be ciclosporin A for example, ciclosporin G, FK-506, ASM 981, rapamycin, 40-O-(2-hydroxyl) ethyl-rapamycin etc., reflunomide, endoxan, azathioprine, methotrexate, FTY 720, take fluorine Lip river rice, mizoribine, mycophenolic acid, mycophenlate mofetil, 15-deoxidation Antibiotic BMG-162aF2, the immunosuppression monoclonal antibody is for example at the monoclonal antibody of leukocyte receptors MHC for example, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 or their part, or other immunomodulatory compounds CTLA4Ig for example, or other adhesion molecule inhibitor mAbs or comprise the low-molecular-weight depressor of selecting protein antagonist and VLA-4 antagonist for example.
Combination comprises fixed combination, and wherein two or more forms of pharmacologically active agents are in the same preparation; Complete medicine box, two or more forms of pharmacologically active agents that wherein are in the independent preparation are sold in same packing, for example have co-administered specification sheets; And independent assortment, wherein forms of pharmacologically active agents is packed separately, but the specification sheets of while or sequential application is provided.
If compound of the present invention and other immunosuppression/immunomodulatory or agent having ahtiphlogistic activity combined administration, for example be used to prevent or treat above given acute or chronic rejection or inflammatory or autoimmune conditions, the dosage of co-administered immunosuppression, immunomodulatory or anti-inflammatory compound will depend on the type (for example it is steroid or ciclosporin) of used coupling medicine, used concrete medicine, the illness of being treated etc. certainly and change.Generally speaking, suitable with co-administered given dosage range dosage may suit.
On the other hand, the invention provides a kind of pharmaceutical composition of the present invention, it also comprises other forms of pharmacologically active agents.
On the other hand, the invention provides:
The method of above-mentioned illness of-treatment or disease, this method comprises compound at least a of the present invention and at least a second kind of forms of pharmacologically active agents of co-administered for example while or sequential application treatment significant quantity, described forms of pharmacologically active agents is selected from immunosuppression, immunomodulatory or agent having ahtiphlogistic activity, for example above-mentioned those; With
-drug regimen, for example complete medicine box, it is used in methods of treatment of the present invention, and it comprises at least a immunosuppression, immunomodulatory or the agent having ahtiphlogistic activity of at least a compound of the present invention and while or sequential application.This complete medicine box can comprise to be used or the specification sheets of sequential application simultaneously.
On the other hand, the invention provides formula I
PCompound:
Wherein:
R
1PBe (C
1-4) alkyl,
R
2PBe (C
1-4) alkyl or-(CH
2)
n-R
4P, wherein:
N is 1,2,3 or 4, and
R
4PBe unsubstituted or replacement
-phenyl or
-with other member ring systems condensed phenyl, this other member ring systems is a 5-or 6-unit heterocycle, has 1 to 4 heteroatoms that is selected from N, O, S, for example substituting group wherein is selected from:
-halogen,
-unsubstituted amino or by one or two (C
1-4) amino that replaces of alkyl,
-cyano group,
-(C
1-4) alkoxyl group,
-(C
1-6) haloalkyl, and
R
3PBe the phenyl that replaces, for example single the replacement or polysubstituted phenyl,, substituting group wherein is selected from:
-halogen,
-(C
1-6) haloalkyl,
-the unsubstituted or phenyl that replaces, substituting group wherein such as R
4PImplication in " phenyl of replacement " described down,
For example be salt and/or solvate form thereof.
In following embodiment, all temperature are all with degree centigrade representing, in reaction process and corresponding the description, and R
2And R
3As defined above.
Used following shortenings:
AcOH acetate
The Boc tertbutyloxycarbonyl
DBU 1,4-diaza-dicyclo [5.4.0] 11 carbon-7-alkene
The DIEA diisopropyl ethyl amine
The DIPCI DIC
DMAP N, N-dimethyl-4-aminopyridine
DMFN, N, dinethylformamide
The EtAc ethyl acetate
Equiv. equivalent
EX embodiment
HOAt 1-hydroxyl-7-azepine benzotriazole
The i-PrOH Virahol
MeOH methyl alcohol
NMM N-methyl-morpholine
The rt room temperature
The THF tetrahydrofuran (THF)
The TFA trifluoroacetic acid
The TsOH tosic acid
The Z carbobenzoxy-(Cbz)
EDC N-ethyl-N`-(3-dimethylamino-propyl)-carbodiimide
N-ethyl-the N`-of EDC-HCl hydrochloride form (3-dimethylamino-propyl)-carbodiimide
Embodiment
Method A
Synthesizing of compound of the present invention
Aa. the ketal intermediate is synthetic
Naphthyl ala amide and the 0.3equiv.NMM of formula A1 are dissolved in the two alkane, add the 1.5equiv. methyl vinyl ketone.The mixture that obtains was stirred under room temperature 15 hours, add 5equiv.2-methoxyl group dioxolane and 1.5equiv.TsOH monohydrate.The mixture that obtains is stirred and dilute with EtAc.With the organic phase that obtains washing and dry, evaporating solvent obtains the ketal intermediate of formula A2, can randomly be purified or without being further purified direct use.
Ab. amine-the protection of phenylglycocoll
To wherein R
3The compound dissolution of formula Phe-gly as defined above is in MeOH.In the above-mentioned solution that obtains, add 2equiv.NaHCO
3With the 1.2equiv.Boc acid anhydrides, with the suspension that obtains in stir, 50 ℃ of heating down.Evaporating solvent from the mixture that obtains adds H
2O and toluene.Separate each phase that obtains, and extract the organic phase that obtains with 1N NaOH.With the pH regulator of the water that obtains to pH 3 and the mixture that obtains with the EtAc extraction.The organic phase that drying obtains, evaporating solvent obtains the Boc-phenylglycocoll of racemic formula A3, wherein R
3As defined above.
Ac. the acidylate of amine
With 1equiv. R wherein
3The compound of formula A2 as defined above, 1.5equiv. be R wherein
3(replacement) Boc-phenylglycocoll and 0.12equiv.HOAt with racemic formula A3 of above-mentioned implication are dissolved among the DMF.At room temperature, in 15 hours, to the EDC that wherein adds 1.5equiv.DIEA and 1.5equiv. free alkali form.Evaporating solvent, with the evaporation residue that obtains with the EtAc dilution and with 1N HCl and 5%NaHCO
3Solution extraction.Dry and the evaporating solvent with the organic phase that obtains.Obtain the compound of the formula A4 of non-enantiomer mixture form, wherein R
3As defined above.
Ad. go protection and reductibility cyclization
Under 0 ℃, incite somebody to action wherein R
3The compound dissolution of formula A4 as defined above is at TFA/H
2Among the O.The mixture that obtains is stirred water termination reaction and evaporating solvent.Obtaining wherein, the Boc-NH-group is dissolved in MeOH/H by the non-enantiomer mixture of de-protected formula A4 compound with it
2Among the O.With the pH regulator of the mixture that obtains to pH 5.Under 0 ℃, in the mixture that obtains, add 0.5equiv.NaCNBH
3At MeOH/H
2Solution among the O stirs the mixture that obtains, evaporating solvent and the evaporation residue that obtains with the EtAc dilution.The 3.5M phosphate buffered saline buffer that adds pH 4 in the mixture that obtains obtains two-phase and with its separation.With the organic phase 5%NaHCO that obtains
3Solution extraction, dry and evaporating solvent.Obtain the compound of formula A5, wherein R
3As defined above.
Ae. the acidylate of Diazesuberane
To wherein R
3The compound of formula A5 as defined above is used in the 1.7equiv. R wherein among the DMF
2R as defined above
2COOH, 1.3equiv.DIEA and 0.2equiv.HOAt handle.With the mixture heating up to 35 that obtains ℃, add 1.7equiv.EDC, the mixture that obtains was stirred 15 hours down in 35 ℃.Evaporating solvent from the mixture that obtains is dissolved among the EtAc evaporation residue that obtains also with 1N HCl and 5%NaHCO
3Solution extraction.Dry and the evaporating solvent with the organic phase that obtains.Obtain the compound of formula A6, if desired, can randomly it be carried out chromatography (silica gel for example, toluene/i-PrOH) so that be further purified.
Method B
At room temperature, 1.5equiv.N-Boc-Beta-alanine or N-Boc-glycine, 1.5equiv.EDC-HCl and the 0.5equiv.DMAP that the compound of embodiment 22 is used in respectively among the DMF handles.The mixture that obtains is diluted with EtAc and 1N HCl, obtain two-phase thus, it is separated, with the organic phase washing that obtains, dry and evaporating solvent.Under 0 ℃, the evaporation residue that obtains is dissolved in TFA/H
2Among the O, stir, with dilution of two alkane and evaporating solvent.The resistates that obtains is handled with reverse-phase chromatography.Obtain the embodiment 31 of trifluoroacetic acid form and the compound of embodiment 29 respectively.When compound that uses embodiment 25 and the sweet amino of N-Boc-, obtain the compound of embodiment 30.
Method C
At room temperature, with the compound of embodiment 31 with excessive at CH
2Cl
2/ K
2CO
3In CH
3J handles, and evaporating solvent from mixture is dissolved in MeOH/H with the evaporation residue that obtains
2Also use solid phase extraction (C-18 post, MeOH/H among the O
2The O gradient) carries out aftertreatment.Obtain the compound of embodiment 32.
Method D
The compound of embodiment 22 or embodiment 23 is handled with succinyl oxide respectively.According to the difference of starting raw material, obtain the compound of embodiment 27 or embodiment 27 respectively.
Method E
6equiv. morpholine and 2equiv.EDC-HCl that the compound of embodiment 27 is used among the DMF under 0 ℃, pH 8 (regulating by adding TFA) handled 4 hours.The mixture that obtains is diluted with EtAc and 1NHCl, separate the two-phase that obtains, with the organic phase washing that obtains, dry and evaporating solvent.Obtain the compound of embodiment 33.
Method F
6equiv. piperazine and 2equiv.EDC-HCl that the compound of embodiment 27 is used among the DMF under pH 8 (regulating by adding TFA) handle.Use the phosphate buffered saline buffer of EtAc and 5M pH 4 to dilute in the mixture that obtains, separate the two-phase that obtains, with the organic phase washing that obtains, dry also evaporating solvent.Obtain the compound of embodiment 34.
Method G
In airtight container, under 130 ℃, with the compound of embodiment 5 respectively with phenyl-boron dihydroxide or pyrimidine-5-boric acid in catalytic amount at glycol dimethyl ether/Na
2CO
3Four triphenyl phosphine palladiums in the aqueous solution (6: 1) exist down to be handled 10 minutes.The mixture that obtains is diluted with EtAc, in pH 4 times with phosphate buffered saline buffer and Na
2CO
3Aqueous solution extraction is from the organic layer evaporating solvent that obtains.According to used boric acid difference, obtain the compound of embodiment 6 or 12b respectively.The compound of embodiment 6 is handled with trifluoroacetic acid, obtained the compound of the embodiment 6 of trifluoroacetic acid salt form.
Similar with above-described method, but use suitable starting raw material, obtain wherein R
1Be methyl and R
2And R
3As defined formula I compound in the following table 1.
The compound of each embodiment
-1-5,7-25,27-28 and 35-38 prepare according to method A;
-6 and 12b prepare according to method G;
-26 and 27 prepare according to method D;
-29-31 prepares according to method B;
-32 prepare according to method C;
-33 prepare according to method E;
-34 prepare according to method F.
Embodiment 6,11,23,25,29 and 31 compound are obtained with the form of trifluoroacetic acid.
Give under " data " item in the table 1
-R
fValue (thin-layer chromatography that on silica gel 60, carries out, toluene/i-PrOH 1: 1 (=T) or EtAc (=E));
-at CDCl
3In
1The H-NMR data,
Except as otherwise noted, otherwise condition as above.
Table 1
The preparation of starting raw material
Naphthyl ala amide (compd A 1)
Naphthalene-1-formic acid is dissolved among the exsiccant THF, adds 5equiv. borine methyl-sulfide mixture.The mixture that obtains is at room temperature stirred, with the EtAc dilution, with 1N HCl and 5%NaHCO
3Solution washing, dry and evaporating solvent.Obtain (naphthalene-1-yl)-methyl alcohol, it is dissolved in CH
2Cl
2In.At room temperature, in the solution that obtains, add 1.5equiv. Dess-Martin reagent.The mixture that obtains is diluted with EtAc, with 1N HCl and 5%NaHCO
3Solution extraction, dry and evaporating solvent.Obtain naphthalene-1-formaldehyde, it is dissolved in CH with the racemic Boc-α of 1equiv.-phosphoryl glycine trimethyl
2Cl
2In, add 1.1equiv.DBU.The mixture that obtains is at room temperature stirred, use 1N HCl and 5%NaHCO successively
3Solution-treated.Separate each phase that obtains, dry and evaporating solvent with the organic phase that obtains.Obtain 2-Boc-amino-3-(naphthalene-1-yl)-methyl acrylate (cis/trans mixture), it is dissolved in MeOH/H under pH 6.5 (phosphate buffered saline buffer)
2Among the O, add the 10%Pd/C of 20% weight ratio.With the mixture hydrogenation under room temperature and 50bar that obtains, filtration catalizer, evaporating solvent from the filtrate that obtains.Obtain racemic naphthyl alanine methyl ester, it is dissolved in NH
3Methanol solution in and stir.The mixture that obtains is extracted aftertreatment.Obtain racemic naphthyl ala amide.
The test implementation example
To restraining effect in the body of contact dermatitis (ACD)
A. method:
The belly of mouse after shaving hair of organizing of every group of 8 female mices carried out epidermis sensitization (the 1st day) and excite (the 8th day) in the auris dextra internal surface of mouse with the oxazolone of 10 μ l0.2% with the oxazolone of 50 μ l2%.The left ear that excites is estimated dermatitis with the auricle weight difference, with its measure (the 9th day) as inflammatory swelling as normal control.In addition, as Bradley etc., J.Invest.Dermatol; Be used as the activity that white corpuscle flows into the myeloperoxidase of measuring (MPO) in the homogenate of the described mensuration ear of 78:206-209 (1982).Excite back 2 hours with the test compound oral processing of animal with embodiment 10.Calculated activity is recently to represent with respect to inflammatory ear swelling and the active inhibition percentage of MPO with the animal of vehicle treated only.For relatively, mouse is handled with 100 μ l monoclonal anti mouse LFA-1 antibody intraperitoneal and estimate according to described method in exciting preceding 1 hour.
B. result
The oral processing of compound with the embodiment 10 of 0.01-10.0mg/kg single dose causes the Inflammatory response of 40-50% to suppress.Observe with the active swelling that suppresses to match of MPO and suppress.Cause the restraining effect of 34-56% with 50-200 μ g/ mouse anti-LFA-1 antibody treatment.
Claims (6)
1. the compound of formula I:
Wherein:
R
1Be C
1-4Alkyl,
R
2Be unsubstituted methyl or the methyl that replaced by following group:
-quinolyl,
-benzo [1,3] dioxolyl,
-phenyl,
-replaced or polysubstituted phenyl by following group list: halogen, halo C
1-4Alkyl, C
1-4Alkoxyl group, cyano group, amino, dimethylamino, carboxyl C
1-2Alkyl carbon acylamino, amino C
1-2Alkyl carbon acylamino, C
2-4Thiazolinyl carbon acylamino, heterocyclic radical carbonyl C
1-2The alkyl carbon acylamino, wherein heterocyclic radical has 6 ring memberses and 2 heteroatomss that are selected from N, O,
R
3Replaced or polysubstituted C by following group list
6-18Aryl:
-halogen,
-halo C
1-6Alkyl,
-halo C
1-6Alkoxyl group,
-cyano group,
-phenyl,
-have an aromatic heterocyclic radical of 6 ring memberses and 2 nitrogen heteroatoms.
2. the compound of claim 1, wherein:
-R
1Be methyl,
-R
2As defined in claim 1, and
-R
3Replaced or polysubstituted phenyl by following group list:
-halogen,
-halo C
1-6Alkyl,
-halo C
1-6Alkoxyl group,
-cyano group,
-phenyl,
-have an aromatic heterocyclic radical of 6 ring memberses and 2 nitrogen heteroatoms.
3. formula I
PREFClaim 1 or 2 compound:
4. each compound in the claim 1 to 3 of salt form.
5. each compound is in the purposes of preparation in the medicine in the claim 1 to 4, and described medicine is used for the treatment of the interact illness or the disease of mediation by LFA-1/ICAM-1, LFA-1/ICAM-2, LFA-1/ICAM-3 or LFA-1/JAM-1.
6. comprise each formula I compound and the pharmaceutical composition of at least a pharmaceutical excipient in the claim 1 to 4.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0301561.7 | 2003-01-23 | ||
| GB0301561A GB0301561D0 (en) | 2003-01-23 | 2003-01-23 | Organic compounds |
| GB0323976.1 | 2003-10-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1735609A CN1735609A (en) | 2006-02-15 |
| CN100378096C true CN100378096C (en) | 2008-04-02 |
Family
ID=9951671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800021638A Expired - Fee Related CN100378096C (en) | 2003-01-23 | 2004-01-22 | Diazepanes derivatives useful as LFA inhibitors |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN100378096C (en) |
| GB (1) | GB0301561D0 (en) |
| ZA (1) | ZA200504672B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001027102A1 (en) * | 1999-10-13 | 2001-04-19 | Novartis Ag | Substituted diazepanes |
| WO2002028842A2 (en) * | 2000-10-02 | 2002-04-11 | Novartis Ag | Diazacycloalkanedione derivatives which are useful as lfa-1 antagonist |
-
2003
- 2003-01-23 GB GB0301561A patent/GB0301561D0/en not_active Ceased
-
2004
- 2004-01-22 CN CNB2004800021638A patent/CN100378096C/en not_active Expired - Fee Related
-
2005
- 2005-06-08 ZA ZA200504672A patent/ZA200504672B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001027102A1 (en) * | 1999-10-13 | 2001-04-19 | Novartis Ag | Substituted diazepanes |
| WO2002028842A2 (en) * | 2000-10-02 | 2002-04-11 | Novartis Ag | Diazacycloalkanedione derivatives which are useful as lfa-1 antagonist |
Non-Patent Citations (1)
| Title |
|---|
| Bioorganic & Medicinal Chemistry Letters. SOMPONG WATTANASIN:,,499-502,1,4-Diazepane-2-ones as Novel Inhibitors of LFA-1. 2003 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1735609A (en) | 2006-02-15 |
| ZA200504672B (en) | 2006-05-31 |
| GB0301561D0 (en) | 2003-02-26 |
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