CN101277965A

CN101277965A - N-phenyl benzamide derivatives as sirtuin modulators

Info

Publication number: CN101277965A
Application number: CNA2006800368553A
Authority: CN
Inventors: J·J·努涅斯; J·米尔恩; J·比米斯; R·谢; C·B·武; P·Y·吴; J·S·迪施
Original assignee: Sirtris Pharmaceuticals Inc
Current assignee: Sirtris Pharmaceuticals Inc
Priority date: 2005-08-04
Filing date: 2006-08-04
Publication date: 2008-10-01
Also published as: CN101282761A; CN101316853B; CN101316853A; CN101282974A; CN101277963A

Abstract

Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treatin and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benfit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.

Description

Regulate imidazo [2, the 1-b] thiazole derivative of compound as SIRTUIN

Related application

The application requires following U.S. Provisional Application No.: 60/792276 of the submission of submitting to 3,60/741783,2006 on the March of submitting to 2,60/705612,2005 on the December of submitting on August 4th, 2005 in 14,60/779370 and 2006 on April is incorporated herein by reference its full content at this.

Background technology

Silent message regulatory factor (SIR) family gene is to be present in the high conservative gene (Frye, 2000) of archeobacteria in the various Eukaryotic organism genomes.Coding SIR albumen relates to the various procedures that is adjusted to the DNA reparation from gene silencing.Show the height sequence conservation by SIR gene cluster member encoded protein matter 250 amino acid whose core domain.The gene that has feature in this family's gene is S.cerevisiae SIR2, and it relates to reticent HM site (Guarente, 1999 of containing decision yeast mating type, telomere position effect and cell aging information; Kaeberlein etc., 1999; Shore, 2000).Yeast Sir2 albumen belongs to histone deacetylase family and (summarizes in Guarente 2000; Shore, 2000).The homologue CobB functional equivalent of Sir2 is in the ADP ribose transferring enzyme (Tsang and Escalante-Semerena, 1998) that depends on NAD (Reduced nicotinamide-adenine dinucleotide) in the Salmonella typhimurium.

Sir2 albumen belongs to III type deacetylase, is cosubstrate (Imai etc., 2000 with NDA; Moazed, 2001; Smith etc., 2000; Tanner etc., 2000; Tanny and Moazed, 2001).Many deacetylases have participated in gene silencing, and different with other deacetylases is that Sit2 is to I type and II type deacetylase inhibitors such as Trichostatin A (TSA) insensitive (Imai etc., 2000; Landry etc., 2000a; Smith etc., 2000).

The acetyl-l-lysine deacetylation and the NAD hydrolytic action that are caused by Sir2 are closely related, and generate niacinamide and new acetyl ADP ribose compound (Tanner etc., 2000; Landry etc., 2000b; Tanny and Moazed, 2001).The deacetylation enzymic activity that depends on NAD of Sir2 can produce function very important (Guarente, 2000 of cellular metabolism biological action for it in yeast; Imai etc., 2000; Lin etc., 2000; Smith etc., 2000).Mammals Sir2 homologue has histone deacetylase activity (Imai etc., 2000 that depend on NAD; Smith etc., 2000).The information of many functions about Sir2 mediation comes from zymic research (Gartenberg, 2000; Gottschling, 2000).

Biochemical Research shows that Sir2 can be easily deacetylated with the aminoterminal of histone H 3 and H4, thereby generates 1-O-acetyl-ADP-ribose and niacinamide.The bacterial strain rDNA that contains the SIR2 that increases is reticent to be increased, and the life-span also prolongs 30%.Recently find, C.elegans SIR2 homologue, the amplification of Sir-2.1 and D.melanogaster dSir2 gene has greatly prolonged the organic life-span.Hint that thus the regulating senescence path that depends on SIR-2 appears at the early stage of development, and will be by fine maintenance.The Sir2 gene is considered to develop into and improves organism health and have stress resistance to increase the chance of its adverse circumstance survival now.

SIRT3 is the homologue of SIRT1, is present in prokaryotic organism and eukaryote (P.Onyango etc., Proc.Natl.Acad.Sci.USA 99:13653-13658 (2002)).SIRT3 albumen is positioned mitochondrial cristae by unique zone that it is positioned at the N end.SIRT3 has the NAD+ of depending on deacetylase protein base enzymic activity, and is expressed ubiquitously, is especially expressed in the metabolic activity tissue.After being transferred to plastosome, SIRT3 is cracked into littler activity form (B.Schwer etc., J.CellBiol.158:647-657 (2002)) by mitochondrial matrix processing peptidase (MPP) immediately.

Improve mammiferous health and prolong that life is known to surpass 70 years (Masoro, 2000) by caloric restriction.The zymic life-span is similar to metazoan, also can prolong as the interference of low sugar by being similar to heat restriction.Yeast and fly lack the SIR2 gene makes its discovery that life-span can not prolong when heat limits beneficial effect (Anderson etc., 2003 of this diet to health that shown the SIR2 gene mediated; Helfand and Rogina, 2004).In addition, that reduces the yeast glucose responding depends on cAMP (adenosine 3 ', 5 '-single phosphoric acid) (PKA) sudden change of pathway activity life-span that can prolong wild-type cell but can not prolong life-span of sudden change sir2 bacterial strain, show that thus SIR2 might be the catchment key ingredient (Lin etc., 2001) of heat restriction path.

Summary of the invention

The invention provides new sirtuin-regulates compound and uses their method.

On the one hand, the sirtuin-that the invention provides formula (I) regulates compound or its salt,

Wherein:

Ring A selectively is substituted or condenses with another ring or two kinds of situations exist simultaneously; And

Ring B is replaced by at least one carboxyl, replacement or unsubstituted arylamide (arylcarboxamine), replacement or unsubstituted arylalkyl amide (aralkylcarboxamine), replacement or unsubstituted heteroaryl groups, replacement or unsubstituted heterocyclic carbonyl ethenyl or polyaromatic group or condenses with aromatic ring, and is selectively replaced by one or more additional group.

In yet another aspect, the sirtuin-that the invention provides formula (II) regulates compound or its salt,

Wherein:

Ring A selectively is substituted;

R ₁, R ₂, R ₃And R ₄Be to be independently selected from :-H, halogen ,-OR ₅,-CN ,-CO ₂R ₅,-OCOR ₅,-OCO ₂R ₅,-C (O) NR ₅R ₆,-OC (O) NR ₅R ₆,-C (O) R ₅,-COR ₅,-SR ₅,-OSO ₃H ,-S (O) _nR ₅,-S (O) _nOR ₅,-S (O) _nNR ₅R ₆,-NR ₅R ₆,-NR ₅C (O) OR ₆,-NR ₅C (O) R ₆With-NO ₂

R ₅And R ₆Be independently-H, replacement or unsubstituted alkyl group, replacement or unsubstituted aromatic yl group or replacement or unsubstituted heterocyclic group; With

N is 1 or 2.

Also having aspect another, the sirtuin-that the invention provides formula (III) regulates compound or its salt,

Wherein:

Ring A selectively is substituted;

R ₅And R ₆Be independently-H, replacement or unsubstituted alkyl group, replacement or unsubstituted aromatic yl group or replacement or unsubstituted heterocyclic group;

R ₇, R ₉, R ₁₀And R ₁₁Be independently selected from :-H, halogen ,-R ₅,-OR ₅,-CN ,-CO ₂R ₅,-OCOR ₅,-OCO ₂R ₅,-C (O) NR ₅R ₆,-OC (O) NR ₅R ₆,-C (O) R ₅,-COR ₅,-SR ₅,-OSO ₃H ,-S (O) _nR ₅,-S (O) _nOR ₅,-S (O) _nNR ₅R ₆,-NR ₅R ₆,-NR ₅C (O) OR ₆,-NR ₅C (O) R ₆With-NO ₂

R ₈It is the polyaromatic group; And

N is 1 or 2.

In yet another aspect, the sirtuin-that the invention provides formula (IV) regulates compound or its salt,

Ar——L——J——M——K——Ar′ (IV)

Wherein:

Each Ar and Ar ' are optional carbocyclic ring or the heterocyclic aryl group of selecting generation independently;

L is optional carbocyclic ring or the heterocycle arylene group of selecting generation;

Each J and K are NR independently ₁', O, S, or can select not exist independently; Perhaps working as J is NR ₁' time, R ₁' be to link to each other with Ar ' to form the C1-C4 alkylidene group or the C2-C4 alkenylene of the ring that is fused to Ar '; Or when K be NR ₁' time, R ₁' be to link to each other with L to form the C1-C4 alkylidene group or the C2-C4 alkenylene of the ring that is fused to L;

Each M is C (O), S (O), S (O) ₂, or CR ₁' R ₁';

Each R ₁' be independently selected from H, C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R ₅'; Halogen; Alkylhalide group; CF ₃SR ₂'; OR ₂'; NR ₂' NR ₂'; NR ₂' R ₃'; COOR ₂'; NO ₂CN; C (O) R ₂'; C (O) C (O) R ₂'; C (O) NR ₂' R ₂'; OC (O) R ₂'; S (O) ₂R ₂'; S (O) ₂NR ₂' R ₂'; NR ₂' C (O) NR ₂' R ₂'; NR ₂' C (O) C (O) R ₂'; NR ₂' C (O) R ₂'; NR ₂' (COOR ₂'); NR ₂' C (O) R ₅'; NR ₂' S (O) ₂NR ₂' R ₂'; NR ₂' S (O) ₂R ₂'; NR ₂' S (O) ₂R ₅'; NR ₂' C (O) C (O) NR ₂' R ₂'; NR ₂' C (O) C (O) NR ₂' R ₃'; By aryl, R ₄' or R ₅The C1-C10 alkyl of ' replacement; Or by aryl, R ₄' or R ₅The C2-C10 thiazolinyl of ' replacement;

Each R ₂' be H independently; The C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R ₆'; By 1-3 individual independently aryl, R ₄' or R ₆The C1-C10 alkyl that ' group replaced; By 1-3 individual independently aryl, R ₄' or R ₆The C3-C10 cycloalkyl that ' group replaced; Or by 1-3 individual independently aryl, R ₄' or R ₆The C2-C10 thiazolinyl that ' group replaced;

Each R ₃' be C (O) R independently ₂', COOR ₂', or S (O) ₂R ₂';

Each R ₄' be halogen independently, CF ₃, SR ₇', OR ₇', OC (O) R ₇', NR ₇' R ₇', NR ₇' R ₈', NR ₈' R ₈', COOR ₇', NO ₂, CN, C (O) R ₇', or C (O) NR ₇' R ₇';

Each R ₅' be 5-8 unit monocycle independently, 8-12 unit dicyclo, or 11-14 unit trinucleated member ring systems, described member ring systems is if monocycle then contains 1-3 heteroatoms, if dicyclo then contains 1-6 heteroatoms, perhaps if three rings then contain 1-9 heteroatoms, described heteroatoms is selected from O, N, or S, these member ring systems can be saturated or unsaturated, and wherein each ring 0,1,2 or 3 atom can be independently selected from following substituting group and replace: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R ₆'; Halogen; Sulphur; Oxygen; CF ₃Alkylhalide group; SR ₂'; OR ₂'; OC (O) R ₂'; NR ₂' R ₂'; NR ₂' R ₃'; NR ₃' R ₃'; COOR ₂'; NO ₂CN; C (O) R ₂'; C (O) NR ₂' R ₂'; By the individual independently R of 1-3 ₄', R ₆', or the C1-C10 alkyl that aryl replaced; Perhaps by the individual independently R of 1-3 ₄', R ₆', or the C2-C10 thiazolinyl that aryl replaced.

Each R ₆' be 5-8 unit monocycle independently, 8-12 unit dicyclo, or 11-14 unit trinucleated member ring systems, described member ring systems is if monocycle then contains 1-3 heteroatoms, if dicyclo then contains 1-6 heteroatoms, perhaps if three rings then contain 1-9 heteroatoms, described heteroatoms is selected from O, N, or S, these member ring systems can be saturated or unsaturated, and wherein each ring 0,1,2 or 3 atom is independently selected from following substituting group and replaces: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Halogen; Sulphur; Oxygen; CF ₃Alkylhalide group; SR ₇'; OR ₇'; NR ₇' R ₇'; NR ₇' R ₈'; NR ₈' R ₈'; COOR ₇'; NO ₂CN; C (O) R ₇'; Or C (O) NR ₇' R ₇';

Each R ₇' be H independently, the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Alkylhalide group; Optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF ₃, OR ₁₀', SR ₁₀', NR ₁₀' R ₁₀', COOR ₁₀', NO ₂, CN, C (O) R ₁₀', C (O) NR ₁₀' R ₁₀', NHC (O) R ₁₀', or OC (O) R ₁₀' C1-C10 the alkyl that replaced; Perhaps optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF ₃, OR ₁₀', SR ₁₀', NR ₁₀' R ₁₀', COOR ₁₀', NO ₂, CN, C (O) R ₁₀', C (O) NR ₁₀' R ₁₀', NHC (O) R ₁₀', or OC (O) R ₁₀' the phenyl that replaced;

Each R ₈' be C (O) R independently ₇', COOR ₇', or S (O) ₂R ₇';

Each R ₉' be H independently, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, the C4-C10 cycloalkenyl group is perhaps optionally by the individual C1-C10 alkyl independently of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, the C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF ₃, OR ₁₀', SR ₁₀', NR ₁₀' R ₁₀', COOR ₁₀', NO ₂, CN, C (O) R ₁₀', C (O) NR ₁₀' R ₁₀', NHC (O) R ₁₀', or OC (O) R ₁₀' the phenyl that replaced;

Each R ₁₀' be H independently; The C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Optionally by halogen, CF ₃, OR ₁₁', SR ₁₁', NR ₁₁' R ₁₁', COOR ₁₁', NO ₂, the C1-C10 alkyl that CN replaced; Or optionally by halogen, CF ₃, OR ₁₁', SR ₁₁', NR ₁₁' R ₁₁', COOR ₁₁', NO ₂, the phenyl that CN replaced;

Each R ₁₁' be H independently; The C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

Each alkylhalide group is independently by one or more F that are selected from, Cl, and Br, or the C1-C10 alkyl that halogen atom replaced of I, wherein the number of halogen atom can not surpass the number that causes forming the whole haloalkyl group; And

Each aryl is independently optionally by 1-3 independently following substituting group: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; R ₆'; Halogen; Alkylhalide group; CF ₃OR ₉'; SR ₉'; NR ₉' R ₉'; COOR ₉'; NO ₂CN; C (O) R ₉'; C (O) C (O) R ₉'; C (O) NR ₉' R ₉'; S (O) ₂R ₉'; N (R ₉') C (O) R ₉'; N (R ₉') (COOR ₉'); N (R ₉') S (O) ₂R ₉'; S (O) ₂NR ₉' R ₉'; OC (O) R ₉'; NR ₉' C (O) NR ₉' R ₉'; NR ₉' C (O) C (O) R ₉'; NR ₉' C (O) R ₆'; NR ₉' S (O) ₂NR ₉' R ₉'; NR ₉' S (O) ₂R ₆'; NR ₉' C (O) C (O) NR ₉' R ₉'; By the individual independently R of 1-3 ₆', halogen, CF ₃, OR ₉', SR ₉', NR ₉' R ₉', COOR ₉', NO ₂, CN, C (O) R ₉', C (O) NR ₉' R ₉', NHC (O) R ₉', NH (COOR ₉'), S (O) ₂NR ₉' R ₉', OC (O) R ₉' C1-C10 the alkyl that replaced; By the individual independently R of 1-3 ₆', halogen, CF ₃, OR ₉', SR ₉', NR ₉' R ₉', COOR ₉', NO ₂, CN, C (O) R ₉', C (O) NR ₉' R ₉', NHC (O) R ₉', NH (COOR ₉'), S (O) ₂NR ₉' R ₉', OC (O) R ₉' C2-C10 the thiazolinyl that replaced; Or R ₉'.

In yet another aspect, the sirtuin that the invention provides formula (IVa) regulates compound or its salt:

Het-L-Q-Ar′(IVa)

Wherein:

Het is a heterocyclic aryl group that selectively replaces;

L is the carbocyclic ring or the heterocycle arylene group that selectively replace;

Ar ' is the carbocyclic ring or the heterocyclic aryl group that selectively replace; And

Q is selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-,

With

Each R ₁' the C that is independently selected from H or selectively replaces ₁-C ₃The straight or branched alkyl, wherein:

When Het is a polyheteroaromatic, L is a phenylene that selectively replaces, and Q and Het are connected to L with meta-orientation ground, and Ar ' is one selectively during the phenyl of replacement; So Q be not-NH-C (O)-.

In aspect also having another, the sirtuin that the invention provides formula V regulates compound or its salt,

Wherein:

Ring A is selectively by at least one R ₁' group replaces;

Y ₁, Y ₂, Y ₃, Y ₄, and Y ₅Be R independently ₁';

Each R ₁' be independently selected from H, C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R ₅'; Halogen; Alkylhalide group; CF ₃SR ₂'; OR ₂'; NR ₂' R ₂'; NR ₂' R ₃'; COOR ₂'; NO ₂CN; C (O) R ₂'; C (O) C (O) R ₂'; C (O) NR ₂' R ₂'; OC (O) R ₂'; S (O) ₂R ₂'; S (O) ₂NR ₂' R ₂'; NR ₂' C (O) NR ₂' R ₂'; NR ₂' C (O) C (O) R ₂'; NR ₂' C (O) R ₂'; NR ₂' (COOR ₂'); NR ₂' C (O) R ₅'; NR ₂' S (O) ₂NR ₂' R ₂'; NR ₂' S (O) ₂R ₂'; NR ₂' S (O) ₂R ₅'; NR ₂' C (O) C (O) NR ₂' R ₂'; NR ₂' C (O) C (O) NR ₂' R ₃'; By aryl, R ₄' or R ₅The C1-C10 alkyl that replaces; Perhaps by aryl, R ₄' or R ₅The C2-C10 thiazolinyl of ' replacement;

Each R ₂' be H independently; The C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R ₆'; By the individual independently aryl of 1-3, R ₄' or R ₆The C1-C10 alkyl that ' group replaced; By the individual independently aryl of 1-3, R ₄' or R ₆The C3-C10 cycloalkyl that ' group replaced; Perhaps by the individual independently aryl of 1-3, R ₄' or R ₆The C2-C10 thiazolinyl that ' group replaced;

Each R ₃' be C (O) R independently ₂', COOR ₂', or S (O) ₂R ₂';

Each R ₅' be 5-8 unit monocycle independently, 8-12 unit dicyclo, or 11-14 unit three ring member ring systems, member ring systems monocycle in this way then contains 1-3 heteroatoms, dicyclo then contains 1-6 heteroatoms in this way, or three rings then contain 1-9 heteroatoms in this way, and described heteroatoms is selected from O, N, or S, described member ring systems can be saturated or unsaturated, and the O of each ring wherein, 1,2 or 3 atom is independently selected from following substituting group and replaces: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R ₆'; Halogen; Sulphur; Oxygen; CF ₃Alkylhalide group; SR ₂'; OR ₂'; OC (O) R ₂'; NR ₂' R ₂'; NR ₂' R ₃'; NR ₃' R ₃'; COOR ₂'; NO ₂CN; C (O) R ₂'; C (O) NR ₂' R ₂'; By the individual independently R of 1-3 ₄', R ₆', or the C1-C10 alkyl that aryl replaced; Or by the individual independently R of 1-3 ₄', R ₆', or the C2-C10 thiazolinyl that aryl replaced;

Each R ₆' be 5-8 unit monocycle independently, 8-12 unit dicyclo, or 11-14 unit three ring member ring systems, member ring systems monocycle in this way then contains 1-3 heteroatoms, dicyclo then contains 1-6 heteroatoms in this way, or three rings then contain 1-9 heteroatoms in this way, and described heteroatoms is selected from O, N, or S, described member ring systems can be saturated or unsaturated, and wherein each ring 0,1,2 or 3 atom is independently selected from following substituting group and replaces: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Halogen; Sulphur; Oxygen; CF ₃Alkylhalide group; SR ₇'; OR ₇'; NR ₇' R ₇'; NR ₇' R ₈'; NR ₈' R ₈'; COOR ₇'; NO ₂CN; C (O) R ₇'; Or C (O) NR ₇' R ₇';

Each R ₇' be H independently, the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Alkylhalide group; Optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF ₃, OR ₁₀', SR ₁₀', NR ₁₀' R ₁₀', COOR ₁₀', NO ₂, CN, C (O) R ₁₀', C (O) NR ₁₀' R ₁₀', NHC (O) R ₁₀', or OC (O) R ₁₀' C1-C10 the alkyl that replaced; Or optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF ₃, OR ₁₀', SR ₁₀', NR ₁₀' R ₁₀', COOR ₁₀', NO ₂, CN, C (O) R ₁₀', C (O) NR ₁₀' R ₁₀', NHC (O) R ₁₀', or OC (O) R ₁₀' the phenyl that replaced;

Each R ₈' be C (O) R independently ₇', COOR ₇', or S (O) ₂R ₇';

Each R ₉' be H independently, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, the C4-C10 cycloalkenyl group, or optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, the C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF ₃, OR ₁₀', SR ₁₀', NR ₁₀' R ₁₀', COOR ₁₀', NO ₂, CN, C (O) R ₁₀', C (O) NR ₁₀' R ₁₀', NHC (O) R ₁₀', or OC (O) R ₁₀' the phenyl that replaced;

Each R ₁₀' be H independently; The C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Optionally by halogen, CF ₃, OR ₁₁', SR ₁₁', NR ₁₁' R ₁₁', COOR ₁₁', NO ₂, the C1-C10 alkyl that CN replaces; Or optionally by halogen, CF ₃, OR ₁₁', SR ₁₁', NR ₁₁' R ₁₁', COOR ₁₁', NO ₂, the phenyl that CN replaced;

Each alkylhalide group is independently by the C1-C10 alkyl that one or more halogen atoms replaced, and described halogen atom is selected from F, Cl, and Br, or I, wherein the number of halogen atom can not surpass the number that causes forming the whole haloalkyl group; With

Each aryl is 5-to 7-unit's monocycle system or 9-to 12-unit bicyclic system independently, and described member ring systems is selectively by the individual independently C1-C10 alkyl of 1-3; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; R ₆'; Halogen; Alkylhalide group; CF ₃OR ₉'; SR ₉'; NR ₉' R ₉'; COOR ₉'; NO ₂CN; C (O) R ₉'; C (O) C (O) R ₉'; C (O) NR ₉' R ₉'; S (O) ₂R ₉'; N (R ₉') C (O) R ₉'; N (R ₉') (COOR ₉'); N (R ₉') S (O) ₂R ₉'; S (O) ₂NR ₉' R ₉'; OC (O) R ₉'; NR ₉' C (O) NR ₉' R ₉'; NR ₉' C (O) C (O) R ₉'; NR ₉' C (O) R ₆'; NR ₉' S (O) ₂NR ₉' R ₉'; NR ₉' S (O) ₂R ₆'; NR ₉' C (O) C (O) NR ₉' R ₉'; By the individual independently R of 1-3 ₆', halogen, CF ₃, OR ₉', SR ₉', NR ₉' R ₉', COOR ₉', NO ₂, CN, C (O) R ₉', C (O) NR ₉' R ₉', NHC (O) R ₉', NH (COOR ₉'), S (O) ₂NR ₉' R ₉', OC (O) R ₉' C1-C10 the alkyl that replaced; By the individual independently R of 1-3 ₆', halogen, CF ₃, OR ₉', SR ₉', NR ₉' R ₉', COOR ₉', NO ₂, CN, C (O) R ₉', C (O) NR ₉' R ₉', NHC (O) R ₉', NH (COOR ₉'), S (O) ₂NR ₉' R ₉', OC (O) R ₉' C2-C10 the thiazolinyl that replaced; Or R ₉'.

In one aspect, the sirtuin-that the invention provides formula (VI) regulates compound or its salt:

Wherein:

Het is the heterocyclic aryl group that selectively replaces; And

Ar ' is carbocyclic ring or the heterocyclic aryl group that selectively replaces.

The present invention also comprises the prodrug and the metabolite of compound disclosed herein.

In yet another aspect, the sirtuin-that the invention provides formula (VII) regulates compound or its salt:

Wherein:

X ₇, X ₈, X ₉And X ₁₀In each be independently selected from N, CR ²⁰, or CR ₁', wherein:

Each R ²⁰Be independently selected from H or solubilizing group;

Each R ₁' the C that is independently selected from H or selectively replaces ₁-C ₃The straight or branched alkyl;

X ₇, X ₈, X ₉And X ₁₀In one be N and other is to be selected from CR ²⁰Or CR ₁'; With

0 to 1 R ²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be independently selected from N, CR ²⁰, or CR ₁'; With

Each Z ₁₄, Z ₁₅And Z ₁₆Be independently selected from N, NR ₁', S, O, CR ²⁰, or CR ₁', wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

0 to 1 R ₁' be the C that selectively replaces ₁-C ₃The straight or branched alkyl; With

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-,

With

R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace, condition is that described compound is not:

Or

Work as R ¹⁹Be

And R ²¹Be-NHC (O)-time, R ³¹It or not the phenyl that selectively replaces.

In some embodiments, the compound of structural formula (VII) has following value:

Each X ₇, X ₈, X ₉And X ₁₀Be independently selected from N, CR ²⁰, or CR ₁', wherein:

Each R ²⁰Be independently selected from H or solubilizing group;

X ₇, X ₈, X ₉And X ₁₀In one be N and other be to be selected from CR ²⁰Or CR ₁'; With

0 to 1 R ²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be to be selected from N, CR independently ²⁰, or CR ₁'; With

Each Z ₁₄, Z ₁₅And Z ₁₆Be to be selected from N, NR independently ₁', S, O, CR ²⁰, or CR ₁', wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace, condition is:

Described compound is not:

With

Work as X ₈And X ₉Be selected from CR independently of one another ²⁰Or CR ₁', R ¹⁹Be

With each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be to be selected from CR independently ²⁰, or CR ₁', so:

A) X ₈And X ₉In at least one be not CH; Or

B) Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃In at least one be CR ²⁰, R wherein ²⁰It is solubilizing group.

In also having another embodiment, the sirtuin-that the invention provides structural formula (VIII) regulates compound or its salt:

Wherein:

R ₁' the C that is selected from H or selectively replaces ₁-C ₃The straight or branched alkyl;

With

Work as R ₁' be methyl, and R ²¹Be-NH-C (O)-time, R ³¹Be not

1-methoxyl group naphthyl; 2-methoxyl group naphthyl; Or unsubstituted 2-thienyl;

Work as R ₁' be methyl, and R ²¹When being-NH-C (O)-CH=CH-, R ³¹Be not

Work as R ₁' be methyl, and R ²¹When being-NH-C (O)-CH-O-, R ³¹It or not unsubstituted naphthyl; The 2-methoxyl group, the 4-nitrophenyl; 4-chlorine, the 2-aminomethyl phenyl; Or 4-tert-butyl phenyl; With

Work as R ²¹Be-NH-C (O)-time, R ³¹It or not the phenyl that selectively replaces.

In another embodiment, the sirtuin-that the invention provides structural formula (IX) regulates compound or its salt:

Wherein:

R ₁' the C that is selected from H or selectively replaces ₁-C ₃The straight or branched alkyl; With

R ⁵⁰Be selected from 2, the 3-Dimethoxyphenyl, Phenoxyphenyl, 2-methyl-3-p-methoxy-phenyl, 2-methoxyl group-4-aminomethyl phenyl, or by the phenyl of 1 to 3 substituting group replacement, one in the wherein said substituting group is solubilizing group; Condition is R ⁵⁰Do not replaced by solubilizing group and nitryl group simultaneously, and R ⁵⁰Do not replaced separately or do not replaced separately by the morpholino group by the ring-type solubilizing group in the 2-position in the 4-position.

In one aspect, the sirtuin-that the invention provides structural formula (X) regulates compound or its salt:

Wherein:

R ⁵¹Be selected from selectively the bicyclic heteroaryl that replaces, the bicyclic heteroaryl of Qu Daiing selectively, or the selectively naphthyl of replacement, wherein R ⁵¹Not also (b) thienyl of chlorobenzene, unsubstituted benzo dioxolyl, unsubstituted benzofuryl, methyl-benzofuryl, unsubstituted furyl, phenyl-, bromo-, or nitro-furyl, chloro-phenyl--isoxazolyls, the oxo benzopyranyl, unsubstituted naphthyl, methoxyl group-, methyl-, or halo-naphthyl, unsubstituted thienyl, unsubstituted pyridine base, or chloropyridine base.

In yet another aspect, the sirtuin-that the invention provides structural formula (XI) regulates compound or its salt:

Wherein:

R ²²Be selected from-NR ²³-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-or-NR ₁'-C (O)-CR ₁' R ₁'-, be R wherein ²³Be the C that selectively replaces ₁-C ₃The straight or branched alkyl; With

R ³¹Be to be selected from monocycle or the bicyclic aryl that selectively replaces, or the monocycle or the bicyclic heteroaryl that selectively replace, condition is:

Work as R ²²When being-NH-C (O)-CH=CH-, R ³¹Not unsubstituted furyl, 5-(2-methyl-3-chloro-phenyl-)-furyl, 2,4 dichloro benzene base, 3,5-two chloro-2-p-methoxy-phenyls, 3-nitrophenyl, 4-chloro-phenyl-, 4-chloro-3-nitrophenyl, the 4-isopropyl phenyl, 4-p-methoxy-phenyl, 2-methoxyl group-5-bromophenyl, or unsubstituted phenyl;

Work as R ²²Be-NH-C (O)-CH ₂-time, R ³¹Not 3,4-Dimethoxyphenyl, 4-chloro-phenyl-, or unsubstituted phenyl;

Work as R ²²Be-NH-C (O)-CH ₂During-O-, R ³¹Not 2,4-dimethyl-6-nitrophenyl, 2-or 4-nitrophenyl, the 4-cyclohexyl phenyl, 4-p-methoxy-phenyl, unsubstituted naphthyl, or unsubstituted phenyl, or be selected from separately straight chain-or the substituting group list of side chain-alkyl or halogen replace two replacements or trisubstd phenyl;

Work as R ²²Be-NH-C (O)-CH (CH ₃During)-O-, R ³¹Not the 2,4 dichloro benzene base, 4-chloro-phenyl-, or unsubstituted phenyl; With

Work as R ²²Be-NH-S (O) ₂-time, R ³¹It or not unsubstituted phenyl.

Also having aspect another, the sirtuin-that the invention provides structural formula (XII) regulates compound or its salt:

Wherein:

Each X ₇, X ₈, X ₉And X ₁₀Be to be selected from N, CR independently ²⁰, or CR ₁', wherein:

Each R ²⁰Be to be selected from H or solubilizing group independently;

Each R ₁' be the C that is selected from H or selectively replaces independently ₁-C ₃The straight or branched alkyl;

0 to 1 R ²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', O or S;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

0 to 1 R ₁' the C that selectively replaces ₁-C ₃The straight or branched alkyl; With

With

R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace,

Condition is to work as R ¹⁹Be

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃All be CH, and R ²¹Be-NHC (O)-time, R ³¹It or not the phenyl that selectively replaces.

In certain embodiments, the compound of structural formula (XI) has following value:

Each R ²⁰Be to be selected from H or solubilizing group independently;

0 to 1 R ²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰Be solubilizing group because of;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Work as X ₇Be N, R ¹⁹Be

With each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be to be selected from CR independently ²⁰, or CR ₁' time, so:

A) X ₈, X ₉Or X ₁₀In at least one be C-(C ₁-C ₃The straight or branched alkyl) or C-(solubilizing group); Or

In yet another aspect, the invention provides the compound or its salt of structural formula (XIII):

Wherein:

R ₁' be the C that is selected from H or selectively replaces ₁-C ₃The straight or branched alkyl;

With

Work as R ²¹Be-NH-C (O)-time, R ³¹Not unsubstituted furyl, 5-bromine furyl, unsubstituted phenyl, the mono-substituted phenyl of halogen or methyl, 3-or 4-p-methoxy-phenyl, 4-butoxy phenyl, 4-tert-butyl phenyl, 3-trifluoromethyl, 2-benzoyl phenyl, 2-or 4-ethoxyl phenenyl, 2,3-, 2,4-, 3,4-, or 3, the 5-Dimethoxyphenyl, 3,4, the 5-trimethoxyphenyl, 2,4-or 2-6 difluorophenyl, 3,4-dioxy methylene radical phenyl, 3,4-or 3, the 5-3,5-dimethylphenyl, 2-chloro-5-bromophenyl, 2-methoxyl group-5-chloro-phenyl-, the unsubstituted quinolines base, the simultaneously-substituted thiazolyl of methyl and phenyl, or the pyridyl of oxyethyl group replacement;

Work as R ²¹Be-NH-C (O)-CH (CH ₂-CH ₃)-time, R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH ₂-time, R ³¹Not unsubstituted phenyl, 3-aminomethyl phenyl, 4-chloro-phenyl-, 4-ethoxyl phenenyl, 4-fluorophenyl or 4-p-methoxy-phenyl;

Work as R ²¹Be-NH-C (O)-CH ₂During-O-, R ³¹Not unsubstituted phenyl or 4-chloro-phenyl-; With

Work as R ²¹Be-NH-S (O) ₂-time, R ³¹Not 3,4-dioxy methylene radical phenyl, 2,2,4,6-trimethylphenyl, 2,4-or 3, the 4-3,5-dimethylphenyl, 2,5-difluorophenyl, 2,5-or 3, the 4-Dimethoxyphenyl, fluorophenyl, 4-chloro-phenyl-, 4-bromophenyl, the 4-ethylphenyl, 4-aminomethyl phenyl, 3-methyl-4-p-methoxy-phenyl, unsubstituted phenyl, the unsubstituted pyridine base, unsubstituted thienyl, the thienyl that chlorine replaces, or methyl substituted benzothiazolyl.

In one aspect, the sirtuin-that the invention provides structural formula (XIV) regulates compound or its salt:

Wherein:

Each R ²³And R ²⁴Be to be selected from H ,-CH independently ₃Or solubilizing group;

R ²⁵Be selected from H, or solubilizing group; With

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', O or S;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z1 ₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group; With

0 to 1 R ₁' be the C that selectively replaces ₁-C ₃The straight or branched alkyl;

Each R ²⁰Be to be selected from H or solubilizing group independently;

Each R ₁' be the C that is selected from H or selectively replaces independently ₁-C ₃The straight or branched alkyl; With

Wherein work as R ¹⁹Be R ²¹Be-NH-C (O)-and R ²⁵Be-during H, R ³¹Be not that phenyl group and the wherein said compound that selectively replaces is not 2-chloro-N-[3-[3-(cyclohexyl amino) imidazo [1,2-a] pyridine-2-yl] phenyl]-the 4-nitrobenzamide.

In yet another aspect, the sirtuin-that the invention provides structural formula (XV) regulates compound or its salt:

Wherein:

With

R ³²Be selected from the bicyclic aryl that selectively replaces, or the monocycle or the bicyclic heteroaryl that selectively replace,

Wherein:

Work as R ²¹Be-NH-C (O)-time, R ³²Not unsubstituted 2-furyl, 2-(3-bromine furyl), unsubstituted 2-thienyl, unsubstituted 3-pyridyl, unsubstituted 4-pyridyl,

Or

With

Work as R ²¹Be-NR ₁'-S (O) ₂-time, R ³²Not unsubstituted 2-thienyl or unsubstituted naphthyl.

Also having aspect another, the sirtuin-that the invention provides structural formula (XVI) regulates compound or its salt:

Wherein:

With

R ³³Be the phenyl that selectively replaces, wherein:

Work as R ²¹Be-NH-C (O)-time, R ³³Be a replacement phenyl except phenyl by halogen, methyl, the mono-substituted situation of nitro or methoxyl group; The 2-carboxyl phenyl; 4-just-the amyl group phenyl; The 4-ethoxyl phenenyl; 2-carboxyl-3-nitrophenyl; 2-chloro-4-nitrophenyl; 2-methoxyl group-5-ethylphenyl; 2, the 4-Dimethoxyphenyl; 3,4, the 5-trimethoxyphenyl; The 2,4 dichloro benzene base; 2, the 6-difluorophenyl; 3, the 5-dinitrophenyl; Or 3, the 4-3,5-dimethylphenyl;

Work as R ²¹Be-NR ₁'-C (O)-CR ₁' R ₁'-or-NH-C (O)-CH (CH ₃During)-O, R ³³It is the phenyl of a replacement;

Work as R ²¹Be-NH-C (O)-CH ₂The time, R ³³Not unsubstituted phenyl, the 4-p-methoxy-phenyl; 3,4-Dimethoxyphenyl or 4-chloro-phenyl-;

Work as R ²¹Be-NH-C (O)-CH ₂During-O, R ³³Not 2, two (1, the 1-dimethyl propyl) phenyl of 4-;

Work as R ²¹When being-NH-C (O)-NH-, R ³³It or not the 4-p-methoxy-phenyl; With

Work as R ²¹Be-NH-S (O) ₂-time, R ³³Be the phenyl that replaces except the 3-aminomethyl phenyl, 3-trifluoromethyl, 2,4; 5-or 2,4,6-trimethylphenyl, 2; 4-or 3,4-3,5-dimethylphenyl, 2,5-or 3; the 4-Dimethoxyphenyl, 2,5-dimethoxy-4 '-chloro-phenyl-; 3,6-dimethoxy, 4-aminomethyl phenyl; 2,5-or 3,4-dichlorophenyl; 2,5-diethoxy phenyl, 2-methyl-5-nitro phenyl; 2-oxyethyl group-5-bromophenyl, 2-methoxyl group-5-bromophenyl, 2-methoxyl group-3; the 4-dichlorophenyl, 2-methoxyl group-4-methyl-5-bromophenyl, 3; 5-dinitrobenzene-4-aminomethyl phenyl, 3-methyl-4-p-methoxy-phenyl, 3-nitro-4-methyl phenyl; 3-methoxyl group-4-halogenophenyl, 3-methoxyl group-5-chloro-phenyl-, 4-just-butoxy phenyl; the 4-halogenophenyl, 4-ethylphenyl, 4-aminomethyl phenyl; the 4-nitrophenyl, 4-ethoxyl phenenyl, 4-acetylamino phenyl; the 4-p-methoxy-phenyl, 4-tert-butyl phenyl, or right-xenyl.

In yet another aspect, the sirtuin-that the invention provides structural formula (XVII) regulates compound or its salt:

Wherein:

Each R ²³And R ²⁴Be independently be selected from H or-CH ₃, R wherein ²³And R ²⁴In at least one be H; With

R ²⁹The phenyl that is replaced by following substituting group:

A) two-O-CH ₃Group;

B) three-O-CH ₃Group is positioned at 2,3 and 4; Or

C) one-N (CH ₃) ₂Group; With;

D) work as R ²³Be CH ₃The time, one 2 or 3-O-CH ₃Group,

R wherein ²⁹Be selectively additionally to be replaced by solubilizing group.

In one aspect, the sirtuin-that the invention provides structural formula (XVIII) regulates compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Each Z ₁₄, Z ₁₅And Z ₁₆Be to be selected from N, NR independently ₁', S, O, CR ²⁰, or CR ₁',

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group; With

Each R ²⁰Be to be selected from H or solubilizing group independently;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-, Each R wherein ₁' be the C that is selected from H or selectively replaces independently ₁-C ₃The straight or branched alkyl; With

R ³¹Be to be selected from monocycle or the bicyclic aryl that selectively replaces, or the monocycle or the bicyclic heteroaryl that selectively replace, condition is to work as R ¹⁹Be

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃All be CH, R ²⁰Be H, and R ²¹Be-NHC (O)-time, R ³¹It or not the phenyl that selectively replaces.

In yet another aspect, the sirtuin-that the invention provides structural formula (XX) regulates compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', O or S;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group; With

Each R ²⁰Be to be selected from H or solubilizing group independently;

R ^20aBe to be selected from H or solubilizing group independently;

Wherein:

R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace, R wherein worked as ¹⁹Be

And Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Each is naturally during CH, R ^20aIt is solubilizing group.

Also having aspect another, the sirtuin-that the invention provides structural formula (XXI) regulates compound or its salt:

Wherein:

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-, Wherein

With

R ³²Be monocycle or the bicyclic heteroaryl that selectively replaces, or the bicyclic aryl that selectively replaces, wherein:

Work as R ²¹Be-NH-C (O)-CH ₂-time, R ³²It or not unsubstituted thiophene-2-base;

Work as R ²¹Be-NH-C (O)-time, R ³²Not furans-2-base, 5-bromine furans-2-base, or 2-phenyl-4-methylthiazol-5-base;

Work as R ²¹Be-NH-S (O) ₂-time, R ³²It or not unsubstituted naphthyl or 5-chlorothiophene-2-base.

In yet another aspect, the sirtuin-that the invention provides structural formula (XXII) regulates compound or its salt:

Wherein:

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁' (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-,

Each R wherein ₁' be the C that is selected from H or selectively replaces independently ₁-C ₃The straight or branched alkyl; With

R ³³Be the phenyl that selectively replaces, wherein:

Work as R ²¹Be-NR ₁'-C (O)-time, R ₁' not H;

Work as R ²¹Be-NH-C (O)-CH ₂Or-NH-C (O)-CH ₂During-O-, R ³³Not unsubstituted phenyl or 4-halogenophenyl; With

Work as R ²¹Be-NH-S (O) ₂-time, R ³³Not unsubstituted phenyl, 2,4-or 3,4-3,5-dimethylphenyl; 2,4-dimethyl-5-p-methoxy-phenyl, 2-methoxyl group-3,4-dichlorophenyl; the 2-methoxyl group, 5-bromophenyl-3,4-dioxy ethylidene phenyl, 3; 4-dimethoxy base, 3,4-dichlorophenyl, 3; the 4-3,5-dimethylphenyl, 3-or 4-aminomethyl phenyl, 4-alkoxyl phenyl, 4-Phenoxyphenyl; the 4-halogenophenyl, 4-xenyl, or 4-acetylamino phenyl.

In one aspect, the sirtuin-that the invention provides structural formula (XXII) regulates compound or its salt:

Wherein:

R ²¹Be be selected from-NH-C (O)-, or-NH-C (O)-CH ₂-; With

R ³³The phenyl that is replaced by following substituting group:

A) one-N (CH ₃) ₂Group;

B) one at 3 CN group;

C) one-S (CH ₃) group; Or

D)

3 and 4 bridgings.

In yet another aspect, the sirtuin-that the invention provides structural formula (XXIII) regulates compound or its salt:

Wherein:

Each R ²⁰And R ^20aBe to be selected from H or solubilizing group independently;

Each R ₁', R ₁" and R ₁" ' independently is the C that is selected from H or selectively replaces ₁-C ₃The straight or branched alkyl;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Work as R ²¹Be-NH-C (O)-time, R ³¹Not 3,5-dinitrophenyl, 4-butyl phenyl ether

Work as R ²¹Be-NH-C (O)-and each R ²⁰, R ^20a, R ₁', R ₁" and R ₁" ' when being hydrogen, R ³¹Be not

Unsubstituted phenyl, 2-or 4-nitrophenyl, 2,4-dinitrophenyl, 2-or 4-chloro-phenyl-, the 2-bromophenyl, 4-fluorophenyl, 2,4 dichloro benzene base, 2-carboxyl phenyl, 2-azido-phenyl, 2-or 4-aminophenyl, 2-acetylamino phenyl, 4-aminomethyl phenyl, or 4-p-methoxy-phenyl;

Work as R ²¹Be-NH-C (O)-time, R ₁" be methyl; With each R ²⁰, R ^20a, R ₁' and R ₁" ' when all being hydrogen, R ³¹Not 2-methylamino phenyl,

Work as R ²¹Be-NH-C (O)-CH ₂-or NH-C (S)-NH-and each R ²⁰, R ^20a, R ₁', R ₁" and R ₁" ' when all being hydrogen, R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-S (O) ₂-, R ₁" be hydrogen or methyl and each R ²⁰, R ^20a, R ₁' and R ₁" ' when all being hydrogen, R ³¹It or not the 4-aminomethyl phenyl; With

Work as R ²¹Be-NH-S (O) ₂-, R ^20aBe hydrogen or-CH ₂-N (CH ₂CH ₃) ₂And each R ²⁰, R ₁', R ₁" and R ₁" ' when all being hydrogen, R ³¹Be not

One special aspect, the sirtuin-that the invention provides structural formula (XXIII) regulates compound or its salt:

Wherein:

At least one R ²⁰Be solubilizing group or at least one R ₁The C that " ' be selectively replaces ₁-C ₃Straight or branched alkyl or the two all are; Or

R ^20aBe to remove CH ₂-N (CH ₂CH ₃) ₂Outside solubilizing group.

Also having aspect another, the sirtuin-that the invention provides structural formula (XXIV) regulates compound or its salt:

Wherein:

R ²¹Be selected from-NR ²³-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁' ,-NR ₁'-C (S)-NR ₁' ,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁' ,-NR ₁'-C (=NR ₁')-NR ₁' ,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Work as R ²¹Be-NH-C (O)-CH ₂-time, R ³¹Not the 2-aminomethyl phenyl, or 3, the 4-Dimethoxyphenyl;

Work as R ²¹When being-NH-C (O)-CH=CH-, R ³¹It or not the 2-chloro-phenyl-;

Work as R ²¹When being-NH-C (O)-NH-, R ³¹It or not unsubstituted benzimidazolyl-;

Work as R ²¹Be-NH-S (O) ₂-and each R ²⁰, R ^20a, R ₁', R ₁" and R ₁" ' when all being hydrogen, R ³¹Not unsubstituted phenyl, 4-chloro-phenyl-, 4-aminomethyl phenyl, or 4-acetylamino phenyl;

Work as R ²¹Be-NH-S (O) ₂-, each R ₁' and R ₁" ' is methyl or hydrogen and each R ²⁰, R ^20a, and R ₁" when all being hydrogen, R ³¹It or not the 4-nitrophenyl;

Work as R ²¹Be-NH-C (O)-CH ₂-O-, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when all being hydrogen, R ³¹Not 2,3-, 2,5-, 2,6-, 3,4-or 3, the 5-3,5-dimethylphenyl, 2,4-dichloromethyl, 2,4-dimethyl-6-bromophenyl, 2-or 4-chloro-phenyl-, 2-(1-methyl-propyl) phenyl, 5-methyl-2-(1-methylethyl) phenyl, 2-or 4-aminomethyl phenyl, 2,4-two chloro-6-aminomethyl phenyls, nitrophenyl, 2,4-dimethyl-6-nitrophenyl, 2-or 4-p-methoxy-phenyl, 4-ethanoyl-2-p-methoxy-phenyl, 4-chloro-3, the 5-3,5-dimethylphenyl, 3-ethylphenyl, 4-bromophenyl, the 4-cyclohexyl phenyl, 4-(1-methyl-propyl) phenyl, 4-(1-methylethyl) phenyl, 4-(1, the 1-dimethyl ethyl) phenyl, or unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH ₂-, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when all being hydrogen, R ³¹Not unsubstituted naphthyl, the 4-chloro-phenyl-, the 4-nitrophenyl, the 4-p-methoxy-phenyl, unsubstituted phenyl, unsubstituted thienyl,

Work as R ²¹Be-NH-C (O)-CH ₂-, R ₁' be methyl and each R ²⁰, R ^20a, R ₁", and R ₁" ' when all being hydrogen, R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH=CH, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when all being hydrogen, R ³¹Not unsubstituted furyl, the furyl that nitrophenyl replaces, 2,4 dichloro benzene base, 3,5-two chloro-2-p-methoxy-phenyls, 3-or 4-nitrophenyl, 4-p-methoxy-phenyl, unsubstituted phenyl, or the thienyl of nitro replacement;

Work as R ²¹Be-NH-C (O)-CH (CH ₂CH ₃)-and each R ²⁰, R ^20a, R ₁', R ₁", and R ₁" ' when all being hydrogen, R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH (CH ₃)-O-, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when being hydrogen, R ³¹It or not the 2,4 dichloro benzene base.

One special aspect, the sirtuin-that the invention provides structural formula (XXIV) regulates compound or its salt:

Wherein:

Each R ²⁰And R ^20aBe to be selected from H or solubilizing group independently, and R ²⁰And R ^20aIn at least one be solubilizing group;

R ²¹Be selected from-NR ²³-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁', R wherein ²³Be the C that selectively replaces ₁-C ₃The straight or branched alkyl; With

R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace.

In yet another aspect, the sirtuin-that the invention provides structural formula (XXV) regulates compound or its salt:

Wherein:

Each R ²⁰And R ^20aBe to be selected from H or solubilizing group, wherein R independently ²⁰And R ^20aIn at least one be solubilizing group;

Each R ₁', R ₁" and R ₁" ' independently is the C that is selected from H or selectively replaces ₁-C ₃The straight or branched alkyl; With

R ³²It is the phenyl that selectively replaces.

In one aspect, the sirtuin-that the invention provides structural formula (XXVI) regulates compound or its salt:

Wherein:

R ³³Be selected from heteroaryl that selectively replaces or the bicyclic aryl that selectively replaces, condition is:

As each R ₁' and R ₁" ' is hydrogen or methyl and each R ₁", R ₂₀And R _20aWhen all being hydrogen, R ³³Not 5,6,7, the 8-tetralyl, unsubstituted benzofuryl, unsubstituted benzothiazolyl, the benzothienyl that chloro-or nitro replace, unsubstituted furyl, phenyl-, the furyl that bromo-or nitro replace, dimethyl replaces De isoxazolyl, unsubstituted naphthyl, 5-bromonaphthalene base, 4-methyl naphthyl, 1-or 3-methoxyl group naphthyl, the naphthyl that azo replaces, unsubstituted pyrazinyl, the methyl substituted pyridyl of S-, the unsubstituted pyridine base, thienyl-or the quinolyl that replaces of phenyl, chloro-, the thienyl that bromo-or nitro replace, unsubstituted thienyl, or

One special aspect, the sirtuin-that the invention provides structural formula (XXVI) regulates compound or its salt:

Wherein:

Each R ²⁰And R ^20aBe to be selected from H or solubilizing group, wherein R independently ²⁰Or R ^20aIn at least one be solubilizing group;

Each R ₁', R ₁" and R ₁" ' independently is the C that is selected from H or selectively replaces ₁- ₃The straight or branched alkyl; With

R ³³Be selected from heteroaryl that selectively replaces or the bicyclic aryl that selectively replaces.

In yet another aspect, the sirtuin-that the invention provides structural formula (XXVII) regulates compound or its salt:

Wherein:

Each R ₁' and R ₁" be the C that is selected from H or selectively replaces independently ₁-C ₃The straight or branched alkyl;

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ' ₁-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Condition is: work as R ²¹Be-NH-C (O)-and R ¹⁹Be

The time, R ³¹Not the unsubstituted pyridine base, 2,6-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

One special aspect, the sirtuin-that the invention provides structural formula (XXVII) regulates compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-, NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Work as R ²¹Be-NH-C (O)-time, R ¹⁹It or not pyrazolyl;

Work as R ²¹Be-NH-, and R ¹⁹When being thiazolyl, R ³¹It or not phenyl that selectively replaces or the pyridyl that selectively replaces;

Work as R ²¹Be-NH-C (O)-CH ₂-, and R ¹⁹When being pyrazolyl, R ³¹Not unsubstituted indyl or unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH ₂-, and R ¹⁹Be

The time, R ³¹Not 2-aminomethyl phenyl or 3, the 4-Dimethoxyphenyl;

Work as R ²¹Be-NH-C (O)-CH=CH-, and R ¹⁹Be

The time, R ³¹It or not the 2-chloro-phenyl-;

Work as R ²¹Be-NH-C (O)-NH-, and R ¹⁹When being pyrazolyl, R ³¹Not unsubstituted isoxazolyl, unsubstituted naphthyl, unsubstituted phenyl, 2,6-difluorophenyl, 2,5-3,5-dimethylphenyl, 3,4-dichlorophenyl, or 4-chloro-phenyl-;

Work as R ²¹Be-NH-C (O)-NH-, and R ¹⁹Be

The time, R ³¹It or not unsubstituted benzimidazolyl-;

Work as R ²¹Be-NH-, and R ¹⁹When being pyrazolyl, R ³¹It or not the unsubstituted pyridine base;

Work as R ^20aBe solubilizing group, R ¹⁹Be 1-methylpyrrole base and R ²¹Be-NH-C (O)-time, R ³¹Not unsubstituted phenyl, unsubstituted furyl, unsubstituted pyrryl, unsubstituted pyrazolyl, unsubstituted isoquinolyl, the benzothienyl that unsubstituted benzothienyl, chlorine replace, 2-fluoro-4-chloro-phenyl-or by the mono-substituted phenyl of solubilizing group;

Work as R ^20aBe solubilizing group, R ¹⁹Be thienyl and R ²¹Be-NH-C (O)-time, R ³¹It or not unsubstituted phenyl;

Work as R ^20aBe solubilizing group, R ¹⁹Be methylimidazolyl and R ²¹Be-NH-C (O)-time, R ³¹It or not 1-methyl-4-(1,1-dimethyl ethoxy carbonyl amino) pyrroles-2-base or by the mono-substituted phenyl of solubilizing group;

Work as R ²¹Be-NH-and R ¹⁹When being pyridyl ， oxadiazole base (oxadiazolyl) or thiadiazolyl group, R ³¹Not unsubstituted phenyl, 3-p-methoxy-phenyl or 4-p-methoxy-phenyl;

Work as R ²¹Be-NH-C (O)-and R ¹⁹When being thiazolyl or pyrimidyl, R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-and R ¹⁹Be

The time, R ³¹Not the unsubstituted pyridine base, unsubstituted thienyl, unsubstituted phenyl, the 2-aminomethyl phenyl, 4-fluorophenyl, 4-p-methoxy-phenyl, the 4-aminomethyl phenyl, 3,4-dioxy ethylidene phenyl, 3-acetylamino-4-aminomethyl phenyl, 3-[(6-amino-1-oxygen hexyl) amino]-the 4-aminomethyl phenyl, 3-amino-4-aminomethyl phenyl, 2, the 6-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 3-halo-4-p-methoxy-phenyl, 3-nitro-4-methyl phenyl, 4-propoxy-phenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl;

Work as R ²¹Be-NH-C (O)-and R ¹⁹Be

The time, R ³¹Not 3, the 5-dinitrophenyl, the 4-butoxy phenyl,

At one more specifically in the embodiment, the sirtuin-that the invention provides structural formula (XXVII) regulates compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 1 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

0 to 1 R ₁The C that " ' be selectively replaces ₁-C ₃The straight or branched alkyl; With

Work as R ²¹Be-NH-C (O)-time, R ¹⁹It or not pyrazolyl;

Work as R ²¹Be-NH-C (O)-NH-, and R ¹⁹When being pyrazolyl, R ³¹Not unsubstituted isoxazolyl, unsubstituted naphthyl, unsubstituted phenyl, 2,6-difluorophenyl; 2, the 5-3,5-dimethylphenyl; 3, the 4-dichlorophenyl; Or 4-chloro-phenyl-;

Work as R ^20aBe solubilizing group, R ¹⁹Be 1-methylpyrrole base and R ²¹Be-NH-C (O)-time, R ³¹It or not unsubstituted phenyl; Unsubstituted furyl; Unsubstituted pyrryl; Unsubstituted pyrazolyl; Unsubstituted isoquinolyl; Unsubstituted benzothienyl; The benzothienyl that chlorine replaces; 2-fluoro-4-chloro-phenyl-or by the mono-substituted phenyl of solubilizing group;

Work as R ^20aBe solubilizing group, R ¹⁹Be methylimidazolyl and R ²¹Be-NH-C (O)-time, R ³¹It or not 1-methyl-4-(1,1-dimethyl ethoxy carbonyl amino) pyrroles-2-base or by the mono-substituted phenyl of solubilizing group; With

Work as R ²¹Be-NH-C (O)-and R ¹⁹When being thiazolyl or pyrimidyl, R ³¹It or not unsubstituted phenyl.Also having aspect another, the invention provides the compound or its salt of structural formula (XXVIII):

Wherein:

R ²⁹Be selected from:

Wherein:

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be to be selected from N, CR independently ²⁰, or CR ₁', Z wherein ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In one be N; With

0 to 1 R ²⁰It is solubilizing group;

The present invention also provides the pharmaceutical composition that contains one or more formulas (I)-(XXVIII) compound or its salt, its prodrug or its metabolite.

In yet another aspect, the invention provides and use sirtuin-to regulate compound, or contain the method that sirtuin-regulates compound compositions.In certain embodiments, increase proteic level of sirtuin and/or active sirtuin-adjusting compound and can be used for multiple treatment application, comprise, for example, increase life-span of cell and treat and/or prevent multiple disease and obstacle, for example comprise, with old and feeble or stress diseases associated or obstacle, diabetes, obesity, neurodegenerative disease, the neuropathy that chemotherapy causes, the neuropathy relevant, vision disease and/or obstacle with the ischemia incident, cardiovascular disorder, the coagulation of blood disease, inflammation, and/or flush etc.Increasing proteic level of sirtuin and/or active sirtuin-regulates compound and can also be used at object treatment disease or obstacle---and described object can be benefited, be used for the strengthen muscle performance from increase mitochondria activity, be used to increase muscle ATP level or be used for the treatment of or muscle tissue damage that prevention is relevant with anoxic or ischemic.In other embodiments, increase proteic level of sirtuin and/or active sirtuin-adjusting compound and can be used for multiple treatment application, comprise, for example, improve cell to stress susceptibility, increase apoptosis, treatment cancer, stimulate appetite and/or stimulate weight increase or the like.As described further below, described method comprises sirtuin-adjusting compound from pharmacy effective dose to the object that needs are arranged that use.

In some respects, sirtuin-adjusting compound can be used separately or be co-administered with other compounds, and described other compounds comprise that other sirtuin-regulates compound or other therapeutical agent.

The accompanying drawing summary

Fig. 1 has shown the synoptic diagram of the ATP test cell line of describing among the embodiment 5.

Fig. 2 has shown the dose response curve of the ATP level in the trans-resveratrol treatment cell afterwards.

Detailed Description Of The Invention

1. definition

As used herein, following term and phrase should have the implication of the following stated. Unless otherwise defined, all technology as used herein and scientific terminology have those of ordinary skills the general identical meanings of understanding.

Singulative " one (a), " " one (an), " and " this (the) " comprise plural implication, unless context clearly indicates in addition.

Term " agent (agent) " is used in reference to a kind of compound herein, the mixture of compound, a kind of large biological molecule (nucleic acid for example, antibody, protein or its part, for example, or a kind of from biomaterial such as bacterium, plant peptide),, fungi, or the extract that makes in animal (particularly mammal) cell or tissue. The activity of these agent can make it be suitable as a kind of " therapeutic agent (therapeutic agent) ", described therapeutic agent is on a kind of biology, the active material (or material type) on physiological or pharmacology, thereby works partly or capapie in object.

When mentioning a kind of compound, term " (bioavailable) of bioavailable " refers to art-recognized implication, and refer to a kind of compound of form, object or patient that the combined thing of a part of the form permission compound of this compound or the compound amount that gives gives absorb, mix object or patient that compound gives, can utilize on the object that perhaps otherwise for compound, gives or patient's physiology.

" biologically-active moiety of sirtuin " refers to the part of the sirtuin albumen with biologically active such as deacetylated ability. The biologically-active moiety of sirtuin can comprise the core space of sirtuin. For example, the GenBank accession number that comprises NAD+ land and Binding Capacity district is the biologically-active moiety of the SIRT1 of No.NP_036370, can include but not limited to that the GenBank accession number is the amino acid 62-293 of No.NP_036370, it is that the nucleotides 237-932 of No.NM_012238 is coded by the GenBank accession number. Therefore, this zone is sometimes referred to as core space. The other biological active part of SIRT1,, sometimes also referred to as core space, comprise that the GenBank accession number is the approximately amino acid 261-447 of No.NP_036370, and it is coded by the nucleotides 834-1394 of GenBank accession number No.NM_012238; The GenBank accession number is the approximately amino acid 242-493 of No. NP_036370, and it is that the nucleotides 777-1532 of No.NM_012238 is coded by the GenBank accession number; Or the GenBank accession number is the approximately amino acid 254-495 of No.NP_036370, and it is coded by the nucleotides 813-1538 of GenBank accession number No.NM_012238.

Term " pet " refers to cat and dog. As used herein, any member in term " dog (class) " expression dog family kind (the species Canis familiaris), there are a large amount of different kinds in described dog family in planting. Term " cat (class) " refers to cats, comprises other members in the cat raised and train and cat family, Felis.

Term " comprises (comprise) " and implication that " comprising (the comprising) " scope that is used to is wide, open, and the meaning refers to comprise other composition.

term " conservative residue " refers to an amino acid member in one group of amino acid with certain general character. term " conservative amino acid replacement " refers to the amino acid in such group and is replaced by the different amino acid on the same group mutually. it is a kind of that to define the functional mode of general character between individual amino acids be to analyze the homology biofacies to answer the normalized frequency (Schulz that between protein, amino acid changes, G.E. and R.H.Schirmer., Principles of Protein Structure, Springer-Verlag). according to these analyses, the amino acid whose group of amino acid preferentially exchange each other that can be defined in a group, and therefore at them, has each other maximum similitude (Schulz aspect the impact of overall protein matter structure, G.E. and R.H.Schirmer, Principles of Protein Structure, Springer-Verlag). an example of one group of amino acid group of definition comprises by this way: (i) charged groups, by Glu and Asp, Lys, Arg and His form, (ii) positively charged group, by Lys, Arg and His form, (iii) electronegative group, formed by Glu and Asp, (iv) aromatic group, by Phe, Tyr and Trp form, (v) azo-cycle group, formed by His and Trp, (vi) large fatty non-polar group, by Val, Leu and Ile form, (vii) low pole group, formed by Met and Cys, (viii) little residue groups, by Ser, Thr, Asp, Asn, Gly, Ala, Glu, Gln and Pro form, (ix) fat group, by Val, Leu, Ile, Met and Cys form and (x) little oh group, formed by Ser and Thr.

" diabetes " refer to hyperglycaemia or ketone acid disease, and long-term hyperglycemia state or caused chronic, the general metabolic disorder of glucose-tolerant decline. " diabetes " comprise all I types and II type (non-insulin-dependent diabetes mellitus or the NIDDM) form of this disease. The risk factors of diabetes comprise following factor: male sex's waistline surpasses 40 inches or women's waistline over 35 inches, blood pressure is 130/85mmHg or higher, triglycerides is higher than 150mg/dl, rapid blood sugar surpass 100mg/dl or HDL in the male sex lower than 40 mg/dl or in the women lower than 50mg/dl.

Sirtuin " directly activator " is by be combined to activate its molecule with sirtuin. Sirtuin " directly inhibitor " is by be combined to suppress its molecule with sirtuin.

Term " ED₅₀" be art-recognized implication. In some embodiments, ED₅₀The meaning refers to produce 50% maximum reaction or the drug dose of effect, perhaps alternatively, produces the drug dose of predetermined reaction in the subjects 50% or preparation. Term " LD₅₀" be art-recognized implication. In some embodiments, LD₅₀Refer to drug dose lethal in 50% subjects. Term " therapeutic index (therapeutic index) " is art-recognized term, and the therapeutic index that it refers to medicine, be defined as LD₅₀/ED ₅₀。

Term " hyperinsulinemia " refers to blood insulin level in individuality higher than normal state.

Term " comprises " that the meaning is " including but not limited to ". " comprise " and " including but not limited to " alternatively used mutually.

Term " insulin resistance (insuin resistance) " refers to a kind of state, and wherein for the biological respinse producing in there is no the object of insulin resistance, the insulin of normal amount produces the biological respinse lower than normal level.

" anti-insulin sexual dysfunction (the insulin resistance disorder) " that discuss in this place refers to, caused by insulin resistance or owing to any disease or the patient's condition of insulin resistance. example comprises: diabetes, fat, metabolic syndrome, the insulin resistance metabolic syndrome, X syndrome, insulin resistance, hypertension (high blood pressure), hypertension (hypertension), high blood cholesterol, dyslipidemia, hyperlipidemia, dyslipidemia, atherosclerosis disease comprises apoplexy, coronary artery disease or myocardial infarction, hyperglycemia, hyperinsulinemia, and/or high proinsulin mass formed by blood stasis, the glucose-tolerant damage, the insulin that postpones discharges, diabetic complication, comprise coronary heart disease, angina pectoris, congestive heart failure, apoplexy, the cognitive function of dementia, retinopathy, peripheral neurophaty, ephrosis, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, certain cancers (carcinoma of endometrium for example, breast cancer, prostate cancer and colon cancer), complications of pregnancy, poor female reproductive health (menstrual disorder for example, sterility, irregular ovulation, Stein-Leventhal syndrome (PCOS)), lipodystrophy, the obstacle that cholesterol is relevant, gall stone for example, cholecystitis and cholelithiasis, gout, obstructive sleep apnea and breathing problem, osteoarthritis, with prevention and treatment bone loss, for example, osteoporosis.

Term " livestock animals (livestock animals) " refers to the quadruped of having tamed, comprise the biological species that meat and different byproducts are provided, for example, bovine comprises ox and other animals of Bos, porcine animals comprises that the pig raised and train and other pig belong to animal, sheep class animal comprises sheep and other Ovis animals, the goat of raising and train and other Capra animals; Be used for particular task domestication quadruped, such as being used for pack animal, for example, horse class animal comprises the horse raised and train and other equine, equus.

Term " mammal " is known in the art, and exemplary mammal comprises the people, primate, livestock animals (comprising bovine, Swine etc.), pet (comprising the dog class, cat class etc.) and rodent (for example, Mouse and rat).

When referring to compound, the meaning is that compound exists with the form that can find in nature to term " naturally occurring form (naturally occurring form) ", for example composition. For example, because resveratrol can find in red wine, it just is present in red wine with naturally occurring form. If compound is not naturally occurring form, for example, compound is from purification and separation at least some other molecules of this compound, obtaining that occurring in nature is found. " naturally occurring compound " refers to compound and can find at occurring in nature, that is, this compound not by the people for designing. Naturally occurring compound can artificially be made or from nature, obtain.

" naturally occurring compound " refers to compound and can find at occurring in nature, that is, this compound not by the people for designing. Naturally occurring compound can artificially be made or from nature, obtain. For example, resveratrol is naturally occurring compound. " compound that non-natural exists " refers to not be the known compound that is present in occurring in nature or is not present in occurring in nature.

" fat " is individual or to suffer the individuality of obesity to refer generally to body mass index (BMI) be 25 or larger individuality. Obesity can be or can not be to interrelate with insulin resistance.

Term " parenteral administration (parenteral administration) " and " parenteral administration (administered parenterally) " are art-recognized implications, refer to mode of administration and be not via in intestines and local application, normally by injection, use, and include but not limited in intravenous, muscle, in artery, in sheath, in capsule, in interior, intracardiac, the corium of socket of the eye, the abdominal cavity film is interior, transtracheal, subcutaneous, in subepidermal, joint, under capsule, subarachnoid, backbone interior and breastbone inner injection and transfusion.

" patient ", " object ", " individuality " or " host " refer to people or inhuman animal.

Term " is equal to percentage (percent identical) " and refers to the sequence homogeneity between two amino acid sequences or two nucleotide sequences. Homogeneity can be measured separately, via relatively by contrast, for the position of each sequence that compares purpose, being measured. By identical base or amino acid when occupied, molecule is same at that point so when the reciprocity position of contrast in sequence. By identical or similar amino acid residue (for example, three-dimensional and/or electrically similar), molecule is (similar) of homology at that point so when equity point. , with homology, similitude, the homogeny that the percentage form represents, refer at the same position same or similar amino acid no purpose function common with the contrast sequence. Can use different contrast algorithm and/or program, comprise FASTA, BLAST, or ENTREZ. FASTA and BLAST are as GCG sequence analysis bag (GCG sequence analysis package) (University of Wisconsin, Madison, Wis.) a part is available, and can use under the parameter of for example default setting. ENTREZ passes through the National Center for Biotechnology Information, National Library of Medicine, and National Institutes of Health, Bethesda, MD are available. In one embodiment, being equal to percentage and can determining by the GCG program of two sequences,, using gap weight (gap weight) is 1, for example, each amino acid gap is heavy by meter, seems that it is unmatched monamino acid or nucleotides in two sequences.

Other correlation technique is described in Enzymology, vol.266:Computer Methods for Macromolecular Sequence Analysis (1996), ed.Doolittle, Academic Press, Inc., a division of Harcourt Brace ﹠ Co., San Diego, California, in the method for USA. Preferably, contrast sequence with a kind of contrast program in the gap in sequence that allows. Smith-Waterman be a kind of in sequence contrast the algorithm of allowable clearance. See Meth.Mol.Biol.70:173-187 (1997). Also have, use the GAP program of Needleman and Wunsch control methods also can be used for the contrast sequence. A kind of optionally search strategy is used MPSRCH software, and this software moves on the MASPAR computer. MPSRCH uses the Smith-Waterman algorithm to estimate sequence on large-scale parallel computer. These methods have been improved the ability of choosing obvious relevant matches, and particularly to little gap and the tolerance of nucleotide sequence mistake. The amino acid sequence of nucleic acid coding can be used to retrieve protein and DNA database.

Term " pharmaceutically acceptable carrier " is art-recognized implication, and refer to pharmaceutically acceptable material, composition or carrier, for example a kind of liquid or solid filler, diluent, excipient, solvent or encapsulated materials, they relate to carries or transports any tested composition or its component. Every kind of carrier must be " acceptable ", and the meaning is exactly and tested composition and its component compatibility, and patient is not injured. Some examples that can be used as the material of pharmaceutically acceptable carrier comprise: (1) sugar, lactose for example, dextrose plus saccharose; (2) starch, for example cornstarch and potato starch; (3) cellulose and derivative thereof, sodium carboxymethylcellulose for example, ethyl cellulose and cellulose acetate; (4) tragacanth of powdered; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum powder; (8) excipient, for example cocoa butter and cured bolt; (9) oils, peanut oil for example, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, for example propane diols; (11) polyalcohols, glycerine for example, sorbierite, sweet mellow wine and polyethylene glycol; (12) ester class, for example ethyl oleate and ethyl laurate; (13) agar; (14) buffer, for example magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18) Ringer ' s solution; (19) ethanol; (20) PBS; (21) the non-toxicity compatible substances of other that use in pharmaceutical preparation.

Term " polynucleotides (polynucleotide) ", and " nucleic acid (nucleic acid) " alternatively used mutually. They refer to the polymer form of any length nucleotides, and described nucleotides is deoxyribonucleotide or ribonucleotide, or their analog. Polynucleotides can have any three-dimensional structure, and can show any function, known or unknown. Following is the non-limitative example of polynucleotides: the code area of gene or genetic fragment or noncoding region, and from the defined site of linkage analysis (loci (locus)), extron, introne, mRNA (mRNA), transfer RNA, rRNA, ribozyme, cDNA, recombination of polynucleotide, side chain polynucleotides, plasmid, carrier, the DNA of the separation of any sequence, the RNA of the separation of any sequence, nucleic acid probe and primer. Polynucleotides can comprise the nucleotides of modified, for example methylated nucleotides and nucleotide analog. If present, the modification of nucleotide structure can be carried out before or after the condensate assembling. Nucleotide sequence can be interrupted by the non-nucleotide component. A kind of polynucleotides can further be modified, for example by with a kind of marker components conjugation. Term " recombination of polynucleotide " meaning refers to the polynucleotides in genome, cDNA, semi-synthetic or synthetic source, described polynucleotides or at occurring in nature, do not exist or with the non-natural arrangement mode, with another polynucleotides, be connected.

Term " preventative " or " therapeutic " treatment are the implications that art technology is generally acknowledged, are to point to host's drug administration. If using is clinical manifestation prior to the undesirable patient's condition (for example, the state of disease or other undesirable host animals), treatment is preventative so, that is, it has protected the host not develop undesirable patient's condition; Yet be after undesirable patient's condition shows when using, this treatment be curative (that is, its objective is reduction, alleviate or keep existed do not wish the patient's condition or its side effect).

Term " blocking group " is art-recognized implication, refers to temporary transient substituting group, thereby undesirable chemical transformation does not occur the possible reactive functional groups of described substituting group protection. The example of this kind blocking group comprises the ester of carboxylic acid, silyl ether, aldehyde and ketone acetal and the ketal separately of alcohol. The field of blocking group chemistry by Greene and Wuts summarize inProtective Groups in Organic Synthesis(2 ^ndEd., Wiley:New York, 1991) in.

When relating to composition, term " apyrogeneity (pyrogen-free) " refers to composition and does not contain can cause unfavorable effect (for example, excitant in the composition subject, heating, inflammation, diarrhoea, expiratory dyspnea, endotoxic shock etc.) the pyrogen of amount. For example, the meaning of this term refers to that the composition that comprises does not contain, or is substantially free of, the endogenous toxin, for example, lipopolysaccharides (LPS).

" life-span of repetition " of cell refers to the quantity by " mother cell " the individual daughter cell that produces. On the other hand, " timeliness is aging " or " timeliness life-span " refers to the time span of Unseparated Cell population maintenance survival after removed nutrients. " life-span of increase cell " or " extending the life-span of cell " are used to cell or organism, refer to the number of the daughter cell that increases certain cell generation; Increase cell or organism and process and stress or resist the ability of damage, for example to DNA, protein; And/or increase cell or organism state survival and ability of existence longer time to live under specific condition, described specific condition be for example stress (stress) (for example, heat shock, osmotic stress, energy-rich radiation, chemical induction stress, DNA damage, not enough salt level, not enough nitrogen level, or not enough nutrient level). Use method described herein, the life-span can be increased at least approximately 20%, 30%, 40%, 50%, between 60% or 20% and 70%, and between 30% and 60%, between 40% and 60%, or more.

" Sirtuin-activating compounds " refers to the level that increases sirtuin albumen and/or the compound that increases at least a activity of sirtuin albumen. In an exemplary embodiment, it is about at least 10%, 25%, 50%, 75%, 100% that the sirtuin-activating compounds can increase at least a biologically active of sirtuin albumen, or more. Exemplary sirtuin protein biological activity comprises deacetylated, and for example, histone and p53's is deacetylated; Life-extending; Increase gene stability; Silence is transcribed; And control the separation of oxidized protein between the primary and secondary cell.

" Sirtuin-Inhibitor " refers to the level that reduces sirtuin albumen and/or the compound that reduces at least a activity of sirtuin albumen. In an exemplary embodiment, it is about at least 10%, 25%, 50%, 75%, 100% that the sirtuin-Inhibitor can reduce at least a biologically active of sirtuin albumen, or more. The biologically active of exemplary sirtuin albumen comprises deacetylated, and for example, histone and p53's is deacetylated; Life-extending; Increase gene stability; Silence is transcribed; And control the separation of oxidized protein between the primary and secondary cell.

" Sirtuin-regulates compound " refers to the compound of formula described herein (I)-(XXVIII). In exemplary embodiment, sirtuin-regulates compound and (for example can raise, activation or stimulate), lower (for example, suppressing or suppress (inhibit or suppress)) or change in addition functional character or the biologically active of sirtuin albumen. Sirtuin-regulates compound can be used for regulating directly or indirectly sirtuin albumen. In some embodiments, sirtuin-adjusting compound can be sirtuin-activating compounds or sirtuin-Inhibitor.

" Sirtuin albumen " refers to a member in sirtuin deacetylase protein family, or the member of preferred sir2 family, it comprises yeast Sir2 (the GenBank accession number is No.P53685), nematode (C.elegans) Sir-2.1 (the GenBank accession number is No.NP_501912), (the GenBank accession number is No. NM_012237 with people SIRT1 (the GenBank accession number is No.NM_012238 and NP_036370 (or AF083106)) and SIRT2, NM_030593, NP_036369, NP_085096, and AF083107) albumen. Other family member comprises four kinds of additional yeast Sir2-sample genes, be called " HST gene " (Sir 2 homologues) HST1, HST2, HST3 and HST4, with five kinds of other people's homologue hSIRT3, hSIRT4, hSIRT5, hSIRT6 and hSIRT77 (Brachmann et al. (1995) Genes Dev.9:2888 and Frye et al. (1999) BBRC 260:273). Preferred sirtuins is such, namely with SIRT2, compares itself and SIRT1, be hSIRT1, and/or Sir2 shares more similitude, and for example those have the albumen of that exist at least a portion SIRT1 and N-terminal sequence that do not have in SIRT2, for example SIRT3.

" SIRT1 albumen " refers to sirtuin and takes off a member in sir2 family in acetyl protease. In one embodiment, SIRT1 albumen comprises yeast Sir2 (the GenBank accession number is No.P53685), nematode (C.elegans) Sir-2.1 (the GenBank accession number is No.NP_501912), people SIRT1 (the GenBank accession number is No.NM_012238 or NP_036370 (or AF083106)), (the GenBank accession number is No.NM_012237 with people SIRT2, NM_030593, NP_036369, NP_085096, or AF083107) albumen, and equivalent and its fragment. In another embodiment, SIRT1 albumen comprises polypeptide, and described polypeptide comprises a kind of sequence, this sequence by or be No.NP_036370 by the GenBank accession number basically, NP_501912, NP_085096, NP_036369, or the amino acid sequence described in P53685 forms. SIRT1 albumen comprises polypeptide, and it is Nos.NP_036370 that described polypeptide comprises the GenBank accession number, NP_501912, NP_085096, NP_036369, or all or part of amino acid sequence described in P53685; The GenBank accession number is Nos.NP_036370, NP_501912, NP_085096, NP_036369, or described in P53685 with 1 to approximately 2,3,5,7,10,15,20,30,50,75 or the substituent amino acid sequence of more conservative amino acid; With the GenBank accession number be Nos.NP_036370, NP_501912, NP_085096, NP_036369, or P53685, and their functional fragment at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or the amino acid sequence of 99% homology. Polypeptide of the present invention also comprises that the GenBank accession number is Nos.NP_036370, NP_501912, NP_085096, NP_036369, or the homologue of P53685 (for example, ortholog thing and paralog thing), variant or fragment.

" SIRT3 albumen " refers to member in sirtuin deacetylase protein family and/or the homologue of SIRT1 albumen. In one embodiment, SIRT3 albumen comprises that (the GenBank accession number is No.AAH01042 to people SIRT3, NP_036371, or NP_001017524) and mouse SIRT3 (the GenBank accession number is No.NP_071878) albumen, and equivalent and its fragment. In another embodiment, SIRT3 albumen comprises polypeptide, and described polypeptide comprises a kind of sequence, this sequence by or be AAH01042 by the GenBank accession number basically, NP_036371, NP_001017524, or the amino acid sequence described in NP_071878 forms. SIRT3 albumen comprises polypeptide, and it is AAH01042 that described polypeptide comprises the GenBank accession number, NP_036371, NP_001017524, or all or part of amino acid sequence described in NP_071878; The GenBank accession number is Nos.AAH01042, NP_036371, NP_001017524, or described in NP_071878 with 1 to approximately 2,3,5,7,10,15,20,30,50,75 or the substituent amino acid sequence of more conservative amino acid; With the GenBank accession number be Nos.AAH01042, NP_036371, NP_001017524, or NP_071878, and their functional fragment at least 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or the amino acid sequence of 99% homology. Polypeptide of the present invention also comprises that the GenBank accession number is Nos.AAH01042, NP_036371, NP_001017524, or the homologue of NP_071878 (for example, ortholog thing and paralog thing), variant or fragment. In one embodiment, SIRT3 albumen comprises the fragment of SIRT3 albumen, the fragment of described SIRT3 albumen is passed through by mitochondrial matrix processing peptidase (mitochondrial processing peptidase, MPP) and/or after mitochondria intermediate peptase (mitochondrial intermediate peptidase, MIP) excision make.

Term " homology basically " is when uniting use with amino acid sequence, refer to following sequence: these sequences are substantially the same or similar on sequence, cause the conformation homology, thereby it is active in useful degree to keep one or more biologies (comprising immunologic). This term is not intended to imply the common evolution of sequence.

Term " synthetic " is that art-recognized implication prepares with referring to by external chemistry or enzymatic synthesis.

Term " systemic administration (systemic administration) ", " use capapie (administered systemically) ", " periphery is used (peripheral administration) " and " using to periphery (administered peripherally) " be art-recognized implication and refer to the non-central nervous system that directly is administered to of tested composition, therapeutic agent or other materials, makes it can enter in patient's system and carry out metabolism and other similar processes.

Term " therapeutic agent " is art-recognized implication and refers to any chemical part of biology, physiology or pharmacological active substance that be, its part or work capapie in object. This term also refers to any diagnosis that is used in the human or animal, cures, and relaxes, and treats or prevent disease, or is used to strengthen the material of desired health or spirit progress and/or the patient's condition.

Term " result for the treatment of " is art-recognized implication and refers to animal, particularly mammal, the part that is more especially caused by pharmacological active substance in the people or whole body effect. Phrase " treatment effective dose " meaning refer to this material with the reasonable benefit that is applicable to any treatment/risk than the part that produces some expectations or the amount of whole body effect. This material for the treatment of effective dose can be according to the object and the disease condition that are treated, the body weight of object and age, and the severity of disease condition, the difference of method of application etc. and changing, and this can easily be determined by those of ordinary skills. For example, thus some compositions that are described in herein can use with the reasonable benefit that is applicable to this treatment/risk than the effect that produces expectation with the amount of abundance.

" transcriptional regulatory sequences " is a gene term, and its use is through the explanation that relates to DNA sequence dna, enabling signal for example, enhancer and promoter, their guiding or control and the transcribing of albumen coded sequence that they are operatively connected. In preferred embodiments, transcribing of one of recombination is under the control of promoter sequence (or other transcriptional regulatory sequences), and described promoter sequence is controlled recombination and expressed with the cell pattern of desired expression. It will also be appreciated that recombination can be subjected to the control of transcriptional regulatory sequences, described transcriptional regulatory sequences and those sequences of controlling natural existence form genetic transcription described herein are identical or different.

" treatment " patient's condition or disease refer to the symptom of curing and alleviating at least a patient's condition or disease.

" carrier " is the nucleic acid molecules of self-replacation, and it shifts the nucleic acid molecules that inserts in host cell and/or between host cell. This term comprises that function is mainly to inserting the carrier of nucleic acid molecules in cell, and function is mainly the replicating vector of replicating nucleic acid, and function is to transcribe and/or translate the expression vector of DNA or RNA. The carrier that provides more than a kind of above-mentioned functions also is provided. As used herein, " expression vector " is defined as polynucleotides, and polypeptide can be transcribed and translate into to described polynucleotides in being introduced in suitable host cell the time. " expression system " means the suitable host cell that function, can consist of for the expression vector that produces the expression product of expecting usually.

Term " impaired vision " refers to the eyesight of reduction, its normally when treatment (for example, operation) only part reversible or irreversible. The impaired vision of especially severe is called " blind " or " vision loss ", refer to vision and lose fully, eyesight than 20/200 poorer and can not improve by correct lens or visual range less than 20 degree diameters (10 degree radius).

2.Sirtuin conditioning agent

In one aspect, the invention provides new sirtuin-and regulate compound, it is used for the treatment of and/or prevents a large amount of various diseases and obstacle, comprise, for example, with disease or obstacle old and feeble or stress be relevant, diabetes, obesity, neurodegenerative disease, eye disease or obstacle, angiocardiopathy, blood clotting obstacle, inflammation, cancer, and/or flush etc. Increasing the level of sirtuin albumen and/or active sirtuin-regulates compound and can also be used at object treatment disease or obstacle---and described object can be benefited from the mitochondria activity that increases, be used for strengthening muscle performance, for increasing muscle ATP level or be used for the treatment of or muscle tissue damage that prevention is relevant to anoxic or ischemic. Other compounds disclosed herein can be suitable for pharmaceutical composition and/or one or more methods disclosed herein.

In one embodiment, sirtuin-of the present invention regulates compound or its salt structural formula (I) expression:

Wherein:

Ring A selectively replaces; With

Ring B is by at least one carboxyl, replace or unsubstituted aryl amide, replace or unsubstituted arylalkyl amide, replace or unsubstituted heteroaryl groups, replace or unsubstituted heterocycle carbonyl ethenyl, or the polyaromatic group replaces or with aromatic ring, condenses, and selectively by one or more additional groups, replaced.

In some embodiments, ring B is replaced by at least one carboxylic group.

In some embodiments, ring B is by at least one replacement or unsubstituted aryl amide, and replacement or unsubstituted arylalkyl amide or polyaromatic group replace.

In some embodiments, ring B is replaced by at least one replacement or unsubstituted heteroaryl groups or replacement or unsubstituted heterocycle carbonyl ethenyl group.

In another embodiment, sirtuin-adjusting compound or its salt of the present invention represents with structural formula (II):

Wherein:

Ring A selectively replaces;

R ₁，R ₂，R ₃And R₄To be independently selected from-H, halogen ,-OR₅，-CN，-CO ₂R ₅，-OCOR ₅， -OCO ₂R ₅，-C(O)NR ₅R ₆，-OC(O)NR ₅R ₆，-C(O)R ₅，-COR ₅，-SR ₅， -OSO ₃H，-S(O) _nR ₅，-S(O) _nOR ₅，-S(O) _nNR ₅R ₆，-NR ₅R ₆，-NR ₅C(O)OR ₆，-NR ₅C(O)R ₆With-NO₂；

R ₅And R₆Be independently-H, replace or unsubstituted alkyl group, replace or unsubstituted aromatic yl group or replacement or unsubstituted heterocyclic group; With

N is 1 or 2.

In another embodiment, sirtuin-adjusting compound or its salt of the present invention represents with structural formula (IIa):

Wherein:

Ring A selectively replaces;

R ₁，R ₂，R ₃And R₄Be independently selected from-H halogen ,-OR₅，-CN，-CO ₂R ₅，-OCOR ₅， -OCO ₂R ₅，-C(O)NR ₅R ₆，-OC(O)NR ₅R ₆，-C(O)R ₅，-COR ₅，-SR ₅， -OSO ₃H，-S(O) _nR ₅，-S(O) _nOR ₅，-S(O) _nNR ₅R ₆，-NR ₅R ₆，-NR ₅C(O)OR ₆，-NR ₅C(O)R ₆With-NO₂；

N is 1 or 2.

In also having another embodiment, sirtuin-of the present invention regulates compound or its salt and represents with structural formula (II):

Wherein:

Ring A selectively replaces;

N is 1 or 2.

In certain embodiments, the R in structural formula (II)-(IIb)₁，R ₂，R ₃And R₄Be independently selected from-H-OR₅With-SR₅, particularly-H and-OR₅(for example ,-H ,-OH ,-OCH₃)。

A is preferably substituted for ring. Suitable substituting group comprises halogen (for example bromine), acyloxy (for example, acetoxyl group), the amino carbonyl group (for example, aromatic yl aminocarbonyl for example replaces, carboxyl substituted particularly, phenyl amino carbonyl group) and alkoxyl is (for example, methoxyl group, ethyoxyl) group.

Also having aspect another, the sirtuin-that the invention provides new formula (III) regulates compound or its salt:

Wherein:

Ring A selectively replaces;

R ₅And R₆Be independently-H, M replaces or unsubstituted alkyl group, replaces or unsubstituted aromatic yl group or replacement or unsubstituted heterocyclic group;

R ₇，R ₉，R ₁₀And R₁₁Be independently selected from-H halogen ,-R₅，-OR ₅，-CN，-CO ₂R ₅，-OCOR ₅， -OCO ₂R ₅，-C(O)NR ₅R ₆，-OC(O)NR ₅R ₆，-C(O)R ₅，-COR ₅，-SR ₅， -OSO ₃H，-S(O) _nR ₅，-S(O) _nOR ₅，-S(O) _nNR ₅R ₆，-NR ₅R ₆，-NR ₅C(O)OR ₆，-NR ₅C(O)R ₆With-NO₂；

R ₈It is the polyaromatic group; With

N is 1 or 2.

In certain embodiments, R₇，R ₉，R ₁₀And R₁₁In one or morely be-H. In special embodiment, R₇，R ₉，R ₁₀And R₁₁Each naturally-H.

In certain embodiments, R₈Be heteroaryl groups, Li such as oxazole be [4,5-b] pyridine radicals group also. In special embodiment, R₈Heteroaryl groups and R₇，R ₉，R ₁₀And R₁₁In one or morely be-H.

A is preferably substituted for ring. Suitable substituting group comprises that halogen (for example, bromine), acyloxy (for example, acetoxyl group), the amino carbonyl group (for example, aromatic yl aminocarbonyl, for example replace, particularly carboxyl substituted, the phenyl amino carbonyl group) and alkoxyl (for example, methoxyl group, ethyoxyl) group, particularly alkoxy base. In certain embodiments, ring A is by at least one alkoxy or halogen group, particularly methoxy substitution.

In certain embodiments, the ring A be selectively by at the most 3 be independently selected from (C₁-C ₃The straight or branched alkyl), O-(C₁-C ₃The straight or branched alkyl), N (C₁-C ₃The straight or branched alkyl)₂, halogen, or the substituting group of 5-6-unit heterocycle replaces.

In certain embodiments, ring A is not replaced by itrile group or pyrrolidinyl group.

In certain embodiments, R₈Be to replace or unsubstituted bicyclic heteroaryl group, for example comprise the individual N, the heteroatomic bicyclic heteroaryl group of the additional ring of O or S of being independently selected from of a ring N atom and 1-2. Preferably, R₈Be connected with the compound remainder by carbon-carbon bond. In some such embodiment, 2 additional ring hetero atoms exist, and being typically wherein at least one additional ring hetero atom is O or S. In some such embodiment, there be (having 0 or 1 O or S) in 2 total theheterocyclic nitrogen atoms, and are typically each nitrogen-atoms in different rings. In some such embodiment, R₈Do not contained carbonyl-group and replaced, particularly worked as R₈While being Thienopyrimidine base or thienopyridine base.

In some such embodiment, R₈Xuan Zi oxazole and pyridine radicals, benzothienyl, benzofuranyl, indyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl or isoindolyl. In some such embodiment, R₈Be selected from thiazole and pyridine radicals, Imidazothiazole base, benzoxazine ketone group (benzoxazinonyl), or imidazopyridyl.

R ₈In special example, when

When expression is connected with the remainder of structural formula (III), comprising:

Wherein at the most 2 not with shown in the ring carbon atom of tie point direct neighbor independently by O-C₁-C ₃The straight or branched alkyl, C₁-C ₃Straight or branched alkyl or halogen, particularly C₁-C ₃Straight or branched alkyl or halogen replace. In certain embodiments, R₈Be

(for example, when conditioning agent is the sirtuin activator) in some embodiments, R₈Be

With the ring A be selectively by at the most 3 be independently selected from (C₁-C ₃The straight or branched alkyl), O-(C₁-C ₃The straight or branched alkyl), N (C₁-C ₃The straight or branched alkyl)₂, halogen, or the substituting group of 5 to 6-unit's heterocycles replaces. In some such embodiment, ring A be not simultaneously in 2-and 6-position by O-(C₁-C ₃The straight or branched alkyl) replace. In some such embodiment, ring A is not simultaneously at 2-, and 4-and 6-position are by O-(C₁-C ₃The straight or branched alkyl) replace. In some such embodiment, ring A is not simultaneously at 2-, 3-, and the 4-position is by O-(C₁-C ₃The straight or branched alkyl) replace. In some such embodiment, ring A is replaced by 5 to 6-unit's heterocycles in the 4-position. In some such embodiment, ring A is not by O-(C in 3-or 4-position (particularly 4-position)₁-C ₃The straight or branched alkyl) the single replacement. In some such embodiment, ring A is not by O-(C in the 4-position₁-C ₃The straight or branched alkyl) with in 2-or 3-position by C₁-C ₃The straight or branched alkyl replaces.

In certain embodiments, R₈Be

Selectively by 3 substituting groups at the most, replaced with ring A, described substituting group is independently selected from (C₁-C ₃The straight or branched alkyl), (C₁-C ₃Straight or branched alkylhalide group, the wherein alkyl group that replaced by one or more halogen atoms of alkylhalide group group), O-(C₁-C ₃The straight or branched alkyl), N (C₁-C ₃The straight or branched alkyl)₂, halogen, or 5 to 6-unit's heterocycles. In some such embodiment, ring A is not by O-(C in 3-or 4-position₁-C ₃The straight or branched alkyl) the single replacement. In some such embodiment, ring A is not by O-(C in the 4-position₁-C ₃The straight or branched alkyl) with in 2-or 3-position by C₁-C ₃The straight or branched alkyl replaces.

In some embodiments, R₈Be

(for example, wherein one or more halo (halogen) are chlorine) and ring A are selectively replaced by 3 substituting groups at the most, and described substituting group is independently selected from (C₁-C ₃The straight or branched alkyl), O-(C₁-C ₃The straight or branched alkyl), N (C₁-C ₃The straight or branched alkyl)₂, halogen, or 5 to 6-unit's heterocycles, but be not by O-(C in the 3-position₁-C ₃The straight or branched alkyl) the single replacement.

In certain embodiments, for example work as R₈While having an above-mentioned value, ring A is by 3 substituting groups replacements at the most, and described substituting group is independently selected from chlorine, methyl, O-methyl, N (CH₃) ₂Or woods generation. In some such embodiment, R₈To be selected from

Wherein at the most 2 directly with shown in the adjacent ring carbon atom of tie point be selected from C independently₁-C ₃Straight or branched alkyl or halogen replace; Each R₇，R ₉, and R₁₁Be-H; And R₁₀To be selected from-H ,-CH₂OH，-CO ₂H，-CO ₂CH ₃，-CH ₂-piperazinyl, CH₂N(CH ₃) ₂，-C(O)-NH-(CH ₂) ₂-N(CH ₃) ₂, or-C (O)-piperazinyl. In some such embodiment, work as R₈Be

While with ring A, being the 3-dimethylaminophenyl, R₇，R ₉，R ₁₀And R₁₁Middle neither one is-CH₂-N(CH ₃) ₂Or-C (O)-NH-(CH₂) ₂-N(CH ₃) ₂, and/or work as R₈Be

While with ring A, being 3,4-Dimethoxyphenyl, R₇，R ₉，R ₁₀And R₁₁Middle neither one is C (O) OCH₃Or C (O) OH.

In certain embodiments, for example work as R₈Have one of above-mentioned value and/or encircle A while selectively being substituted as mentioned above, R₇，R ₉，R ₁₀And R₁₁In at least one be-H. in some such embodiment, R₇，R ₉，R ₁₀And R₁₁Each naturally-H.

In certain embodiments, R₇，R ₉，R ₁₀Or R₁₁Be selected from-C (O) OH ,-N (CH₃) ₂，-CH ₂OH，-CH ₂OCH ₃，-CH ₂-piperazinyl ,-CH₂-methyl piperazine base ,-CH₂-pyrrolidinyl ,-CH₂-piperidyl ,-CH₂-morpholino ,-CH₂-N(CH ₃) ₂，-C(O)-NH-(CH ₂) _n-piperazinyl ,-C (O)-NH-(CH₂) _n-methyl piperazine base ,-C (O)-NH-(CH₂) _n-pyrrolidinyl ,-C (O)-NH-(CH₂) _n-morpholino ,-C (O)-NH-(CH₂) _n-piperidyl, or-C (O)-NH-(CH₂) _n-N(CH ₃) ₂, wherein n is 1 or 2. in some such embodiment, R₁₀Be selected from-C (O) OH ,-N (CH₃) ₂，-CH ₂OH，-CH ₂OCH ₃，-CH ₂-piperazinyl ,-CH₂-methyl piperazine base ,-CH₂-pyrrolidinyl ,-CH₂-piperidyl ,-CH₂-morpholino ,-CH₂-N(CH ₃) ₂，-C(O)-NH-(CH ₂) _n-piperazinyl ,-C (O)-NH-(CH₂) _n-methyl piperazine base ,-C (O)-NH-(CH₂) _n-pyrrolidinyl ,-C (O)-NH-(CH₂) _n-morpholino ,-C (O)-NH-(CH₂) _n-piperidyl, or-C (O)-NH-(CH₂) _n-N(CH ₃) ₂, wherein n is 1 or 2, and each R₇，R ₉, and R₁₁H.

In certain embodiments, ring A is replaced by 5-or 6-unit heterocycle by the itrile group group or in contraposition. The typical example of heterocycle comprises pyrrolidinyl, piperidyl and morpholinyl.

Also having aspect another, the sirtuin-that the invention provides new formula (IV) regulates compound or its salt:

Ar——L——J——M——K——Ar′(IV)

Wherein:

Each Ar and Ar ' are carbocyclic ring or the heterocyclic aryl group that selectively replaces independently;

L is carbocyclic ring or the heterocycle arylene group that selectively replaces;

Each J and K are NR independently₁', O, S, or selectively do not exist independently; Or when J be NR₁' time, R₁' be to be connected to form C1-C4 alkylidene or the C2-C4 alkenylene of the ring that condenses with Ar ' with Ar '; Or when K be NR₁' time, R₁' be to be connected to form C1-C4 alkylidene or the C2-C4 alkenylene of the ring that condenses with L with L;

Each M is C (O), S (O), S (O)₂, or CR₁′R ₁′；

Each R₁' be to be selected from H, the C1-C10 alkyl independently; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R₅'; Halogen; Alkylhalide group; CF₃；SR ₂′；OR ₂′； NR ₂′R ₂′；NR ₂′R ₃′；COOR ₂′；NO ₂；CN；C(O)R ₂′；C(O)C(O)R ₂′；C(O)NR ₂′R ₂′；OC(O)R ₂′； S(O) ₂R ₂′；S(O) ₂NR ₂′R ₂′；NR ₂′C(O)NR ₂′R ₂′；NR ₂′C(O)C(O)R ₂′；NR ₂′C(O)R ₂′； NR ₂′(COOR ₂′)；NR ₂′C(O)R ₅′；NR ₂′S(O) ₂NR ₂′R ₂′；NR ₂′S(O) ₂R ₂′；NR ₂′S(O) ₂R ₅′； NR ₂′C(O)C(O)NR ₂′R ₂′；NR ₂′C(O)C(O)NR ₂′R ₃'; By aryl, R₄' or R₅The C1-C10 alkyl that replaces; Or by aryl, R₄' or R₅The C2-C10 thiazolinyl of ' replacement;

Each R₂' be H independently; The C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R₆'; By the individual independently aryl of 1-3, R₄' or R₆The C1-C10 alkyl that ' group replaces; By the individual independently aryl of 1-3, R₄' or R₆The C3-C10 cycloalkyl that ' group replaces; Or by the individual independently aryl of 1-3, R₄' or R₆The C2-C10 thiazolinyl of ' replacement;

Each R₃' be C (O) R independently₂′，COOR ₂', or S (O)₂R ₂′；

Each R₄' be halogen independently, CF₃，SR ₇′，OR ₇′，OC(O)R ₇′，NR ₇′R ₇′，NR ₇′R ₈′， NR ₈′R ₈′，COOR ₇′，NO ₂，CN，C(O)R ₇', or C (O) NR₇′R ₇′；

Each R₅' be 5-8 unit monocycle independently, 8-12 unit dicyclo, or the member ring systems of 11-14 unit three rings, described member ring systems is if monocycle contains 1-3 hetero atom, if dicyclo contains 1-6 hetero atom, perhaps if three rings contain 1-9 hetero atom, described hetero atom is selected from O, N, or S, these member ring systems can be saturated or unsaturated, and wherein each ring 0,1,2 or 3 atom is independently selected from following substituting group and replaces: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Aryl; R₆'; Halogen; Sulphur; Oxygen; CF₃ Alkylhalide group; SR₂′；OR ₂′；OC(O)R ₂′； NR ₂′R ₂′；NR ₂′R ₃′；NR ₃′R ₃′；COOR ₂′；NO ₂；CN；C(O)R ₂′；C(O)NR ₂′R ₂'; By the individual independently R of 1-3₄′，R ₆', or the C1-C10 alkyl that replaces of aryl; Perhaps by the individual independently R of 1-3₄′，R ₆', or the C2-C10 thiazolinyl that replaces of aryl.

Each R₆' be 5-8 unit monocycle independently, 8-12 unit dicyclo, or the member ring systems of 11-14 unit three rings, described member ring systems is if monocycle contains 1-3 hetero atom, if dicyclo contains 1-6 hetero atom, perhaps if three rings contain 1-9 hetero atom, described hetero atom is selected from O, N, or S, these member ring systems can be saturated or unsaturated, and wherein each ring 0,1,2 or 3 atom is independently selected from following substituting group and replaces: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Halogen; Sulphur; Oxygen; CF₃ Alkylhalide group; SR₇′；OR ₇′；NR ₇′R ₇′；NR ₇′R ₈′；NR ₈′R ₈′ COOR ₇′；NO ₂；CN；C(O)R ₇'; Or C (O) NR₇′R ₇′；

Each R₇' be H independently, the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Alkylhalide group; Optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF₃，OR ₁₀′，SR ₁₀′， NR ₁₀′R ₁₀′，COOR ₁₀′，NO ₂，CN，C(O)R ₁₀′，C(O)NR ₁₀′R ₁₀′，NHC(O)R ₁₀', or OC (O) R₁₀' C1-C10 the alkyl that replaces; Perhaps optionally by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF₃，OR ₁₀′，SR ₁₀′， NR ₁₀′R ₁₀′，COOR ₁₀′，NO ₂，CN，C(O)R ₁₀′，C(O)NR ₁₀′R ₁₀′，NHC(O)R ₁₀', or OC (O) R₁₀' the phenyl that replaces;

Each R₈' be C (O) R independently₇′，COOR ₇', or S (O)₂R ₇′；

Each R₉' be H independently, C1-C10 alkyl, C2-C10 thiazolinyl, C2-C10 alkynyl, C3-C10 cycloalkyl, the C4-C10 cycloalkenyl group, perhaps selectively by the individual independently C1-C10 alkyl of 1-3, C2-C10 thiazolinyl, C2-C10 alkynyl, the C3-C10 cycloalkyl, C4-C10 cycloalkenyl group, halogen, CF₃，OR ₁₀′，SR ₁₀′，NR ₁₀′R ₁₀′， COOR ₁₀′，NO ₂，CN，C(O)R ₁₀′，C(O)NR ₁₀′R ₁₀′，NHC(O)R ₁₀', or OC (O) R₁₀' the phenyl that replaces;

Each R₁₀' be H independently; The C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; Optionally by halogen, CF₃，OR ₁₁′，SR ₁₁′，NR ₁₁′R ₁₁′，COOR ₁₁′， NO ₂, the C1-C10 alkyl that CN replaces; Or optionally by halogen, CF₃，OR ₁₁′，SR ₁₁′， NR ₁₁′R ₁₁′，COOR ₁₁′，NO ₂, the phenyl that CN replaces;

Each R₁₁' be H independently; The C1-C10 alkyl; C3-C10 cycloalkyl or phenyl;

Each alkylhalide group is independently by one or more F that are selected from, Cl, and Br, or the C1-C10 alkyl that replaces of the halogen atom of I, wherein the number of halogen atom can not surpass the number that causes forming the whole haloalkyl group; And

Each alkyl is independently optionally by 1-3 independently following substituting group replacement: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; R₆'; Halogen; Alkylhalide group; CF₃；OR ₉′；SR ₉′；NR ₉′R ₉′；COOR ₉′；NO ₂；CN；C(O)R ₉′；C(O)C(O)R ₉′； C(O)NR ₉′R ₉′；S(O) ₂R ₉′；N(R ₉′)C(O)R ₉′；N(R ₉′)(COOR ₉′)；N(R ₉′)S(O) ₂R ₉′； S(O) ₂NR ₉′R ₉′；OC(O)R ₉′；NR ₉′C(O)NR ₉′R ₉′；NR ₉′C(O)C(O)R ₉′；NR ₉′C(O)R ₆′； NR ₉S(O) ₂NR ₉′R ₉′；NR ₉′S(O) ₂R ₆′；NR ₉′C(O)C(O)NR ₉′R ₉'; By the individual independently R of 1-3₆', halogen, CF₃，OR ₉′，SR ₉′，NR ₉′R ₉′，COOR ₉′，NO ₂，CN，C(O)R ₉′，C(O)NR ₉′R ₉′，NHC(O)R ₉′， NH(COOR ₉′)，S(O) ₂NR ₉′R ₉′，OC(O)R ₉' C1-C10 the alkyl that replaces; By the individual independently R of 1-3₆', halogen, CF₃，OR ₉′，SR ₉′，NR ₉′R ₉′，COOR ₉′，NO ₂，CN，C(O)R ₉′，C(O)NR ₉′R ₉′， NHC(O)R ₉′，NH(COOR ₉′)，S(O) ₂NR ₉′R ₉′，OC(O)R ₉' C2-C10 the thiazolinyl that replaces; Or R₉′。

In a preferred embodiment of the invention, each Ar, L, and Ar ' is the first monocycle member ring systems of 5-to 7-that selectively replaces or the 9-to 12-unit dicyclo member ring systems that selectively replaces independently.

Embodiment preferred according to another,

Ar is

X ₁，X ₂，X ₃，X ₄, and X₅To be selected from CR independently₁' and N; With

X ₆To be selected from NR₁', O, and S;

According to also having another preferred embodiment, X₁And X₂N; X₃，X ₄, and X₅CR₁'; And X₆O.

According to also having another preferred embodiment, X₁And X₃N; X₂，X ₄, and X₅CR₁'; And X₆O.

According to also having another preferred embodiment, X₁And X₄N; X₂，X ₃, and X₅CR₁'; And X₆O.

According to also having another preferred embodiment, X₁And X₅N; X₂，X ₃, and X₄CR₁'; And X₆O.

In another embodiment, the compound in above-mentioned formula is NR for J wherein₁', K does not exist, and M is those compounds of C (O).

In also having another embodiment, the compound in above-mentioned formula does not exist for J wherein, and K is NR₁', and M is those compounds of C (O).

In another embodiment, formula (IV) compound is for wherein not exist with K be NR as J₁' time, M be not C (O) and when J be NR₁' while with K, not existing, M is not those compounds of C (O).

In a preferred embodiment, above-claimed cpd is 5-to 7-unit's carbocyclic ring of selectively replacing or those compounds of heterocyclic aryl group for L wherein.

In also having another preferred embodiment, compound is that wherein L is the phenylene that selectively replaces, inferior pyridine radicals, inferior imidazole radicals ， Ya oxazolyl, or those compounds of inferior thiazolyl.

In an especially preferred embodiment, L is the phenylene that selectively replaces.

In another particularly preferred embodiment, L is the inferior pyridine radicals that selectively replaces.

In a preferred embodiment, L is phenylene.

In another even preferred embodiment, L is inferior pyridine radicals.

In any of these embodiments, Ar and J can with L adjacent, or contraposition be connected. Particularly preferably be those embodiments of position between being connected to.

In certain embodiments, when Ar ' was phenyl, L was not phenylene. The example of this embodiment comprises those embodiments, wherein L is that heterocyclic aryl group and the Ar ' that selectively replaces is carbocyclic ring or the heterocyclic aryl group that selectively replaces, or wherein L is that the carbocyclic ring that selectively replaces or heterocyclic aryl group and Ar ' are the heterocyclic aryl groups that selectively replaces.

Also having aspect another, the sirtuin-that the invention provides new formula (I) regulates compound or its salt, wherein:

Ring A is by at least one R₁' group replaces;

R ₁′，R ₂′，R ₃′，R ₄′，R ₅′，R ₆′，R ₇′，R ₈′，R ₉′，R ₁₀', and R₁₁' as defined above;

Each alkylhalide group is independently by the C1-C10 alkyl that one or more halogen atom replaced, and described halogen atom is selected from F, Cl, and B, or I, wherein the number of halogen atom is no more than the Number of Halogen Atoms that forms the whole haloalkyl group;

Each aryl is 5-to 7-unit's monocycle member ring systems or 9-to 12-unit dicyclo member ring systems independently, and described member ring systems is selectively replaced by the individual independently following substituting group of 1-3: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; R₆'; Halogen; Alkylhalide group; CF₃； OR ₉′；SR ₉′；NR ₉′R ₉′；COOR ₉′；NO ₂；CN；C(O)R ₉′；C(O)C(O)R ₉′；C(O)NR ₉′R ₉′； S(O) ₂R ₉′；N(R ₉′)C(O)R ₉′；N(R ₉′)(COOR ₉′)；N(R ₉′)S(O) ₂R ₉′；S(O) ₂NR ₉′R ₉′；OC(O)R ₉′； NR ₉′C(O)NR ₉R ₉′；NR ₉′C(O)C(O)R ₉′；NR ₉′C(O)R ₆′；NR ₉′S(O) ₂NR ₉′R ₉′；NR ₉′S(O) ₂R ₆′； NR ₉′C(O)C(O)NR ₉′R ₉'; By the individual independently R of 1-3₆', halogen, CF₃，OR ₉′，SR ₉′，NR ₉′R ₉′， COOR ₉′，NO ₂，CN，C(O)R ₉′，C(O)NR ₉′R ₉′，NHC(O)R ₉′，NH(COOR ₉′)，S(O) ₂NR ₉′R ₉′， OC(O)R ₉The C1-C10 alkyl of ' replacement; By the individual independently R of 1-3₆', halogen, CF₃，OR ₉′，SR ₉′， NR ₉′R ₉′，COOR ₉′，NO ₂，CN，C(O)R ₉′，C(O)NR ₉′R ₉′，NHC(O)R ₉′，NH(COOR ₉′)， S(O) ₂NR ₉′R ₉′，OC(O)R ₉The C2-C10 thiazolinyl of ' replacement; Or R₉'; With the ring B by at least one

Replace; Wherein

X ₆Be selected from NR₁', O, and S.

In a preferred embodiment, ring B is phenyl or pyridine radicals.

In yet another aspect, the sirtuin-that the invention provides new formula (IVa) regulates compound or its salt:

Het-L-Q-Ar′(IVa)

Wherein:

Het is the heterocyclic aryl group that selectively replaces;

Ar ' is carbocyclic ring or the heterocyclic aryl group that selectively replaces; With

Q is selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁ -NR ₁′-，-MR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′-，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，- NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R′ ₁-C (O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)- NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁-，

With

Each R₁' be the C that is selected from H or selectively replaces independently₁-C ₃The straight or branched alkyl,

Wherein:

When Het is polyheteroaromatic, L is the phenylene that selectively replaces, and Q is connected with metaorientation with L with Het, and Ar ' is while being the phenyl that selectively replaces; So Q be not-NH-C (O)-.

In certain embodiments, when Het is polyheteroaromatic, L is the phenylene that selectively replaces, and Ar ' is while being the phenyl that selectively replaces; So Q be not-NH-C (O)-.

(for example, when compound is the sirtuin activator) in certain embodiments, Het and Q and L be with 1-, 2-or 1-, the 3-conformation be connected (for example, when L is phenylene, Het with Q at ortho position or metaorientation be connected). In certain embodiments, wherein Het and Q and L are with 1-, and the 3-conformation is connected, if Het is benzoxazolyl, L is that inferior pyridine radicals and Q are-NH-C (O)-NH, and Ar ' is not 3,4 dioxy methylene phenyl so; If Het is the methylthiazol base, L be phenylene and Q be-NH-C (O)-, Ar ' is not the 3-dimethylaminophenyl so;-NH-C (O)-NH that Ar ' is not the 4-dimethylaminophenyl so if Het Shi oxazole and pyridine radicals, L are inferior pyridine radicals and Q; If Het Shi oxazole and pyridine radicals or benzoxazolyl and L are

Q is not-NH-(SO) so₂-; If with Het Shi oxazole and pyridine radicals, L is

With Q be-NH-C (O)-, Ar ' is not 3,4-Dimethoxyphenyl or pyridine radicals so.

When Het is substituted, replace generally on 2 carbon atoms at the most, substituting group is independently selected from R₁₂， N(R ₁₂) ₂，NH(R ₁₂)，OR ₁₂，C(O)-NH-R ₁₂，C(O)-N(R ₁₂) ₂，N(R ₁₂)-OR ₁₂，CH ₂-N(R ₁₂) ₂， C(O)OR ₁₂，C(O)OH， Or

Each R wherein₁₂To be selected from the C that selectively replaces independently₁-C ₃The straight or branched alkyl.

In certain embodiments, Het is Xuan Zi oxazole and pyridine radicals, benzothienyl, benzofuranyl, indyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl or isoindolyl. In other embodiments, Het comprises ring N hetero atom and 1 to 2 and is independently selected from N, the additional ring hetero atom of O or S, thiazolyl for example, triazolyl ， oxadiazolyl (oxadiazolyl), thiazole and pyridine radicals, the Imidazothiazole base, benzoxazine ketone group (benzoxazinonyl), or imidazopyridyl.

The object lesson of Het comprises:

Wherein at the most 2 directly with shown in the adjacent ring carbon atom of tie point be substituted independently, substituting group is the optional C that selects generation₁-C ₃The straight or branched alkyl, phenyl, halogen, N (R₁₂) ₂，NH(R ₁₂)，OR ₁₂， C(O)-NH-R ₁₂，C(O)-N(R ₁₂) ₂，N(R ₁₂)-OR ₁₂，CH ₂-N(R ₁₂) ₂，C(O)OR ₁₂，C(O)OH，

Each R wherein₁₂To be selected from the C that selectively replaces independently₁-C ₃The straight or branched alkyl. In certain embodiments, L is selected from

Wherein:

Each Z₁，Z ₂，Z ₃And Z₄Be to be selected from CH or N independently, wherein be no more than three described Z₁， Z ₂，Z ₃Or Z₄N;

Each Z₅And Z₆To be selected from C independently, N, O or S, condition is at least one Z₅And Z₆N; With

L selectively is substituted on 1 to 2 carbon atom, substituting group is independently selected from R₁₂，N(R ₁₂) ₂， NH(R ₁₂)，OR ₁₂，C(O)-NH-R ₁₂，C(O)-N(R ₁₂) ₂，N(R ₁₂)-OR ₁₂，CH ₂-N(R ₁₂) ₂，C(O)OR ₁₂，

In preferred embodiments, L is selected from phenylene or inferior pyridine radicals, for example unsubstituted phenylene or by, be selected from C (O) OCH₃，C(O)OH，CH ₂OH，N(CH ₃) ₂, or CH₂N(CH ₃) ₂The phenylene that replaces of substituting group, or unsubstituted inferior pyridine radicals.

In certain embodiments, Q is selected from-NH-C (O)-,-NH-S (O)₂-，-NH-C(O)-NH-，-C(O)-NH-，-CH ₂-，-N(CH ₃)-C(O)-N H-，-NH-C(O)-N(CH ₃)-, or-NH-S (O)₂-NH-, particularly-NH-C (O)-,-C (O)-NH-,-NH-,-NH-C (O)-NH, or-NH-S (O)₂-。

In certain embodiments, Ar ' is selected from the phenyl that selectively replaces, benzothiazolyl, or benzoxazolyl. When Ar ' is phenyl, the typical optional substituting group of selecting is 1 to 3 substituting group, and this substituting group is independently selected from halogen, (the C that selectively replaces₁-C ₃The straight or branched alkyl), the O-(C that selectively replaces₁-C ₃The straight or branched alkyl), the S-(C that selectively replaces₁-C ₃The straight or branched alkyl), N (CH₃) ₂Or the heterocyclic radical that selectively replaces, or wherein two substituting groups on the adjacent ring atom form two Oxymethylenes together. In certain embodiments, Het is selected from

Wherein at the most 2 not with shown in the ring carbon atom that directly is connected of tie point be substituted independently, substituting group is the C that selectively replaces₁-C ₃The straight or branched alkyl, phenyl or halogen;

L is selected from unsubstituted phenylene, by one, is selected from C (O) OCH₃，C(O)OH，CH ₂OH， N(CH ₃) ₂, or CH₂N(CH ₃) ₂The phenylene that replaces of substituting group, or unsubstituted inferior pyridine radicals;

Q is selected from-NH-C (O)-,-C (O)-NH-,-NH-,-NH-C (O)-NH, or-NH-S (O)₂-; With

Ar ' is selected from the phenyl that selectively replaces, and benzothiazolyl, or benzoxazolyl, wherein said phenyl are selectively by 1-3 substituting group, to be replaced, and described substituting group is independently selected from chlorine, methyl, O-methyl, S-methyl, N (CH₃) ₂, morpholino, or 3,4-, two Oxymethylenes.

In certain embodiments, Q is selected from-NH-C (O)-,-C (O)-NH-,-NH-or-NH-C (O)-NH.

In certain embodiments, the substituting group on Ar ' is selected from chlorine, methyl, O-methyl, S-methyl or N (CH₃) ₂. In certain embodiments, the upper unique substituting group of Ar ' is the O-methyl group, particularly at the Q ortho position or the O-methyl group of a position. In certain embodiments, when two or more O-methyl group or Ar ' times are arranged, at least one ortho position at Q or a position.

In certain embodiments, L is that pyridine radicals and Het and Q are at 1 of pyridine radicals nitrogen-atoms, 3-or 2,4-position. In some such embodiment, Q is-NH-S (O)₂-。

In certain embodiments, wherein L further is substituted, substituting group generally all Het and Q both between position.

In certain embodiments, Q be-NH-and Het are thiazolyl Huo oxazole and pyridine radicals.

In certain embodiments, Q be-NH-and Ar are benzothiazolyl or benzoxazolyl. In certain embodiments, for example when the sirtuin conditioning agent was the sirtuin activator, L was

-NH-(SO) with Q₂-. In some such embodiment, Het Shi oxazole and pyridine radicals. Work as L, Q and when selectively Het has these values, Ar ' is naphthyl or phenyl advantageously, and wherein Ar ' is selectively replaced by 1-3 substituting group, and this substituting group is independently selected from CN, halogen, (C₁-C ₃The straight or branched alkyl), O-(C₁-C ₃The straight or branched alkyl), N (C₁-C ₃The straight or branched alkyl)₂, or 5 to 6-unit's heterocycles.

In certain embodiments, for example when the sirtuin conditioning agent was the sirtuin activator, L wasWith Q be-NH-C (O)-. In some such embodiment, Het Shi oxazole and pyridine radicals. Work as L, Q and when selectively Het has these values, pyridine radicals or phenyl that Ar ' is advantageously selectively replaced by 1-3 substituting group, described substituting group is independently selected from CN, halogen, (C1-C3 straight or branched alkyl), O-(C1-C3 straight or branched alkyl), N (C1-C3 straight or branched alkyl)₂, or 5 to 6-unit's heterocycles.

In certain embodiments, for example when the sirtuin conditioning agent is the sirtuin inhibitor, Het comprises a N hetero atom and 1 to 2 and is independently selected from N, the additional hetero atom of O or S;

The apparent molecular weight of proteins, including protein complexes of all components (cofactors And non-covalent domain), and all of translational modification or post-translational modification (group covalently attached to the peptide Removal of the peptide or a monovalent group). Apparent molecular weight of usually translated by post-translational modification or repair Decorative effect. The apparent molecular weight of proteins by SDS-PAGE (sodium dodecyl sulfate poly Acrylamide gel electrophoresis) to determine, in the way of its analogs, 2D-PAGE (D PP Polyacrylamide gel electrophoresis) is also a two-dimensional. However, the apparent molecular weight of proteins by mass Spectrum (MS) - can be changed by generating an auxiliary matrix of electron-ion laser desorption ionization - Time of flight (MALDI-TOF) MS or generating a plurality of peaks with a charge EFI more sensitive Fog ionization (ESI) MS determined more precise. Protein or chimeric molecule of apparent molecular weight Can range from 1 to 1000kDa. Accordingly, the present invention is an isolated protein or chimeric Molecules 1,2,3,4,5,6,7,8,9,10,10,12,13,14,15, 16,17,18,19,20,21,22,23,24,25,26,27,28,29,30, 31,32,33,34,35,36,37,38,39,40,41,42,43,44,45, 46,47,48,49,50,51,52,53,54,55,56,57,58,59,60, 61,62,63,64,65,66,67,68,69,70,71,72,73,74,75, 76,77,78,79,80,81,82,83,84,85,86,87,88,89,90, 91,92,93,94,95,96,97,98,99,1 O0, 101,102,103,104, 105,106,107,108,109,110,111,112,113,114,115,116, 117,118,119,120,121,122,123,124,125,126,127,128, 129,130,131,132,133,134,135,136,137,138,139,140, 141,142,143,144,145,145, 147,148,149,150,151,152, 153,154,155,156,157,158,159,16 O, 161,162,163,164, 165,166,167,168,169,170,171,172,173,174,175,176, 177,178,179,180,181,182,183,184,185,186,187,188, 189,190,191,192,193,194,195,196,197,198,199,200, 201,202,203,204,205,206,2 O7, 208,209,210,210,212, 213,214,215,216,217,218,219,220,221,222,223,224, 225,226,227,228,229,230,231,232,233,234,235,236, 237,238,239,240,241,242,243,244,245,246,247,248, 249,250,251,252,253,254,255,256,257,258,259,260, 261,262,263,264,265,266,267,268,269,27 O, 271,272, 273,274,275,276,277,278,279,280,281,282,283,284, 285,286,287,288,289,290,291,292,293,294,295,296, 297,298,299,300,3 O1, 302,303,304,305,306,307,308, 309,310,310,312,313,314,315,316,317,318,319,320, 321,322,323,324,325,326,327,328,329,330,331,332, 333,334,335,336,337,338,339,340,341,342,343,344, 345,346,347,348,349,350,351,352,353,354,355,356, 357,358,359,360,361,362,363,364,365,366,367,368, 369,370,371,372,373,374,375,376,377,378,379,380, 381,382,383,384,385,386,387,388,389,390,391,392, 393,394,395,396,397,398,399,400,401,402,403,404, 405,4 O6, 407,408,409,410,411,412,413,414,415,416, 417,418,419,420,421,422,423,424,425,426,427,428, 429,430,431,432,433,434,435,436,437,438,439,440, 441,442,443,444,445,446,447,448,449,450,451,452, 453,454,455,456,457,458,459,460,461,462,463,464, 465,466,467,468,469,470,471,472,473,474,475,476, 477,478,479,480,481,482,483,484,485,486,487,488, 489,490,491,492,493,494,495,496,497,498,499,500, 501,502,503,504,505,506,507,508,509,510,511,512, 513,514,515,516,517,518,519,520,521,522,523,524, 525,526,527,528,529,530,531,532,533,534,535,536, 537,538,539,540,541,542,543,544,545,546,547,548, 549,550,551,552,553,554,555,556,557,558,559,560, 561,562,563,564,565,566,567,568,569,570,571,572, 573,574,575,576,577,578,579,580,581,582,583,584, 585,586,587,588,589,590,591,590, 593,594,595,596, 597,598,599,600,601,602,603,604,6 O5, 606,607,608, 609,610,611,612,613,614,615,616,617,618,619,620, 621,622,623,624,625,626,627,628,629,630,631,632, 633,634,635,636,637,638,639,640,641,642,643,644, 645,646,647,648,649,650,651,652,653,654,655,656, 657,658,659,660,661,662,663,664,665,666,667,668, 669,670,671,672,673,674,675,676,677,678,679,680, 681,682,683,684,685,686,687,688,689,690,691,692, 693,694,695,696,697,698,699,700,701,702,703,7 O4, 705,706,707,708,709,710,710,712,713,714,715,716, 717,7 l8, 719,720,721,722,723,724,725,726,727,728, 729,730,731,732,733,734,735,736,737,738,739,740, 741,742,743,744,745,746,747,748,749,750,751,752, 753,754,755,756,757,758,759,760,761,762,763,764, 765,766,767,768,769,770,771,772,773,774,775,776, 777,778,779,78 O, 781,782,783,784,785,786,787,788, 789,79 O, 791,792,793,794,795,796,797,798,799,800, 801,802,803,804,805,806,807,808,809,810,811,812, 813,814,815,816,817,818,819,820,821,822,823,824, 825,826,827,828,829,830,831,832,833,834,835,836, 837,838,839,840,841,842,843,844,845,846,847,848, 849,850,851,852,853,854,855,856,857,858,859,860, 861,862,863,864,865,866,867,868,869,870,871,872, 873,874,875,876,877,878,879,880,881,882,883,884, 885,886,887,888,889,890,891,892,893,894,895,896, 897,898,899,900,901,902,903,904,905,906,907,908, 909,910,911,912,913,914,915,916,917,918,919,920, 921,922,923,924,925,926,927,928,929,930,93 l, 932, 933,934,935,936,937,938,939,940,941,942,943,944, 945,946,947,948,949,95 O, 951,952,953,954,955,956, 957,958,959,960,961,962,963,964,965,966,967,968, 969,970,971,972,973,974,975,976,977,978,979,980, 981,982,983,984,985,986,987,988,989,990,991,992 993,994,995,996,997,998,999,1000 kDa apparent molecular weight. Egg White matter of the molecular weight or molecular weight may be determined by any convenient method, such as electrophoresis, MS, gradient centrifugation. ...

With selectively replace;

Q is-NH-C (O)-; With

The phenyl that Ar ' is replaced by 1-3 substituting group, this substituting group is independently selected from CN, halogen, C₁-C ₃The straight or branched alkyl, O-(C₁-C ₃The straight or branched alkyl), N (C₁-C ₃The straight or branched alkyl)₂, or 5 to 6-unit's heterocycles,

Wherein work as R₈Unsubstituted

The time, encircle so A and be:

A) not simultaneously in 2-and 6-position by O-(C₁-C ₃The straight or branched alkyl) replace;

B) not simultaneously in the 2-position by C₁-C ₃Straight or branched alkyl or O-(C₁-C ₃The straight or branched alkyl) with in the 3-position by O-(C₁-C ₃The straight or branched alkyl) replace;

C) not in the 4-position by O-(C₁-C ₃The straight or branched alkyl) unless replace---simultaneously in the 3-position by halogen or O-(C₁-C ₃The straight or branched alkyl) replace and in every other position, be not substituted;

Not in the 4-position by N (C₁-C ₃The straight or branched alkyl) 2 replace, or described 5-to 6-unit heterocycle. In some such embodiment, L is unsubstituted and/or Het Shi oxazole and pyridine radicals.

Also having aspect another, the sirtuin-that the invention provides new formula (V) regulates compound or its salt:

Wherein:

Ring A is selectively by at least one R₁' group replaces;

Y ₁，Y ₂，Y ₃，Y ₄, and Y₅R independently₁′；

Each alkylhalide group is selected from F by one or more independently, Cl, and Br, or the C1-C10 alkyl that replaces of the halogen atom of I, wherein the number of halogen atom can not surpass the number that causes forming whole haloalkyl; With

Each aryl is 5-to 7-unit's monocycle system or 9-to 12-unit bicyclic system independently, and described member ring systems is selectively replaced by the individual independently following substituting group of 1-3: the C1-C10 alkyl; The C2-C10 thiazolinyl; The C2-C10 alkynyl; The C3-C10 cycloalkyl; The C4-C10 cycloalkenyl group; R₆'; Halogen; Alkylhalide group; CF₃；OR ₉′； SR ₉′；NR ₉′R ₉′；COOR ₉′；NO ₂；CN；C(O)R ₉′；C(O)C(O)R ₉′；C(O)NR ₉′R ₉′；S(O) ₂R ₉′； N(R ₉′)C(O)R ₉′；N(R ₉′)(COOR ₉′)；N(R ₉′)S(O) ₂R ₉′；S(O) ₂NR ₉′R ₉′；OC(O)R ₉′； NR ₉C(O)NR ₉′R ₉′；NR ₉′C(O)C(O)R ₉′；NR ₉C(O)R ₆′；NR ₉′S(O) ₂NR ₉′R ₉′；NR ₉′S(O) ₂R ₆′； NR ₉C(O)C(O)NR ₉′R ₉'; By the individual independently R of 1-3₆', halogen, CF₃，OR ₉′，SR ₉′，NR ₉′R ₉′， COOR ₉′，NO ₂，CN，C(O)R ₉′，C(O)NR ₉′R ₉′，NHC(O)R ₉′，NH(COOR ₉′)，S(O) ₂NR ₉′R ₉′， OC(O)R ₉' C1-C10 the alkyl that replaces; By the individual independently R of 1-3₆', halogen, CF₃，OR ₉′，SR ₉′， NR ₉′R ₉′，COOR ₉′，NO ₂，CN，C(O)R ₉′，C(O)NR ₉′R ₉′，NHC(O)R ₉′，NH(COOR ₉′)， S(O) ₂NR ₉′R ₉′，OC(O)R ₉' C2-C10 the thiazolinyl that replaces; Or R₉′。

In a preferred embodiment of above-claimed cpd,

Y ₂Or Y₃In any is

X ₆Be selected from NR₁', O, and S.

According to a preferred embodiment, X₁And X₂N; X₃，X ₄, and X₅CR₁'; And X₆O.

Embodiment preferred according to another, X₁And X₃N; X₂，X ₄, and X₅CR₁'; And X₆O.

Embodiment preferred according to another, X₁And X₄N; X₂，X ₃, and X₅CR₁'; And X₆O.

Embodiment preferred according to another, X₁And X₅N; X₂，X ₃, and X₄CR₁'; And X₆O.

In yet another aspect, the sirtuin-that the invention provides structural formula (VII) regulates compound or its salt:

Wherein:

Each X₇，X ₈，X ₉And X₁₀To be selected from N, CR independently²⁰, or CR₁', wherein:

Each R²⁰To be selected from H or solubilizing group independently;

Each R₁' be the C that is selected from H or selectively replaces independently₁-C ₃The straight or branched alkyl;

X ₇，X ₈，X ₉And X₁₀In one be N and other be to be selected from CR²⁰Or CR₁'; With

0 to 1 R²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Each Z₁₀，Z ₁₁，Z ₁₂And Z₁₃To be selected from N, CR independently²⁰, or CR₁'; With

Each Z₁₄，Z ₁₅And Z₁₆To be selected from N, NR independently₁′，S，O，CR ²⁰, or CR₁', wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 2 be N or NR₁′；

0 to 1 R²⁰It is solubilizing group;

0 to 1 R₁' be the C that selectively replaces₁-C ₃The straight or branched alkyl; With

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′，-C(O)-NR ₁′，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-，-CR ₁′R ₁′-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-O-，-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁ ′R ₁′-O-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-; With

Or

Work as R¹⁹Be

And R²¹Be-NHC (O)-time, R³¹It not the phenyl that selectively replaces.

In certain embodiments, the compound of structural formula (VII) has following value:

Each R²⁰To be selected from H or solubilizing group independently;

0 to 1 R²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 2 be N or NR₁′；

0 to 1 R²⁰It is solubilizing group;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′，-CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-O-，-NR ₁′-C(O)-CR ₁′R ₁′-C R ₁′R ₁′-O-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-; With

Described compound is not:

Work as X₈And X₉Be selected from independently of one another CR²⁰Or CR₁′，R ¹⁹Be

With each Z₁₀，Z ₁₁，Z ₁₂And Z₁₃To be selected from CR independently²⁰, or CR₁', so:

a)X ₈And X₉In at least one be not CH; Or

b)Z ₁₀，Z ₁₁，Z ₁₂And Z₁₃In at least one be CR²⁰, R wherein²⁰It is solubilizing group.

In certain embodiments, work as Z₁₂CR²⁰And R²⁰While being solubilizing group, described solubilizing group is not-C (O) OCH₂CH ₃，-COOH，

In certain embodiments, work as X₈And X₉Be selected from independently of one another CR²⁰Or CR₁′，R ¹⁹Be

With each Z₁₀，Z ₁₁，Z ₁₂And Z₁₃To be selected from CR independently²⁰, or CR₁' time, so:

a)X ₈And X₉In at least one be not CH; Or

b)Z ₁₀，Z ₁₁, and Z₁₃In at least one be CR²⁰, R wherein²⁰It is solubilizing group.

In certain embodiments, work as R¹⁹BeWith each Z₁₀，Z ₁₁，Z ₁₂And Z₁₃CR²⁰, or CR₁′；X ₈And X₉CR²⁰Or CR₁′；R ²¹Be-NHC (O)-; And R³¹While being the phenyl that selectively replaces, R so³¹The phenyl that replaces, at CR₁At least one R in ' part₁' be the C that selectively replaces₁-C ₃The straight or branched alkyl, or at CR²⁰In at least one R²⁰Solubilizing group, or their combination.

In certain embodiments, R¹⁹Be selected from phenyl, pyridine radicals, thienyl or furyl.

In certain embodiments, R¹⁹Be

Each Z wherein₁₀，Z ₁₁，Z ₁₂And Z₁₃To be selected from CR independently²⁰Or CR₁'; With

R ²¹Be-NH-C (O)-; With

R ³¹It is the phenyl that replaces.

In some such embodiment, work as X₉While being N, R³¹Not 2,4-Dimethoxyphenyl and/or work as X₁₀While being N, R³¹It not the phenyl that halogen replaces; 3,4-dioxo ethylidene phenyl; Or 3,5-Dimethoxyphenyl.

In preferred embodiments, R³¹Selectively by 1-3, be independently selected from-OCH₃，-CH ₃，-N(CH ₃) ₂, the substituting group of pyrazine oxygen base (pyrazinoxy) or solubilizing group replaces. R³¹Suitable example comprise 3-methoxyl group-4-((4-methylpiperazine-1-yl) methyl) phenyl, 3-methoxyl group-4-morpholino aminomethyl phenyl, 3-methoxyl group-4-diaminourea aminomethyl phenyl, 3-methoxyl group-4-((pyrrolidin-1-yl) methyl) phenyl, 3, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 2,3, the 4-trimethoxyphenyl, 3,4, the 5-trimethoxyphenyl, the 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, or 3,5-3,5-dimethylphenyl.

In certain embodiments, R¹⁹To be selected fromZ wherein₁₀，Z ₁₁，Z ₁₂, and Z₁₃In one be N and other be to be independently selected from CR²⁰Or CR₁′；

R ²¹Be selected from-NH-,-NH-C (O)-,-NH-C (O)-NH ,-NH-C (S)-NH-or-NH-S (O)₂-; With

R ³¹Be selected from the phenyl that selectively replaces, the naphthyl that selectively replaces, or the heteroaryl that selectively replaces.

In some such embodiment,

A) work as R²¹-NH-S (O)₂-time,

i)Z ₁₀N; Perhaps

ii)Z ₁₁N and R³¹Halogenophenyl or 2-methoxyl group-5-aminomethyl phenyl;

B) work as R¹⁹Be

The time, R³¹Not the 4-dimethylaminophenyl, 2,3,4-trimethoxyphenyl, or 3,5-Dimethoxyphenyl; And/or

C) work as R²¹-NH-C (O)-NH-and Z₁₀While being N, R³¹It not the 4-dimethylaminophenyl.

In some such embodiment, R³¹Be selected from the phenyl that selectively replaces, benzothiazolyl, or benzoxazolyl.

In also having another embodiment, the sirtuin-that the invention provides structural formula (VII) regulates compound or its salt:

Wherein:

R ₁' the C that is selected from H or selectively replaces₁-C ₃The straight or branched alkyl;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O)- NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-，-CR ₁′R ₁′-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′ -CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-O-，-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁′ R ₁′-O-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-; With

Work as R₁' be methyl, and R²¹Be-NH-C (O)-time, R³¹Be not

1-methoxyl group naphthyl, 2-methoxyl group naphthyl, or unsubstituted 2-thienyl;

Work as R₁' be methyl, and R²¹While being-NH-C (O)-CH=CH-, R³¹Be not

Work as R₁' be methyl, and R²¹While being-NH-C (O)-CH-O-, R³¹Not unsubstituted naphthyl, 2-methoxyl group, 4-nitrobenzophenone, 4-chloro-2-methyl phenyl, or 4-tert-butyl phenyl; With

Work as R²¹Be-NH-C (O)-time, R³¹It not the phenyl that selectively replaces.

In certain embodiments, R²¹Be-NH-C (O)-; And R³¹Be the phenyl that selectively by 1-3 substituting group, is replaced, described substituting group is independently selected from-OCH₃，-CH ₃，-N(CH ₃) ₂, or solubilizing group.

In some such embodiment, R²¹Be-NH-C (O)-and R³¹Be selected from unsubstituted phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2,3,4-trimethoxy base, 3,4,5-trimethoxyphenyl, 2, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 2-methyl-3-methoxyphenyl, 2-morpholino phenyl, 2-methoxyl group-4-aminomethyl phenyl, the 2-dimethylaminophenyl, the 4-dimethylaminophenyl, or

Phenyl particularly; The 2-methoxyphenyl; The 3-methoxyphenyl; 2,3,4-trimethoxyphenyl; 3,4,5-trimethoxyphenyl; 2,4-Dimethoxyphenyl; 3,5-Dimethoxyphenyl; 2-methyl-3-methoxyphenyl; 2-morpholino phenyl; 2-methoxyl group-4-aminomethyl phenyl; 2-dimethylamino phenyl; Or 4-dimethylaminophenyl.

Wherein:

R ₁' the C that is selected from H or selectively replaces₁-C ₃The straight or branched alkyl; With

R ⁵⁰Be selected from 2,3-Dimethoxyphenyl, Phenoxyphenyl, 2-methyl-3-methoxyphenyl, 2-methoxyl group-4-aminomethyl phenyl, or by the phenyl of 1-3 substituting group replacement, one in wherein said substituting group is solubilizing group; Condition is R⁵⁰Not to be replaced by solubilizing group and nitryl group simultaneously, and R⁵⁰Not to be replaced by morpholino group list by the ring-type solubilizing group or in the 2-position in the 4-position.

Wherein:

R ⁵¹Be selected from the bicyclic heteroaryl that selectively replaces, the bicyclic heteroaryl that selectively replaces, or the naphthyl that selectively replaces, wherein R⁵¹Not also (b) thienyl of chlorobenzene, unsubstituted benzo dioxolyl (benzodioxolyl), unsubstituted benzofuranyl, methyl-benzofuranyl, unsubstituted furyl, phenyl-, bromo-, or nitro-furyl, chlorphenyl-isoxazolyls, the oxo benzopyranyl, unsubstituted naphthyl, methoxyl group-, methyl-, or halo-naphthyl, unsubstituted thienyl, unsubstituted pyridine radicals, or chloropyridine base.

In certain embodiments, R⁵¹To be selected from pyrazolyl, thiazolyl ， oxazolyl, pyrimidine radicals, furyl, thienyl, pyridine radicals ， isoxazolyl, indyl, benzopyrazoles base, benzothiazolyl, benzoxazolyl, quinoxalinyl, benzofuranyl, benzothienyl, quinolyl, benzoisoxazole base, phentriazine base, triazine radical, naphthyl, or

R wherein⁵¹Optional selecting generation. In some such embodiment, R⁵¹To be selected from pyrazolyl, thiazolyl ， oxazolyl, pyrimidine radicals, indyl, pyrazinyl, triazine radical,

And R⁵¹Optional selecting generation.

Wherein:

R ²²Be selected from-NR²³-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁ ′-CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-，-NR ₁′-C(＝NRR ₁′)-NR ₁′-，-C(O)-NR ₁′-，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-，-CR ₁′R ₁′-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-O-，-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁ ′R ₁′-O-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-, be R wherein²³The C that selectively replaces₁-C ₃The straight or branched alkyl; With

R ³¹To be selected from monocycle or the bicyclic aryl that selectively replaces, or the monocycle or the bicyclic heteroaryl that selectively replace, condition is:

Work as R²²While being-NH-C (O)-CH=CH-, R³¹Not unsubstituted furyl, 5-(2-methyl-3-chlorphenyl)-furyl, 2, the 4-dichlorophenyl, 3,5-, two chloro-2-methoxyphenyls, the 3-nitrobenzophenone, the 4-chlorphenyl, 4-chloro-3-nitrobenzophenone, 4-isopropyl phenyl, 4-methoxyphenyl, 2-methoxyl group-5-bromophenyl, or unsubstituted phenyl;

Work as R²²-NH-C (O)-CH₂-time, R³¹Not 3,4-Dimethoxyphenyl, 4-chlorphenyl, or unsubstituted phenyl;

Work as R²²-NH-C (O)-CH₂During-O-, R³¹Not 2,4-dimethyl-6-nitrobenzophenone, 2-or 4-nitrobenzophenone, the 4-cyclohexyl phenyl, 4-methoxyphenyl, unsubstituted naphthyl, or unsubstituted phenyl, or only be selected from that straight chain-or side chain-alkyl or halogen replaced singly replaces, two replacement or trisubstd phenyl;

Work as R²²-NH-C (O)-CH (CH₃During)-O-, R³¹Not 2,4-dichlorophenyl, 4-chlorphenyl, or unsubstituted phenyl; With

Work as R²²-NH-S (O)₂-time, R³¹It not unsubstituted phenyl.

In certain embodiments, R²²Be selected from-C (O)-NH-,-NH-, or-C (O)-NH-CH₃。

In certain embodiments, for example work as R²²To be selected from-C (O)-NH-,-NH-, or-C (O)-NH-CH₃The time, R³¹To be selected from the phenyl that selectively replaces, benzothiazolyl, quinoxalinyl, or benzoxazolyl.

Wherein:

Each R²⁰To be selected from H or solubilizing group independently;

0 to 1 R²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', O or S;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 2 be N or NR₁′；

0 to 1 R²⁰It is solubilizing group;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′-，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-，-CR ₁′R ₁′-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-O-，-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁ ′R ₁′-O-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-; With

Condition is to work as R¹⁹Be

Z ₁₀，Z ₁₁，Z ₁₂And Z₁₃Each is CH naturally, and R²¹Be-NHC (O)-time, R³¹It not the phenyl that selectively replaces.

Each R²⁰To be selected from H or solubilizing group independently;

0 to 1 R²⁰It is solubilizing group;

R ¹⁹Be selected from:

Wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 2 be N or NR₁′；

0 to 1 R²⁰It is solubilizing group;

Work as X₇N, R¹⁹Be

a)X ₈，X ₉Or X₁₀In at least one be C-(C₁-C ₃The straight or branched alkyl) or C-(solubilizing group); Or

In certain embodiments, R²¹Be-NH-C (O)-and R¹⁹Be selected from:

In certain embodiments, R¹⁹Be selected from the phenyl that selectively replaces, the pyridine radicals that selectively replaces, the thienyl that selectively replaces or the furyl that selectively replaces.

In certain embodiments, R¹⁹Be

R ²¹Be selected from-NH-C (O)-,-NH-C (O)-CH (CH₃)-O-，-NH-C(O)-CH ₂-O-, or-NH-S (O)₂-CH ₂-CH ₂-; With

R ³¹Be selected from the aryl that selectively replaces, or the heteroaryl that selectively replaces.

In some such embodiment, R³¹Selectively replaced by 1-3 substituting group, described substituting group is independently selected from-OCH₃，-CH ₃，-N(CH ₃) ₂, phenyl, phenoxy group, 3,4-, two Oxymethylenes, fluorine, or another solubilizing group. R³¹Suitable example comprise the unsubstituted quinolines base, 2,4-dimethoxy base, 3, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3, the 4-trimethoxyphenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3,5-3,5-dimethylphenyl, 3,5-difluorophenyl, the 3-Trifluoromethoxyphen-l, unsubstituted quinoxalinyl, unsubstituted benzo pyrimidine radicals

In some such embodiment, R³¹It not the furyl of phenyl substituted.

In certain embodiments, R¹⁹To be selected fromEach Z₁₀，Z ₁₁，Z ₁₂And Z₁₃To be selected from CR independently²⁰, or CR₁′；

R ²¹Be selected from-NH-C (O)-, NH-C (O)-CH₂-CH(CH ₃)-O，-NH-C(O)-NH-，-NH-C(S)-NH-，-NH-C(S)-NH-CH ₂-, or-NH-S (O)₂-; With

R ³¹Be selected from the phenyl that selectively replaces, the base that selectively replaces, or the heteroaryl that selectively replaces.

In some such embodiment, R³¹Be selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridine radicals ， isoxazolyl, the benzopyrazoles base, benzofuranyl, benzothienyl, quinolyl, Ben Bing Yi Evil azoles base, or

And R³¹Be selectively replace (for example, by 3 substituting groups at the most, selectively replaced, described substituting group is independently selected from-OCH₃，-CH ₃，-N(CH ₃) ₂,-O-phenyl, or another solubilizing group). R³¹Suitable example comprise unsubstituted phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-Dimethoxyphenyl, 2,4-Dimethoxyphenyl, 2,5-two (trifluoromethyl) phenyl, 3, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3, the 4-trimethoxyphenyl, 2-methoxyl group-4-aminomethyl phenyl, 2-Phenoxyphenyl, 3-dimethylaminophenyl, the 4-dimethylaminophenyl, unsubstituted 2-furyl, unsubstituted 2-thienyl

In certain embodiments, one or more being suitable in following situation:

Work as X₈N, R²¹-NH-C (S)-NH-, and R¹⁹While being phenyl, R³¹Not 2-methoxyl group-5-nitrobenzophenone, 2-S-aminomethyl phenyl or 2-acetylphenyl;

Work as X₈N, R²¹-NH-S (O)₂-, and R¹⁹While being phenyl, R³¹Not thienyl or the 4-methyl sulphonyl phenyl that thiadiazoles replaces;

Work as X₈N, R²¹Be-NH-CO-, and R¹⁹While being phenyl, R³¹Not 2,4-difluorophenyl, the thienyl that pyridine radicals replaces, 3,4-dichlorophenyl, 4-tert-butyl phenyl, or 3-benzyloxy phenyl;

Work as X₉N, R²¹Be-NH-C (O)-and R¹⁹Be

The time, R³¹Not 2,3,4-trimethoxyphenyl or 3,5-Dimethoxyphenyl; With

Work as X₉N, R²¹Be-NH-C (O)-and R¹⁹While being phenyl, R³¹It not 3,5-Dimethoxyphenyl.

In another embodiment, the invention provides the compound or its salt of structural formula (XIII):

Wherein:

R ₁' be the C that is selected from H or selectively replaces₁-C ₃The straight or branched alkyl;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁-′，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-，-CR ₁′R ₁′-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R ₁′-O-，-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁ ′R ₁′-O-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-，-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-; With

R ³¹Be selected from the monocycle or the dicyclo aryl that selectively replace, or the monocycle or the dicyclo heteroaryl that selectively replace, condition is:

Work as R²¹Be-NH-C (O)-time, R³¹it not unsubstituted furyl, 5-bromine furyl, unsubstituted phenyl, the mono-substituted base of halogen or methyl, 3-or 4-methoxyl group base, the 4-butoxy phenyl, uncle 4--butyl phenyl, 3-trifluoromethyl phenyl, the 2-benzoylphenyl, 2-or 4-ethoxyl phenenyl, 2, 3-, 2, 4-, 3, 4-, or 3, the 5-Dimethoxyphenyl, 3, 4, the 5-trimethoxyphenyl, 2, 4-or 2-6 difluorophenyl, 3, 4-dioxy methylene phenyl, 3, 4-or 3, the 5-3,5-dimethylphenyl, 2-chloro-5-bromophenyl, 2-methoxyl group-5-chlorphenyl, unsubstituted quinolyl, by methyl and the simultaneously-substituted thiazolyl of phenyl, or the pyridine radicals of ethyoxyl replacement,

Work as R²¹-NH-C (O)-CH (CH₂-CH ₃)-time, R³¹It not unsubstituted phenyl;

Work as R²¹-NH-C (O)-CH₂-time, R³¹Not unsubstituted phenyl, 3-aminomethyl phenyl, 4-chlorphenyl, 4-ethoxyl phenenyl, 4-fluorophenyl or 4-methoxyphenyl;

Work as R²¹-NH-C (O)-CH₂During-O-, R³¹Not unsubstituted phenyl or 4-chlorphenyl; With

Work as R²¹-NH-S (O)₂-time, R³¹Not 3,4-dioxy methylene phenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 2,4-or 3, the 4-3,5-dimethylphenyl, 2,5-difluorophenyl, 2,5-or 3, the 4-Dimethoxyphenyl, fluorophenyl, 4-chlorphenyl, 4-bromophenyl, 4-ethyl phenyl, 4-aminomethyl phenyl, 3-methyl-4-methoxyphenyl, unsubstituted phenyl, unsubstituted pyridine radicals, unsubstituted thienyl, the thienyl that chlorine replaces, or methyl substituted benzothiazolyl.

In certain embodiments, R₁' the C that is selected from H or selectively replaces₁-C ₃The straight or branched alkyl;

R ³¹Be selected from monocycle or bicyclic aryl or monocycle or bicyclic heteroaryl, and comprise the solubilizing group substituting group.

In certain embodiments, R³¹Be selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridine radicals ， isoxazolyl, the benzopyrazoles base, benzofuranyl, benzothienyl, quinolyl, the benzoisoxazole base, or

And R³¹Optional selecting generation.

In certain embodiments, R²¹Be selected from-NH-C (O)-, NH-C (O)-CH₂-CH(CH ₃)-O，-NH-C(O)-NH-，-NH-C(S)-NH-，-NH-C(S)-NH-CH ₂-, or-NH-S (O)₂-; With

In some such embodiment, particularly work as R²¹Be-NH-C (O)-time, R³¹To be selected from unsubstituted phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-Dimethoxyphenyl, 2,4-Dimethoxyphenyl, 2,5-two (trifluoromethyl) phenyl, 3, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,3, the 4-trimethoxyphenyl, 2-methoxyl group-4-aminomethyl phenyl, 2-Phenoxyphenyl, 3-dimethylaminophenyl, the 4-dimethylaminophenyl, unsubstituted 2-furyl, unsubstituted 2-thienyl

Wherein:

Each R²³And R²⁴To be selected from H ,-CH independently₃Or solubilizing group;

R ²⁵Be selected from H or solubilizing group; With

R ¹⁹Be selected from:

Wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', O or S;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N or NR₁′；

0 to 1 R²⁰It is solubilizing group; With

0 to 1 R₁' be the C that selectively replaces₁-C ₃The straight or branched alkyl;

Each R²⁰To be selected from H or solubilizing group independently;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R′ ₁-C(O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁-O-，-NR ₁′-C(O)-CR ₁′R′ ₁-C R ₁′R′ ₁-O-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁ -CR ₁′R′ ₁-，-NR ₁′-C(S)-NR ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁'-C (O)-O-or-NR₁′-C(O)-CR ₁′R ₁'-; With

Each R₁' be the C that is selected from H or selectively replaces independently₁-C ₃The straight or branched alkyl; With

Wherein work as R¹⁹Be

R ²¹Be-NH-C (O)-and R²⁵Be-during H, R³¹Be not the phenyl group that selectively replaces, and wherein said compound is not 2-chloro-N-[3-[3-(cyclohexyl is amino) imidazo [1,2-a] pyridine-2-yl] phenyl]-the 4-nitrobenzamide.

In certain embodiments, each R²³And R²⁴To be selected from H ,-CH independently₃Or solubilizing group;

R ²⁵Be selected from H, or solubilizing group; With

R ¹⁹Be selected from:

Wherein:

Each Z₁₄，Z ₁₅And Z₁₆To be selected from N, NR independently₁′，S，O，CR ²⁰, or CR₁′，

Wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', O or S;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 2 be N or NR₁′；

0 to 1 R²⁰It is solubilizing group; With

Each R²⁰To be selected from H or solubilizing group independently;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′-，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R′ ₁-C(O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁-O-，-NR ₁′-C(O)-CR ₁′R′ ₁-C R ₁′R′ ₁-O-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁ -CR ₁′R′ ₁-，-NR ₁′-C(S)-NR ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁'-C (O)-O-or-NR₁′-C(O)-CR ₁′R ₁'-(particularly-NH-C (O)-); With

In some such embodiment, R³¹It not 2,4-Dimethoxyphenyl.

Typically, R²⁵Be selected from H ,-CH₂-N(CH ₃) ₂, or

Typically, R²³And R²⁴H.

Typically, R¹⁹To be selected from phenyl, pyridine radicals, thienyl or furyl, the phenyl that selectively replaces in particular. Preferably, phenyl is selectively replaced by following radicals:

A) three-O-CH at the most₃Group; Or

B) 1-N (CH₃) ₂Group.

R ²⁵Be selected from H, or solubilizing group; With

R ¹⁹Be selected from:

Wherein:

Z ₁₀，Z ₁₁，Z ₁₂Or Z₁₃In 0 to 2 be N;

Z ₁₄，Z ₁₅And Z₁₆In at least one be N, NR₁', O or S;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 1 be S or O;

Z ₁₄，Z ₁₅And Z₁₆In 0 to 2 be N or NR₁′；

0 to 1 R²⁰It is solubilizing group; With

Each R²⁰To be selected from H or solubilizing group independently;

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(0) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′-，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R′ ₁-C(O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁-O-，-NR ₁′-C(O)-CR ₁′R′ ₁-C R ₁′R′ ₁-O-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁ -CR ₁′R′ ₁-，-NR ₁′-C(S)-NR ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁'-C (O)-O-or-NR₁′-C(O)-CR ₁′R ₁'-(particularly-NH-C (O)-); With

R ³¹To be selected from monocycle or the bicyclic aryl that selectively replaces, or the monocycle or the bicyclic heteroaryl that selectively replace,

Wherein work as R¹⁹While being phenyl, R²³，R ²⁴, or R²⁵In at least one be that solubilizing group and wherein said compound are not 2-chloro-N-[3-[3-(cyclohexyl amino) imidazo [1,2-a] pyridine-2-yls] phenyl]-the 4-nitrobenzamide.

Typically, R²⁵Be selected from H ,-CH₂-N(CH ₃) ₂, or

Typically, R²³And R²⁴H.

Typically, R¹⁹Be selected from phenyl, pyridine radicals, thienyl or furyl, the phenyl that particularly selectively replaces. Preferably, phenyl is selectively by following radicals, to be replaced:

B) 3-O-CH at the most₃Group; Or

B) one-N (CH₃) ₂Group.

Wherein:

R ³²Be selected from the bicyclic aryl that selectively replaces, or the monocycle or the bicyclic heteroaryl that selectively replace, wherein:

Work as R²¹Be-NH-C (O)-time, R³²Not unsubstituted 2-furyl, 2-(3-bromine furyl), unsubstituted 2-thienyl, unsubstituted 3-pyridine radicals, unsubstituted 4-pyridine radicals,

With

Work as R²¹Be-NR₁′-S(O) ₂-time, R³²Not unsubstituted 2-thienyl or unsubstituted naphthyl.

Wherein:

R ²¹Be selected from-NR₁′-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁′ -CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′-，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R′ ₁-C(O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁- O-，-NR ₁′-C(O)-CR ₁′R′ ₁-CR ₁′R′ ₁-O-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-CR ₁′ R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁- CR ₁′R′ ₁-，-NR ₁′-C(S)-NR ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-，-NR ₁'-C (O)-O-or-NR₁′-C(O)-CR ₁′R ₁'-(particularly-NH-C (O)-); With

R ³³The phenyl that selectively replaces, wherein:

Work as R²¹Be-NH-C (O)-time, R³³Except by halogen, methyl, the phenyl of the replacement outside the mono-substituted phenyl of nitro or methoxyl group; The 2-carboxyl phenyl; 4-just-the amyl group phenyl; The 4-ethoxyl phenenyl; 2-carboxyl-3-nitrobenzophenone; The 2-chloro-4 nitrophenyl; 2-methoxyl group-5-ethylphenyl; 2,4-Dimethoxyphenyl; 3,4,5-trimethoxyphenyl; 2,4-dichlorophenyl; 2,6-difluorophenyl; 3,5-dinitrophenyl; Or 3,4-3,5-dimethylphenyl;

Work as R²¹Be-NR₁′-C(O)-CR ₁′R ₁'-or-NH-C (O)-CH (CH₃During)-O, R³³It is the phenyl that replaces;

Work as R²¹-NH-C (O)-CH₂The time, R³³Not unsubstituted phenyl, the 4-methoxyphenyl; 3,4-Dimethoxyphenyl or 4-chlorphenyl;

Work as R²¹-NH-C (O)-CH₂During-O, R³³It not 2,4-two (1,1-dimethyl propyl) phenyl;

Work as R²¹While being-NH-C (O)-NH-, R³³It not the 4-methoxyphenyl; With

Work as R²¹-NH-S (O)₂-time, R³³it is the phenyl that replaces, but not the 3-aminomethyl phenyl, the 3-trifluoromethyl, 2, 4, 5-or 2, 4, the 6-trimethylphenyl, 2, 4-or 3, the 4-3,5-dimethylphenyl, 2, 5-or 3, the 4-Dimethoxyphenyl, 2, 5-dimethoxy-4 '-chlorphenyl, 3, the 6-dimethoxy, the 4-aminomethyl phenyl, 2, 5-or 3, the 4-dichlorophenyl, 2, 5-diethoxy phenyl, the 2-methyl-5-nitrophenyl, 2-ethyoxyl-5-bromophenyl, 2-methoxyl group-5-bromophenyl, 2-methoxyl group-3, the 4-dichlorophenyl, 2-methoxyl group-4-methyl-5-bromophenyl, 3, 5-dinitro-4-aminomethyl phenyl, 3-methyl-4-methoxyphenyl, 3-nitro-4-methyl phenyl, 3-methoxyl group-4-halogenophenyl, 3-methoxyl group-5-chlorphenyl, 4-just-butoxy phenyl, the 4-halogenophenyl, the 4-ethylphenyl, the 4-aminomethyl phenyl, the 4-nitrobenzophenone, the 4-ethoxyl phenenyl, 4-acetyl-amino phenyl, the 4-methoxyphenyl, 4-tert-butyl phenyl base, p-xenyl.

In certain embodiments, R²¹Be selected from-NR²²-C(O)-，-NR ₁′-S(O) ₂-，-NR ₁′-C(O)-NR ₁′-，-NR ₁′-C(S)-NR ₁′-，-NR ₁′-C(S)-NR ₁ ′-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′R′ ₁-NR ₁′-，-NR ₁′-C(＝NR ₁′)-NR ₁′-，-C(O)-NR ₁′，-C(O)-NR ₁′-S(O) ₂-，-NR ₁′-，-CR ₁′R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-，-NR ₁′-S(O) ₂-NR ₁′-，-NR ₁′-C(O) -NR ₁′-S(O) ₂-，-NR ₁′-CR ₁′R′ ₁-C(O)-NR ₁′-，-CR ₁′R′ ₁-C(O)-NR ₁′-，-NR ₁′-C(O)-CR ₁′R′ ₁- O-，-NR ₁′-C(O)-CR ₁′R′ ₁-CR ₁′R′ ₁-O-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-，-NR ₁′-S(O) ₂-CR ₁′R′ ₁-CR ₁′ R′ ₁-，-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-，-NR ₁′-C(＝N-CN)-NR ₁'-, or-NR₁′-C(O)-CR ₁′R ₁'-; With

R ²²The C that selectively replaces₁-C ₃The straight or branched alkyl; With

R ³³Be to contain the substituent phenyl of solubilizing group, wherein: work as R ²¹Be-NH-S (O) ₂The time, described phenyl contains an additional substituting group.

In certain embodiments, R ²¹Be selected from-NR ²²-C (O)-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ' ₁-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁' ,-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-, or-NR ₁'-C (=N-CN)-NR ₁'-,

R ²²Be the C that selectively replaces ₁-C ₃The straight or branched alkyl.

In certain embodiments, R ³³Selectively be substituted on 3 carbon atoms at the most, substituting group is independently selected from-O-CH ₃,-CH ₃,-N (CH ₃) ₂,-S (CH ₃), or CN; Or on adjacent carbons by with described adjacent carbons bridging

Replace.

In another embodiment, the sirtuin-that the invention provides structural formula (XVII) regulates compound or its salt:

Wherein:

R ²⁹The phenyl that is replaced by following substituting group:

A) two-O-CH ₃Group;

B) be positioned at 2,3 and 4 three-O-CH ₃Group; Or

C) one-N (CH ₃) ₂Group; With

D) work as R ²³Be CH ₃The time, one 2 or 3-O-CH ₃Group, wherein R ²⁹Be selectively additionally to be replaced by solubilizing group.

In certain a few embodiment, R ²⁹The phenyl that is replaced by following substituting group:

A) be positioned at 2,3 and 4 three-O-CH ₃Group; Or

B) one-N (CH ₃) ₂Group.

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group; With

Each R ²⁰Be to be selected from H or solubilizing group independently;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁' ,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-,

R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace, condition is to work as R ¹⁹Be Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Each is CH naturally, R ²⁰Be H, and R ²¹Be-NHC (O)-time, R ³¹It or not the phenyl that selectively replaces.

In certain embodiments, R ¹⁹Be selected from:

Wherein:

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be to be selected from N, CR independently ²⁰, or CR ₁'; With each Z ₁₄, Z ₁₅And Z ₁₆Be to be selected from N, NR independently ₁', S, O, CR ²⁰, or CR ₁', wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group; With

Each R ²⁰Be to be selected from H or solubilizing group independently;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁' ,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-,

In some such embodiment, the compound of structural formula (XVIII) has following formula or its salt:

Wherein:

R ²⁰Be selected from H or solubilizing group;

R ²¹Be selected from-NH-C (O)-, or-NH-C (O)-CH ₂-; With

Typically, the R in the compound of structural formula (XVIII) ¹⁹Be to be selected from phenyl, pyridyl, thienyl or furyl, the particularly phenyl that selectively replaces.

Typically, R ²⁰Be selected from H ,-CH ₂-N (CH ₃) ₂,

Typically, R ³¹Be selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidyl, thienyl, naphthyl, benzopyrazoles base, benzofuryl, quinolyl, quinoxalinyl, or benzothienyl and R wherein ³¹Selectively replace.

Typically, R ²¹Be selected from-NH-C (O)-or-NH-C (O)-CH ₂-.

In some such embodiment, work as R ²¹Be-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And/or work as R ²¹Be-NR ₁'-S (O) ₂-time, R ³¹Not 4-p-methoxy-phenyl or 4-tert-butyl phenyl.

In some such embodiment, work as R ¹⁹Be

And R ²¹Be-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And/or work as R ¹⁹Be

And R ²¹Be-NR ₁'-S (O) ₂-time, R ³¹Not 4-p-methoxy-phenyl or 4-tert-butyl phenyl.

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', O or S;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group; With

Each R ²⁰Be to be selected from H or solubilizing group independently;

R ^20aBe to be selected from H or solubilizing group independently;

Wherein

Each R ₁' be the C that is selected from H or selectively replaces independently ₁-C ₃The straight or branched alkyl; And R ³¹Be selected from the monocycle or the bicyclic aryl that selectively replace, or the monocycle or the bicyclic heteroaryl that selectively replace, R wherein worked as ¹⁹Be

Typically, the R in structural formula (XX) compound ¹⁹Be selected from phenyl, pyridyl, thienyl or furyl, the particularly phenyl that selectively replaces.

Typically, R ^20aBe selected from H ,-CH ₂-N (CH ₃) ₂,

Typically, R ²¹Be selected from-NH-C (O)-or-NH-C (O)-CH ₂-.

Also having aspect another, the invention provides structure the sirtuin-of formula (XXI) regulate compound or its salt:

Wherein:

Wherein

In certain embodiments, R ³²Be selected from pyrryl, pyrazolyl, pyrazinyl, furyl, pyridyl, pyrimidyl, or thienyl, and R ³²Be selectively replace and be selectively benzo-fused.

In certain embodiments, R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-;-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-,

Wherein

R ³²Be selected from benzofuryl, methyl furan base, benzothienyl, pyridyl, pyrazinyl, pyrimidyl, pyrazolyl, wherein said methyl furan base, pyridyl, pyrazinyl, pyrimidyl or pyrazolyl are selectively benzo-fused and R wherein ³²Be that selectively replace or further substituted.

Wherein:

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁' ,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,

R ³³Be the phenyl that selectively replaces, wherein:

Work as R ²¹Be-NR ₁'-C (O)-time, R ₁' not H;

Work as R ²¹Be-NH-S (O) ₂-time, R ³³Not unsubstituted phenyl, 2,4-or 3,4-3,5-dimethylphenyl; 2,4-dimethyl-5-p-methoxy-phenyl, 2-methoxyl group-3,4-dichlorophenyl; the 2-methoxyl group, 5-bromophenyl-3,4-dioxy ethylidene phenyl, 3; the 4-Dimethoxyphenyl, 3,4-dichlorophenyl, 3; the 4-3,5-dimethylphenyl, 3-or 4-aminomethyl phenyl, 4-alkoxyl phenyl, 4-Phenoxyphenyl; the 4-halogenophenyl, 4-xenyl, or 4-acetylamino phenyl.

Preferably, R ²¹Be selected from-NH-C (O)-or-NH-C (O)-CH ₂-.

Wherein:

R ²¹Be be selected from-NH-C (O)-, or-NH-C (O)-CH ₂-; With

R ³³The phenyl that is replaced by following substituting group:

E) one-N (CH ₃) ₂Group;

F) one at 3 CN group;

G) one-S (CH ₃) group; Or

Bridging 3 and 4 s'

Wherein:

Work as R ²¹-NH-C (O)-time, R ³¹Not 3,5-dinitrophenyl, 4-butyl phenyl ether

Work as R ²¹Be-NH-C (O)-, R ₁" be methyl; With each R ²⁰, R ^20a, R ₁' and R ₁" ' when being hydrogen, R ³¹Not 2-methylamino phenyl,

Work as R ²¹Be-NH-C (O)-CH ₂-or NH-C (S)-NH-and each R ²⁰, R ^20a, R ₁', R ₁" and R ₁" ' when being hydrogen, R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-S (O) ₂-, R ₁" be hydrogen or methyl and each R ²⁰, R ^20a, R ₁' and R ₁" ' when being hydrogen, R ³¹It or not the 4-aminomethyl phenyl; With

Work as R ²¹Be-NH-S (O) ₂-, R ^20aBe hydrogen or-CH ₂-N (CH ₂CH ₃) ₂And each R ²⁰, R ₁', R ₁" and R ₁" ' when being hydrogen, R ³¹Be not

In certain embodiments, R ²¹Be be selected from-NH-C (O)-, or-NH-C (O)-NR ₁'.

In certain embodiments, R ³¹Be to be selected from phenyl, quinoxalinyl or the quinolyl that selectively replaces.For example, R ³¹Be selectively to be replaced by 3 substituting groups at the most, described substituting group is independently selected from-OCH ₃,-N (CH ₃) ₂, or solubilizing group.R ³¹Suitable example comprise the 4-dimethylaminophenyl, 3, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4, the 5-trimethoxyphenyl, 3-methoxyl group-4-((piperazine-1-yl) methyl) phenyl, 3-methoxyl group-4-((morpholino) methyl) phenyl, 3-methoxyl group-4-((tetramethyleneimine-1-yl) methyl) phenyl, unsubstituted phenyl, unsubstituted quinoxalinyl and unsubstituted quinolines base.

Wherein:

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁' ,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

R ³¹Be selected from selectively the monocycle or the bicyclic aryl that replace, or the monocycle that selectively replaces or the assorted virtue of dicyclo admire,

Wherein:

I) at least one R ²⁰Be solubilizing group or at least one R1 " ' be the C that selectively replaces ₁-C ₃Straight or branched alkyl or the two all are; Perhaps

Ii) R ^20aBe solubilizing group but be not CH ₂-N (CH ₂CH ₃) ₂

In certain embodiments, R ²¹Be selected from-NH-C (O)-, or-NH-C (O)-NR ₁'.

In certain embodiments, R ³¹Be selected from the phenyl, quinoxalinyl or the quinolyl that selectively replace.For example, R ³¹Selectively by 3 substituting groups replacements at the most, described substituting group is independently selected from-OCH ₃,-N (CH ₃) ₂, or solubilizing group.R ³¹Suitable example comprise the 4-dimethylaminophenyl, 3, the 4-Dimethoxyphenyl, 3,5-Dimethoxyphenyl, 3,4, the 5-trimethoxyphenyl, 3-methoxyl group-4-((piperazine-1-yl) methyl) phenyl, 3-methoxyl group-4-((morpholino) methyl) phenyl, 3-methoxyl group-4-((tetramethyleneimine-1-yl) methyl) phenyl, unsubstituted phenyl, unsubstituted quinoxalinyl and unsubstituted quinolines base.

Wherein:

R ²¹Be selected from-NR ²³-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Work as R ²¹When being-NH-C (O)-CH=CH-, R ³¹It or not the 2-chloro-phenyl-;

Work as R ²¹Be-NH-S (O) ₂-and each R ²⁰, R ^20a, R ₁', R ₁" and R ₁" ' when being hydrogen, R ³¹Not unsubstituted phenyl, 4-chloro-phenyl-, 4-aminomethyl phenyl, or 4-acetylamino phenyl;

Work as R ²¹Be-NH-S (O) ₂-, each R ₁' and R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, and R ₁" when being hydrogen, R ³¹It or not the 4-nitrophenyl;

Work as R ²¹Be-NH-C (O)-CH ₂-O-, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when being hydrogen, R ³¹Not 2,3-, 2,5-, 2,6-, 3,4-or 3, the 5-3,5-dimethylphenyl, 2,4-dichloromethyl, 2,4-dimethyl-6-bromophenyl, 2-or 4-chloro-phenyl-, 2-(1-methyl-propyl) phenyl, 5-methyl-2-(1-methylethyl) phenyl, 2-or 4-aminomethyl phenyl, 2,4-two chloro-6-aminomethyl phenyls, nitrophenyl, 2,4-dimethyl-6-nitrophenyl, 2-or 4-p-methoxy-phenyl, 4-ethanoyl-2-p-methoxy-phenyl, 4-chloro-3, the 5-3,5-dimethylphenyl, 3-ethylphenyl, 4-bromophenyl, the 4-cyclohexyl phenyl, 4-(1-methyl-propyl) phenyl, 4-(1-methylethyl) phenyl, 4-(1, the 1-dimethyl ethyl) phenyl, or unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH ₂-, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when being hydrogen, R ³¹Not unsubstituted naphthyl, 4-chloro-phenyl-, 4-nitrophenyl, 4-p-methoxy-phenyl, unsubstituted phenyl, unsubstituted thienyl

Work as R ²¹Be-NH-C (O)-CH ₂-, R ₁' be methyl and each R ²⁰, R ^20a, R ₁", and R ₁" ' when being hydrogen,

R ³¹It or not unsubstituted phenyl;

Work as R ²¹Be-NH-C (O)-CH=CH, R ₁" ' be methyl or hydrogen and each R ²⁰, R ^20a, R ₁', and R ₁" when being hydrogen, R ³¹Not unsubstituted furyl, the furyl that nitrophenyl replaces, 2,4 dichloro benzene base, 3,5-two chloro-2-p-methoxy-phenyls, 3-or 4-nitrophenyl, 4-p-methoxy-phenyl, unsubstituted phenyl, or the thienyl of nitro replacement;

Work as R ²¹Be-NH-C (O)-CH (CH ₂CH ₃)-and each R ²⁰, R ^20a, R ₁', R ₁", and R ₁" ' when being hydrogen, R ³¹It or not unsubstituted phenyl;

Wherein:

R ²¹Be selected from-NRR ²³-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-, or-NR ₁'-C (O)-CR ₁' R ₁'-, be R wherein ²³Be the C that selectively replaces ₁-C ₃The straight or branched alkyl; With

In certain embodiments, work as R ²¹Be-NH-C (O)-CH ₂-time, R ³¹It or not the 2-aminomethyl phenyl; Or 3, the 4-Dimethoxyphenyl; Work as R ²¹When being-N-C (O)-CH=CH-, R ³¹It or not the 2-chloro-phenyl-; And/or work as R ²¹When being-NH-C (O)-NH-, R ³¹It or not unsubstituted benzimidazolyl-.

Wherein:

R ³²It is the phenyl that selectively replaces.

In certain embodiments, R ³²Be selected from 3, the 4-Dimethoxyphenyl, 2, the 6-Dimethoxyphenyl, or 2, the 4-Dimethoxyphenyl; R wherein ³²Be further selectively to be replaced by solubilizing group.

In certain embodiments, R ³²It or not unsubstituted thienyl; Unsubstituted phenyl; The 2-aminomethyl phenyl; The 4-fluorophenyl; The 4-p-methoxy-phenyl; The 4-aminomethyl phenyl; 3,4-dioxy ethylidene support phenyl; 3-acetylamino-4-aminomethyl phenyl; 3-[(6-amino-1-oxo-hexyl) amino]-the 4-aminomethyl phenyl; 3-amino-4-aminomethyl phenyl; 3, the 5-Dimethoxyphenyl; 3-halo-4-p-methoxy-phenyl; 3-nitro-4-methyl phenyl; Or 4-propoxy-phenyl.

Wherein:

As each R ₁' and R ₁" ' be hydrogen or methyl and each R ₁", R ₂₀And R _20aWhen being hydrogen, R ³³Not 5,6,7, the 8-tetralyl, unsubstituted benzofuryl, unsubstituted benzothiazolyl, the benzothienyl that chloro-or nitro replace, unsubstituted furyl, phenyl-, the furyl that bromo-or nitro replace, dimethyl replaces De isoxazolyl, unsubstituted naphthyl, 5-bromonaphthalene base, 4-methyl naphthyl, 1-or 3-methoxyl group naphthyl, the naphthyl that azo replaces, unsubstituted pyrazinyl, the methyl substituted pyridyl of S-, the unsubstituted pyridine base, thienyl-or the quinolyl that replaces of phenyl, chloro-, the thienyl that bromo-or nitro replace, unsubstituted thienyl, or

Wherein:

In yet another aspect, the sirtuin-that the invention provides structural formula (XXVII) regulates compound:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

R ²¹Be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-N ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ' ₁-, or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Condition is to work as R ²¹Be-NH-C (O)-and R ¹⁹Be The time, R ³¹Not the unsubstituted pyridine base, 2,6-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl.

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

R ²¹Be to be selected from-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ' ₁-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ' ₁-C (O)-NR ₁'-,-CR ₁' R ' ₁-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ' ₁-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁', or-NR ₁'-C (O)-CR ₁' R ₁'-; With

Work as R ²¹Be-NH-C (O)-time, R ¹⁹It or not pyrazolyl;

Work as R ²¹Be-NH-C (O)-CH ²-, and R ¹⁹Be The time, R ³¹Not 2-aminomethyl phenyl or 3, the 4-Dimethoxyphenyl;

Work as R ²¹Be-NH-C (O)-CH=CH-, and R ¹⁹Be

The time, R ³¹It or not the 2-chloro-phenyl-;

Work as R ²¹Be-NH-C (O)-NH-, and R ¹⁹Be

The time, R ³¹It or not unsubstituted benzimidazolyl-;

Work as R ²¹Be-NH-C (O)-and R ¹⁹Be

The time, R ³¹Not the unsubstituted pyridine base, unsubstituted thienyl, unsubstituted phenyl, the 2-aminomethyl phenyl, 4-fluorophenyl, 4-p-methoxy-phenyl, the 4-aminomethyl phenyl, 3,4-dioxy ethylidene phenyl, 3-acetylamino-4-aminomethyl phenyl, 3-[(6-amino-1-oxo-hexyl) amino]-the 4-aminomethyl phenyl, 3-amino-4-aminomethyl phenyl, 2, the 6-Dimethoxyphenyl, 3, the 5-Dimethoxyphenyl, 3-halo-4-p-methoxy-phenyl, 3-nitro-4-methyl phenyl, 4-propoxy-phenyl, 3,4,5-trimethoxyphenyl or unsubstituted furyl;

Work as R ²¹Be-NH-C (O)-and R ¹⁹Be

The time, R ³¹Not 3, the 5-dinitrophenyl, the 4-butoxy phenyl,

In certain embodiments, R ²¹Be selected from-NH-C (O)-or-NH-C (O)-NR ₁', preferred-NH-C (O)-.

In certain embodiments, R ³¹Be selected from the phenyl that selectively replaces, quinoxalinyl or quinolyl; The preferred phenyl that selectively replaces.For example, R ³¹Be selectively to be replaced by 3 substituting groups at the most, described substituting group is independently selected from-OCH ₃,-N (CH ₃) ₂, or solubilizing group.R ³¹Suitable example comprise the 4-dimethylaminophenyl; 3, the 4-Dimethoxyphenyl; 3, the 5-Dimethoxyphenyl; 3,4, the 5-trimethoxyphenyl; 3-methoxyl group-4-((piperazine-1-yl) methyl) phenyl; 3-methoxyl group-4-((morpholino) methyl) phenyl; 3-methoxyl group-4-((tetramethyleneimine-1-yl) methyl) phenyl; Unsubstituted phenyl; Unsubstituted quinoxalinyl; With the unsubstituted quinolines base.R ³¹Preferred example comprise 3, the 4-Dimethoxyphenyl; 2, the 6-Dimethoxyphenyl; Or 2, the 4-Dimethoxyphenyl; R wherein ³¹Further selectively replaced by solubilizing group.

In preferred embodiments, R ²¹Be-NH-C (O)-and R ³¹Be to be selected from the 3-p-methoxy-phenyl; 3, the 4-Dimethoxyphenyl; 3,4, the 5-trimethoxyphenyl; Or 4-dimethylaminophenyl.

In certain embodiments, work as R ²¹Be-NH-C (O)-time, R ¹⁹Be not

In certain embodiments, work as R ²¹Be-NH-C (O)-time, R ¹⁹Not the pyrazolyl that selectively replaces, thiazolyl, thienyl, pyrryl or pyrimidyl; Work as R ²¹Be-NH-C (O)-CH2-or-during NH-C (O)-NH-, R ¹⁹It or not pyrazolyl; And/or work as R ²¹Be-during NH-, R ¹⁹Not the pyridyl that selectively replaces, thiazolyl, pyrazolyl, thiadiazolyl group ， Huo oxadiazole base (oxadiazolyl).

One more particularly aspect, the sirtuin-that the invention provides structural formula (XXVII) regulates compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In 0 to 2 be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 1 be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In 0 to 2 be N or NR ₁';

0 to 1 R ²⁰It is solubilizing group;

Work as R ²¹Be-NH-C (O)-time, R ¹⁹It or not pyrazolyl;

Work as R ²¹Be-NH-C (O)-and R ¹⁹When being thiazolyl or pyrimidyl, R ³¹It or not unsubstituted phenyl.

In certain embodiments, R ²¹Be selected from-NH-C (O)-or-NH-C (O)-NR ₁'-, be preferred-NH-C (O)-.

In certain embodiments, R ³¹Be selected from the phenyl that selectively replaces, quinoxalinyl or quinolyl; The preferred phenyl that selectively replaces.For example, R ³¹Selectively by 3 substituting groups replacements at the most, described substituting group is independently selected from-OCH ₃,-N (CH ₃) ₂, or solubilizing group.R ³¹Suitable example comprise the 4-dimethylaminophenyl; 3, the 4-Dimethoxyphenyl; 3, the 5-Dimethoxyphenyl; 3,4, the 5-trimethoxyphenyl; 3-methoxyl group-4-((piperazine-1-yl) methyl) phenyl; 3-methoxyl group-4-((morpholino) methyl) phenyl; 3-methoxyl group-4-((tetramethyleneimine-1-yl) methyl) phenyl; Unsubstituted phenyl; Unsubstituted quinoxalinyl; With the unsubstituted quinolines base.R ³¹Preferred example comprise 3, the 4-Dimethoxyphenyl; 2, the 6-Dimethoxyphenyl; Or 2, the 4-Dimethoxyphenyl; R wherein ³¹Further selectively replaced by solubilizing group.

In preferred embodiments, R ²¹Be-NH-C (O)-and R ³¹Be to be selected from the 3-p-methoxy-phenyl;

3, the 4-Dimethoxyphenyl; 3,4, the 5-trimethoxyphenyl; Or 4-dimethylaminophenyl.

Also having aspect another, the invention provides the compound or its salt of structural formula (XXVIII):

Wherein:

R ²⁹Be selected from:

Wherein:

0 to 1 R ²⁰It is solubilizing group;

In certain embodiments, R ³¹The phenyl of Qu Daiing selectively, 3-p-methoxy-phenyl for example, 3,4-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, or 4-dimethylaminophenyl.

In certain embodiments, R ²¹Be-NH-C (O)-.

In preferred embodiments, R ²¹Be-NH-C (O)-and R ³¹Be the phenyl that selectively replaces, 3-p-methoxy-phenyl for example, 3,4-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, or 4-dimethylaminophenyl.

In yet another aspect, for example when the sirtuin conditioning agent is the sirtuin inhibitor, the invention provides new sirtuin-and regulate compound or its salt (VI):

Wherein:

Het is the heterocyclic aryl group that selectively replaces; With

In certain embodiments, Het comprises a N heteroatoms and 1 to 2 and is independently selected from N, the additional heteroatoms of O or S, Li such as oxazole and pyridyl.

In certain embodiments, Ar ' is selected from the phenyl that selectively replaces, benzothiazolyl, or benzoxazolyl.When Ar ' was the phenyl that replaces, typically it was replaced by 1 to 3 substituting group, and described substituting group is independently selected from halogen, methyl, O-methyl, S-methyl or N (CH ₃) ₂, morpholino, or 3,4-dioxy methylene radical.

Compound of the present invention comprises new compound of the present invention, all can be used in the method described herein.

Compound described herein and salt thereof also comprise their corresponding hydrate (for example, semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate) and solvate.The suitable solvent of preparation solvate and hydrate can be by general the choosing of those of ordinary skills.

Compound and salt thereof can present the form (comprising cocrystallization and polymorph) of amorphous or crystalline form.

In compound described above, can have arbitrary orientation as the disclosed divalent group of the value of possible variable, condition is that this orientation causes forming stable molecule.Yet, divalent group (for example ,-NR ₁'-C (O)-) the left hand end preferably with divalence arylidene or heteroarylidene group (for example, R ¹⁹) link to each other, and the right hand end of divalent group and monovalence aromatic yl group (for example, R ³¹) link to each other.

Except as otherwise noted, the Sirtuin-of the present invention with hydroxyl substituent regulates compound and also comprises relevant secondary metabolite, for example; phosphoric acid salt; vitriol, acyl group (for example, ethanoyl; fatty acid acyl) and sugar (for example; glucuronic acid (glucurondate), glucose) derivative (for example, the derivative of oh group); particularly vitriol, acyl group and sugar derivatives.In other words ,-the OH substituted radical also comprises-OSO ₃ ^-M ⁺, M wherein ⁺Be suitable positively charged ion (preferred H ⁺, NH ₄ ⁺Or alkalimetal ion Na for example ⁺Or K ⁺) and sugar for example

These groups generally split into-OH by hydrolysis or by metabolism (for example enzyme is urged) cracking.

In certain embodiments, The compounds of this invention has been got rid of disclosed one or more materials among the table 4-6.In some such embodiment, compound of the present invention has been got rid of compound 7.

Sirtuin-of the present invention regulates compound and advantageously regulates proteic level of sirtuin and/or the proteic deacetylase activity of activity, particularly sirtuin.

Individually or except that above-mentioned character, effectively (for example regulating sirtuin albumen, such as SIRT1 and/or SIRT3 albumen) the active compound concentration of deacetylase under, some sirtuin-of the present invention regulate compound and do not have one or more following activity simultaneously: suppress the PI3-kinases, suppress aldose reductase, suppress Tyrosylprotein kinase, trans-activation EGFR Tyrosylprotein kinase is expanded crown arteries and veins or spasmolysis activity.

Alkyl group is complete saturated straight chain, side chain or ring-type non-aromatic hydrocarbon.Usually, the straight or branched alkyl group has 1 to about 20 carbon atoms, and preferred 1 to about 10 carbon atoms, and the cyclic alkyl group has 3 to about 10 carbon atoms, and preferred 3 to about 8 carbon atoms.The example of straight chain and branched alkyl group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, hexyl, amyl group and octyl group.C1-C4 straight or branched alkyl group is also referred to as " low alkyl group " group.

Alkenyl group is straight chain, side chain or the ring-type non-aromatic hydrocarbon that contains one or more pairs of keys.Usually, two keys are not positioned at the end of alkenyl group, and two like this keys are just not adjacent with another functional group.

Alkynyl group is to contain one or more triple-linked straight chains, side chain or ring-type non-aromatic hydrocarbon.Usually, triple bond is not positioned at the end of alkynyl group, and triple bond is just not adjacent with another functional group like this.

Ring (for example, 5-to 7-unit ring) or cyclic group comprise carbocyclic ring and heterocycle.Such ring can be saturated or unsaturated, comprises aromatic nucleus.Heterocycle generally contains 1 to 4 heteroatoms, but Sauerstoffatom and sulphur atom can not be adjacent one another are.

Fragrance (aryl) group comprises for example phenyl of carbocyclic ring aromatic group, naphthyl, and anthryl and heteroaryl groups imidazolyl for example, thienyl, furyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrryl, pyrazinyl, thiazolyl ， oxazolyl, and tetrazyl.

Aromatic group also comprises the fragrant member ring systems of the many cyclophanes of condensed, and wherein carbocyclic ring aromatic nucleus or heteroaromatic ring and one or more other heteroaryl ring condense.Example comprises benzothienyl, benzofuryl, indyl, quinolyl, benzothiazole, benzoxazole, benzoglyoxaline, quinolyl, isoquinolyl and pseudoindoyl.

The carbocyclic ring of nonaromatic heterocycles right and wrong fragrance comprises one or more heteroatomss in ring, for example nitrogen, oxygen or sulphur.This ring can be five, six, seven or eight yuan.Example comprises tetrahydrofuran base, tetrahydro-thienyl (tetrahyrothiophenyl), and morpholino, thiomorpholine generation, pyrrolidyl, piperazinyl, piperidyl, and thiazolidyl also have cyclic sugar.

Share at least one common key with second ring condensed ring.

At alkyl, thiazolinyl, alkynyl, aryl, the suitable substituent on nonaromatic heterocycles or the aromatic yl group (carbocyclic ring and heteroaryl) is that those do not disturb disclosed compound to have the substituting group of the ability of one or more character disclosed herein basically.Compare with not containing this substituent compound, if the size of compound property is lowered more than about 50%, this substituting group is exactly a character of having disturbed compound basically so.The example of suitable substituents comprises-OH, halogen (Br ,-Cl ,-I and-F) ,-OR ^a,-O-COR ^a,-COR ^a,-C (O) R ^a,-CN ,-NO ²,-COOH ,-COOR ^a,-OCO ₂R ^a,-C (O) NR ^aR ^b,-OC (O) NR ^aR ^b,-SO ₃H ,-NH ₂,-NHR ^a,-N (R ^aR ^b) ,-COOR ^a,-CHO ,-CONH ₂,-CONHR ^a,-CON (R ^aR ^b) ,-NHCOR ^a,-NRCOR ^a,-NHCONH ₂,-NHCONR ^aH ,-NHCON (R ^aR ^b) ,-NR ^cCONH ₂,-NR ^cCONR ^aH ,-NR ^cCON (R ^aR ^b) ,-C (=NH)-NH ₂,-C (=NH)-NHR ^a,-C (=NH)-N (R ^aR ^b) ,-C (=NR ^c)-NH ₂,-C (=NR ^c)-NHR ^a,-C (=NR ^c)-N (R ^aR ^b) ,-NH-C (=NH)-NH ₂,-NH-C (=NH)-NHR ^a,-NH-C (=NH)-N (R ^aR ^b) ,-NH-C (=NR ^c)-NH ₂,-NH-C (=NR ^c)-NHR ^a,-NH-C (=NR ^c)-N (R ^aR ^b) ,-NR ^dH-C (=NH)-NH ₂,-NR ^d-C (=NH)-NHR ^a,-NR ^d-C (=NH)-N (R ^aR ^b) ,-NR ^d-C (=NR ^c)-NH ₂,-NR ^d-C (=NR ^c)-NHR ^a,-NR ^d-C (=NR ^c)-N (R ^aR ^b) ,-NHNH ₂,-NHNHR ^a,-NHR ^aR ^b,-SO ₂NH ₂,-SO ₂NHR _a,-SO ₂NR ^aR ^b,-CH=CHR ^a,-CH=CR ^aR ^b,-CR ^c=CR ^aR ^b, CR ^c=CHR ^a,-CR ^c=CR ^aR ^b,-CCR ^a,-SH ,-SO _kR ^a(k is 0,1 or 2) ,-S (O) _kOR ^a(K is 0,1 or 2) and-NH-C (=NH)-NH ₂R ^a-R ^dBe aliphatic independently of one another, replacement aliphatic, benzyl, the benzyl of replacement, group, preferred alkyl, benzyl or the aromatic yl group of fragrance fragrance or that replace.In addition ,-NR ^aR ^bAlso can form together and replace or unsubstituted nonaromatic heterocycles group.Nonaromatic heterocycles group, benzyl group or aromatic yl group also can have the aliphatic group of aliphatic or replacement as substituting group.The aliphatic group that replaces can also have nonaromatic heterocycles, the nonaromatic heterocycles of replacement, and benzyl, the benzyl of replacement, the aromatic yl group of aryl or replacement is as substituting group.The aliphatic group that replaces, the nonaromatic heterocycles group, the aryl of replacement, or the benzyl group that replaces can have the substituting group more than.

The substituting group of the present invention anticipation and the combination of variable only are to cause forming those of stable compound.As used herein, term " is stablized " and is referred to those compounds, and described compound has is enough to allow the stability of producing, and keeps the purpose of integrity to be used for describing in detail of compound in the sufficiently long time herein.

The group that can provide hydrogen bond is functional group (for example ,-the OH ,-NH that contains the hydrogen atom of part positive charge ₂,-SH) or a kind of metabolism form the group (for example, ester) that can provide hydrogen bond group.

As used herein, " solubilizing group " is a part, compares with the similar compound that does not comprise this group, and described fragment has the water miscible wetting ability that is enough to improve or increase its place compound.Wetting ability can realize with any method, for example by be included in the functional group that ionization under the working conditions forms electrically charged part (for example, carboxylic acid, sulfonic acid, phosphoric acid, amine, etc.); The group (for example, quaternary ammonium group) that comprises lasting electric charge; And/or heteroatoms or heteroatom group (for example, O, S, N, NH, N-(CH ₂) _y-R ^a, N-(CH ₂) _y-C (O) R ^a, N-(CH ₂) _y-C (O) OR ^a, N-(CH ₂) _y-S (O) ₂R ^a-, N-(CH ₂) _y-S (O) ₂OR ^a, N-(CH ₂) _y-C (O) NR ^aR ^a, etc., R wherein ^aBe selected from hydrogen, low alkyl group, low-grade cycloalkyl, (C6-C14) aryl, phenyl, naphthyl, (C7-C20) arylalkyl and benzyl, wherein R ^aSelectively replace; With y be 0 to 6 integer), selectively the heterocyclic group of Qu Daiing (for example-(CH ₂) _n-R ^b,-(CH ₂) _n-C (O)-R ^b,-(CH ₂) _n-O-(CH ₂) _n-R ^b, R wherein ^bBe selected from selectively the saturated monocyclic heterocycles that replaces, the saturated bicyclic annelated heterocycles of Qu Daiing selectively, the saturated bicyclic Spirocyclic heterocyclic of Qu Daiing selectively, the selectively heteroaryl of Qu Daiing and the selectively non--aryl-heterocyclic of the fractional saturation of replacement; With n be 0 to 2 integer).It should be understood that with the unsubstituted counterpart in this range of definition and compare, be present in R ^aOr R ^bOn substituting group needn't improve or increase that it is water-soluble.Necessary is that these substituting groups can not reverse unsubstituted R significantly ^aOr R ^bThe water miscible improvement that part is provided.

In one embodiment, solubilizing group will lack at least 5 times of the water-soluble increases of solubilizing group compound, preferably at least 10 times, more preferably at least 20 times and most preferably at least 50 times accordingly.

In a preferred embodiment, solubilizing group is the part of following formula:

-(CH ₂) _n-R ¹⁰⁰-N (R ¹⁰¹) (R ¹⁰¹), wherein:

N is selected from 0,1 or 2;

R ¹⁰⁰Be selected from key ,-C (O)-, or-O (CH ₂) _nWith

Each R ¹⁰¹Be independently selected from:

A. hydrogen;

B.C ₁-C ₄Straight or branched alkyl, wherein said alkyl are selectively by halogen, CN, OH, O-(C ₁-C ₄The straight or branched alkyl), N (R ₁') (R ₁'), or=O replaces;

F. whole R ¹⁰¹Part forms the ring of following structure with the nitrogen-atoms of their institute's bonding

G. whole R ¹⁰¹Part forms 5 yuan of heteroaryl rings that contain 1 to 3 additional nitrogen atom with their nitrogen-atoms of institute's bonding, and wherein said heteroaryl ring is selectively by R ₁' replace:

Wherein:

Each Z is selected from-O-,-S-,-NR ₁', or-C (R ⁵⁰) (R ⁵⁰)-, be wherein:

Z ₂₀, Z ₂₁, Z ₂₂, and Z ₂₃In at least three be-C (R ⁵⁰) (R ⁵⁰)-;

Z ₂₄, Z ₂₅, Z ₂₆, Z ₂₇, and Z ₂₈In at least three be-C (R ⁵⁰) (R ⁵⁰)-;

Z ₃₀, Z ₃₁, Z ₃₂, and Z ₃₃In at least four be-C (R ⁵⁰) (R ⁵⁰)-; With

Z ₃₄, Z ₃₅, Z ₃₆, Z ₃₇, and Z ₃₈In at least four be-C (R ⁵⁰) (R ⁵⁰)-;

Each R ₁' be to be selected from hydrogen or C independently ₁-C ₃The straight or branched alkyl, described alkyl is selectively replaced by one or more substituting group, and described substituting group is independently selected from halogen ,-CN ,-OH ,-OCH ₃,-NH ₂,-NH (CH ₃) ,-N (CH ₃) ₂, or=O;

Each R ⁵⁰Be to be selected from R independently ₁', halogen, CN, OH, O-(C ₁-C ₄The straight or branched alkyl), N (R ₁') (R ₁') ,=CR ₁', SR ₁' ,=NR ₁' ,=NOR ₁', or=O;

Any two suitable acyclic R ⁵⁰Selectively each other directly or via C ₁To C ₂Alkylidene group, alkenylene or alkylene two bases (alkanediylidene) bridged bond close, and form the condensed ring or the volution of dicyclo; With

Any

Ring structure is selectively benzo-fused or condenses the formation dicyclo with bicyclic heteroaryl.

For clarity sake, term " C ₁To C ₂Alkylidene group, alkenylene or alkylene two bases (alkanediylidene) bridge " refer to these multivalence structure :-CH ₂-,-CH ₂-CH ₂-,-CH=,=CH-,-CH=CH-, or=CH-CH=.Two of bonding R each other selectively ⁵⁰Part can be on the same carbon atom or on the different carbon atoms.The former forms the spiral shell dicyclo, and the latter forms condensed-bicyclic.It will be apparent to those skilled in the art that as two R ⁵⁰When bonding forms ring each other (no matter directly or by a described bridge), at each R ⁵⁰On one or more terminal hydrogen atom will lose.Therefore, be fit to form " the suitable acyclic R of ring ⁵⁰" be those acyclic R that comprise at least one terminal hydrogen atom partly ⁵⁰

In another preferred embodiment, solubilizing group is the following formula part :-(CH ₂) _n-O-R ¹⁰¹, wherein n and R ¹⁰¹As defined above.

In another preferred embodiment, solubilizing group is the following formula part :-(CH ₂) _n-C (O)-R ₁', wherein n and R ₁' as defined above.

In a preferred embodiment, solubilizing group is selected from-(CH ₂) _n-R ¹⁰², wherein n is 0,1 or 2; And R ¹⁰²Be selected from

R wherein ₁' as defined above.

In a preferred embodiment; solubilizing group is selected from 2-dimethyl aminoethyl formamyl; piperazine-1-base carbonyl, piperazinyl methyl, dimethylaminomethyl; 4-methylpiperazine-1-ylmethyl; 4-amino piperidine-1-base-methyl, 4-fluorine piperidines-1-base-methyl, morpholino methyl; tetramethyleneimine-1-ylmethyl; 2-oxo-4-benzyl diethylenediamine-1-ylmethyl, 4-benzyl diethylenediamine-1-ylmethyl, 3-oxo piperazine-1-ylmethyl; piperidines-1-ylmethyl; piperazine-1-base ethyl, 2,3-dioxo propyl group amino methyl; thiazolidine-3-ylmethyl; 4-ethanoyl piperazine-1-ylmethyl, 4-ethanoyl piperazine-1-base, morpholino; 3; 3-difluoro azete is stung-the 1-ylmethyl, 2H-tetrazolium-5-ylmethyl, thiomorpholine-4-ylmethyl; 1-oxo thiomorpholine-4-ylmethyl; 1,1-dioxo thiomorpholine-4-ylmethyl, 1H-imidazoles-1-ylmethyl; 3; 5-lupetazin-1 ylmethyl, 4-hydroxy piperidine-1-ylmethyl, N-methyl (1-ethanoyl piperidin-4-yl)-amino methyl; N-methyl quinuclidine ring-3-base amino methyl; 1H-1,2,4-triazol-1-yl methyl; 1-methyl piperidine-3-base-oxygen methyl, or 4-fluorine piperidines-1-base.

Degree all not to be covered to above-mentioned arbitrary definition, term " solubilizing group " also comprises, be disclosed and 1-cyclopropyl-6-fluoro-1,7 continuous parts of 4--dihydro-4-Oxoquinoline-3-formic acid (Ciprofloxacin) and derivative thereof are disclosed in the open WO 2005026165 of PCT, WO 2005049602, with WO 2005033108 and the open EP 0343524 of European patent, EP 0688772, EP 0153163, among the EP 0159174; " water solubilizing group " is described among the U.S. Patent Publication US 2006/0035891.Disclosure in these patent disclosures all is incorporated herein by reference.

With structure

The expression two keys mean comprise all (E)-with (Z)-configuration.Preferably, two keys are (E)-configurations.

Sugar is the aldehydes or ketones derivative of straight chain polyhydroxy-alcohol, and it contains at least three carbon atoms.Sugar can linear molecule form exist, or preferably, have (for example, the form of pyranose or furanose) with the form of ring molecule.Preferably, sugar is monose, for example glucose or glucuronic acid.Those for example expect to prolong in the embodiment that retains with sugared derived compounds in the present invention, and sugar is the sugar of non-natural existence preferably.For example, one or more hydroxyls are replaced by another group such as halogen (for example chlorine).Compare with naturally occurring sugar, the three-dimensional chemical configuration of one or more carbon atoms also can be changed.An example of the sugar that suitable non-natural exists is Sucralose (sucralose).

Lipid acid is the carboxylic acid with long chain hydrocarbon part.Usually, lipid acid has the even carbon atom, and scope is from 12 to 24, often is from 14 to 20.Lipid acid can be saturated or unsaturated and replacement or unsubstituted, but generally is unsubstituted.Lipid acid can be naturally occurring or the form of non-natural existence.Prolong in the embodiment of retention time at the compound that those for example expect to contain fatty acid part of the present invention, lipid acid preferably non-natural exists.The carboxyl groups of lipid acid is made up of the carbonyl moiety of hydrocarbon part and carboxylic acid functional, but do not comprise link to each other with carboxylic acid functional-the OH part.

Comprise also among the present invention that sirtuin described herein regulates the salt, particularly pharmacy acceptable salt of compound.Have enough acidity, enough alkalescence or the The compounds of this invention of the two functional group that all has can form salt with any reaction in many mineral alkalis and inorganic and the organic acid.Alternatively, have the compound of intrinsic charge, for example contain the compound of quaternary nitrogen, can form salt with suitable counter ion (for example, halogenide such as bromide, muriate or fluorochemical, particularly bromide).

The acid that is commonly used to form acid salt be mineral acid for example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid etc. and organic acid for example tosic acid, methylsulfonic acid, oxalic acid, to bromo-benzene sulfonic acid, carbonic acid, succsinic acid, citric acid, phenylformic acid, acetic acid etc.The example of these salt comprises vitriol, pyrosulphate, hydrosulfate, sulphite, hydrosulphite, phosphoric acid salt, one hydrogen orthophosphate, dihydrogen orthophosphate, metaphosphate, pyrophosphate salt, muriate, bromide, iodide, acetate, propionic salt, caprate, octylate, acrylate, formate, isobutyrate, hexanoate, enanthate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1, the 4-diformate, hexin-1, the 4-diformate, benzoate, chloro benzoate, tolyl acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulfonate, xylenesulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, Citrate trianion, lactic acid salt, gamma hydroxybutyrate, the glycol hydrochlorate, tartrate, mesylate, propanesulfonic acid salt, how-1-sulfonate, how-2-sulfonate, mandelate or the like.

Base addition salt comprises those salt of deriving and obtaining from mineral alkali, the oxyhydroxide of ammonium or basic metal or alkaline-earth metal for example, carbonate, supercarbonate etc.Can be used for preparing such alkali of salt of the present invention thereby comprise sodium hydroxide, potassium hydroxide, ammonium hydroxide, salt of wormwood or the like.

According to another embodiment, the invention provides the method for the sirtuin-adjusting compound of the above definition of preparation.These compounds can use routine techniques synthetic.Advantageously, these compounds are to obtain from the raw material of easy acquisition is synthetic easily.

Therefore, an embodiment relates to the method for preparing structural compounds described herein, uses following synthetic schemes:

One skilled in the art will realize that this synthetic schemes, or similarly change, usefully allow a large amount of R groups are introduced in the compounds and compound still falls into scope of the present invention, for example, the compound in the following form.

As it may occur to persons skilled in the art that, above synthetic schemes be not intended to comprise can be used for described in synthetic the application with claim in the comprehensive tabulation of all synthetic methods of claimed compounds.Further method is clearly for those of ordinary skills.In addition, above-mentioned various synthesis step can obtain desired compounds with tradable order or order.The synthetic chemistry transformation and the method that can be used for sirtuin adjusting compound synthetic described herein are known in the art, comprise, for example, are described in R.Larock, Comprehensive Organic Transformations (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 2d.Ed. (1991); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis (1994); And L.Paquette, ed., the method among the Encyclopedia of Reagents for Organic Synthesis (1995).

In an exemplary embodiment, sirtuin regulates the cytoplasmic membrane that compound can pass cell.For example, compound can have the cell permeability at least about 20%, 50%, 75%, 80%, 90% or 95%.

Sirtuin described herein regulates compound also can have one or more following characteristics: compound pair cell or object can be nontoxic basically; It can be organic molecule or 2000amu or littler, 1000amu or littler small molecules that sirtuin regulates compound; Compound can have the transformation period at least about 30 days, 60 days, 120 days, 6 months or 1 year under standard atmosphere conditions; Compound can have the transformation period at least about 30 days, 60 days, 120 days, 6 months or 1 year in solution; Sirtuin regulates compound can be more stable at least about 50%, 2 times, 5 times, 10 times, 30 times, 50 times or 100 times than trans-resveratrol in solution; Sirtuin regulates compound can promote that DNA reparative factor Ku70's is deacetylated; Sirtuin regulates compound can promote that RelA/p65's is deacetylated; Compound can increase general reversion rate and strengthen cell to the apoptotic susceptibility of TNF inductive.

In certain embodiments, (for example effectively regulating under the active concentration of sirtuin deacetylase, in vivo), sirtuin adjusting compound does not have the ability of inhibition I class histone deacetylase (HDACs), II class HDAC or I and the II class HDACs of any essence.For example, in preferred embodiments, it is the sirtuin activating compounds that sirtin regulates compound, and selects the active EC of its activation sirtuin deacetylase ₅₀Less than the EC that suppresses HDAC I and/or HDAC II ₅₀At least 5 times, even more preferably at least 10 times, 100 times or even 1000 times.It is well known in the art measuring HDAC I and/or the active method of HDAC II, implements the test kit of this mensuration and can commercially buy.Referring to for example, BioVision, Inc. (Mountain View, CA; World wide web at biovision.com) and Thomas Scientific (Swedesboro, NJ; World wide web at tomassci.com).

In certain embodiments, sirtuin adjusting compound does not have the ability of the adjusting sirtuin homologue of any essence.In one embodiment, under the effective active concentration of activation people's sirtuin deacetylase (for example, in vivo), the activation that the agent of people sirtuin protein activation does not have any essence derives from lower eukaryotes, particularly the proteic ability of the sirtuin of yeast or human pathogen.For example, can select sirtuin activating compounds activation people sirtuin, for example SIRT1 and/or the active EC of SIRT3 deacetylase ₅₀Less than activation yeast sirtuin, for example EC of Sir2 (for example mycocandida, S. beer genus etc.) ₅₀At least 5 times, even more preferably at least 10 times, 100 times or even 1000 times.In another embodiment, under the concentration of the sirtuin deacetylase protein enzymic activity that effectively suppresses to derive from lower eukaryotes (for example, in vivo), derive from lower eukaryotes, particularly the inhibition that do not have any essence of the proteic inhibitor of the sirtuin of yeast or human pathogen derives from people's the proteic ability of sirtuin.For example, can select sirtuin to suppress compound and suppress people sirtuin, for example SIRT1 and/or the active IC of SIRT3 deacetylase ₅₀Less than suppressing yeast sirtuin, for example IC of Sir2 (for example mycocandida, S. beer genus etc.) ₅₀At least 5 times, even more preferably at least 10 times, 100 times or even 1000 times.

In certain embodiments, sirtuin regulates compound can have one or more sirtuin albumen homologues of adjusting, for example, and the ability of one or more of people SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 or SIRT7.In one embodiment, sirtuin adjusting compound has the SIRT1 of adjusting and the proteinic ability of SIRT3.

In other embodiments, under the effective active concentration of mediator SIRT1 deacetylase (for example, in vivo), the SIRT1 conditioning agent does not have other sirtuin albumen homologues of adjusting of any essence, for example, the ability of one or more of people SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 or SIRT7.For example, can select sirtuin to regulate the active ED of compound mediator's SIRT1 deacetylase ₅₀One or more ED less than mediator SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 or SIRT7 ₅₀At least 5 times, even more preferably at least 10 times, 100 times or even 1000 times.In one embodiment, the SIRT1 conditioning agent does not have the proteinic ability of adjusting SIRT3 of any essence.

In other embodiments, under the effective active concentration of mediator SIRT3 deacetylase (for example, in vivo), the SIRT3 conditioning agent does not have other sirtuin albumen homologues of adjusting of any essence, for example, the ability of one or more of people SIRT1, SIRT2, SIRT4, SIRT5, SIRT6 or SIRT7.For example, can select sirtuin to regulate the active ED of compound mediator's SIRT3 deacetylase ₅₀One or more ED less than mediator SIRT1, SIRT2, SIRT4, SIRT5, SIRT6 or SIRT7 ₅₀At least 5 times, even more preferably at least 10 times, 100 times or even 1000 times.In one embodiment, the SIRT3 conditioning agent does not have the proteinic ability of adjusting SIRT1 of any essence.

In certain embodiments, sirtuin adjusting compound can have sirtuin proteic about 10 ^-9M, 10 ^-10M, 10 ^-11M, 10 ^-12M or binding affinity still less.Sirtuin regulate compound can reduce (activator) or increase (inhibitor) sirtuin albumen to the apparent Km of its substrate or NAD+ (or other cofactors) at least about 2,3,4,5,10,20,30,50 or 100 times.In certain embodiments, the Km value can use mass spectrometry described herein to measure.Under similar concentration, preferred activating compounds than trans-resveratrol reduce sirtuin to the Km of its substrate or cofactor to bigger degree, or it is similar to trans-resveratrol to the Km of its substrate or cofactor to reduce sirtuin under lower concentration.Sirtin regulates compound can increase the proteic Vmax of sirtuin at least about 2,3,4,5,10,20,30,50 or 100 times.Sirtuin regulates compound adjusting SIRT1 and/or the active ED50 of the proteinic deacetylase of SIRT3 can be less than about 1nM, less than about 10nM, less than about 100nM or about 1-10nM, about 10-100nM, about 0.1-1 μ M, about 1-10 μ M or about 10-100 μ M.As what measure in cell analysis or the analysis based on cell, sirtuin regulates compound can regulate SIRT1 and/or the proteinic deacetylase activity of SIRT3 at least about 5,10,20,30,50 or 100 times.With respect to the identical concentration of trans-resveratrol, the sirtun activating compounds can cause inducing at least about the sirtuin deacetylase protein enzymic activity of 10%, 30%, 50%, 80%, 2 times, 5 times, 10 times, 50 times or 100 times bigger.The ED of the adjusting SIRT5 that sirtuin adjusting compound has ₅₀Than the ED that regulates SIRT1 and/or SIRT3 ₅₀Greatly at least about 10 times, 20 times, 30 times, 50 times.

3. exemplary application

In some aspects, the invention provides the adjusting proteic level of sirtuin and/or active method and using method thereof.

In certain embodiments, the invention provides the method for using sirtuin to regulate compound, wherein sirtuin regulates compound activating sirtuin albumen, for example, increases proteic level of sirtuin and/or activity.Increasing proteic level of sirtuin and/or active sirtuin adjusting compound is useful to many treatments application, for example comprise, increase the life-span of cell and treat and/or prevent many kinds of diseases and obstacle, for example comprise, with old and feeble or stress diseases associated or obstacle, diabetes, obesity, neurodegenerative disease, cardiovascular disorder, blood coagulation disorders, inflammation, cancer and/or flush etc.This method comprise the object that needs pharmaceutically the sirtuin of significant quantity regulate compound, for example, the sirtuin activating compounds.

In other embodiments, the invention provides the method for using sirtuin to regulate compound, wherein sirtuin regulates the activity that compound reduces sirtuin, for example, reduces proteic level of sirtuin and/or activity.Reducing proteic level of sirtuin and/or active sirtuin adjusting compound is useful to many treatments application, for example comprise, increase to stress cellular sensitivity (comprise and increase radiosensitivity and/or chemosensitivity), increase apoptotic quantity and/or ratio, treatment for cancer (optional with other chemotherapeutics combinations), stimulate appetite and/or stimulate weight increase etc.This method comprise the object that needs pharmaceutically the sirtuin of significant quantity regulate compound, for example, sirtuin suppresses compound.

The applicant is reluctant to be bound by theory, and thinks that activator of the present invention and inhibitor can interact with sirtuin the same position in the sirtuin albumen (for example, avtive spot or influence the site of avtive spot Km or Vmax).This is considered to the sirtuin activator of some kind and the reason that inhibitor can have the structural similarity of essence.

In certain embodiments, sirtuin adjusting compound described herein can be used in combination separately or with other compounds.In one embodiment, two or more sirtuin regulate the object that the mixture of compounds can need.In another embodiment, one or more that increase that proteic level of sirtuin and/or active sirtuin regulate that compound can be in following compounds give: trans-resveratrol, butein, Zante Fustic, piceatannol or Quercetin.In an exemplary embodiment, increasing proteic level of sirtuin and/or active sirtuin adjusting compound can give with the nicotinic acid combination.In another embodiment, one or more that reduce that proteic level of sirtuin and/or active sirtuin regulate that compound can be in following compounds give: niacinamide (NAM), suranim; NF023 (G protein antagonist); NF279 (purinergic receptor antagonists); Trolox (6-hydroxyl-2,5,7,8, tetramethyl-chromanane-2-carbonyl acid); (-)-l-Epicatechol (3,5,7,3 ', 4 ', 5 ' position hydroxyl); (-)-epicatechin gallate (5,7,3 ', 4 ', 5 ' position hydroxyl and 3 gallic acid esters); The Cyanidin muriate (3,5,7,3 ', 4 '-the penta hydroxy group Huang

The salt muriate); The delphisine muriate (3,5,7,3 ', 4 ', 5 '-the hexahydroxy-Huang

The salt muriate); Myricetin (hemp flavones; 3,5,7,3 ', 4 ', 5 '-quercetagetin); 3,7,3 ', 4 ', 5 '-pentahydroxyflavone; Gossypetin (3,5,7,8,3 ', 4 '-quercetagetin); Sirtinol; And splitomicin (referring to for example, Howitz etc., (2003) Nature 425:191; Grozinger etc., (2001) J.Bio1.Chem.276:38837; Dedalov etc., (2001) PNAS 98:15113; With Hirao etc., (2003) J.Biol.Chem 278:52773).In another embodiment, one or more sirtuin regulate compound and can give with the medicine of one or more treatments or prevention various diseases, described disease for example comprises, cancer, diabetes, neurodegenerative disease, cardiovascular disorder, blood coagulation, inflammation, flush, obesity, aging, stress wait.In various embodiments, comprise the treatment of sirtuin adjusting combination of compounds and may be meant that (1) comprises the pharmaceutical composition that one or more sirtuin regulate compounds and one or more medicines (for example, one or more medicines described herein) combination; (2) one or more sirtuin regulate compound and one or more medicine Combined Preparation, wherein sirtuin adjusting compound and medicine are not formulated in the same composition and (still may be present in same test kit or the packing, for example blister pack (blister pack) or other multicells packing; The user can isolating connection, the container (for example, metallic foil bag (foil pouches)) of sealing separately; Perhaps sirtuin adjusting compound and other treatment medicine are in the test kit in the separation vessel).When use separating preparation, sirtuin regulate compound can with another kind of medicine simultaneously, at interval, intersects, formerly, subsequently or make up and give.

In certain embodiments, the method for using sirtuin to regulate compound reduction, prevention or treatment disease or obstacle can also comprise the protein level that increases sirtuin such as people SIRT1, SITR2 and/or SIRT3 or its homologue.Increasing protein level can be by realizing in a of the sirtuin that will encode or many parts of nucleic acid introducing cells.For example, the increase of sirtuin level can realize by the nucleic acid introducing mammalian cell of the sirtuin that will encode in the mammalian cell, for example, increase the SIRT3 level by the nucleic acid increase SIRT1 level of introducing the described aminoacid sequence of coding GenBank accession number NP_036370 and/or the nucleic acid that passes through the aminoacid sequence of introducing coding GenBank accession number AAH01042.Nucleic acid can be under the control of the promotor of regulating SIRT1 and/or SIRT3 expression of nucleic acid.Alternatively, nucleic acid can be introduced in the cell that is in promotor downstream position in the genome.The method of using these methods to increase protein level is well known in the art.

The nucleic acid codified of introducing cell increase sirtuin protein level and sirtuin sequence are at least about 80%, 85%, 90%, 95%, 98% or 99% homologous protein, for example, SIRT1 (GenBank accession number NP_036370) and/or SIRT3 (GenBank accession number AAH01042) protein.For example, the nucleic acid of coded protein can be at least about 80%, 85%, 90%, 95%, 98% or 99% with (for example coming from coding SIRT1, GenBank accession number NM_012238) and/or the proteinic nucleic acid of SIRT3 (for example, GenBank accession number BC001042).Nucleic acid also may preferably be in the nucleic acid of hybridizing under the stringent hybridization condition to encoding wild type sirtuin such as SIRT1 (for example, GenBank accession number NM_012238) and/or the proteinic nucleic acid of SIRT3 (for example, GenBank accession number BC001042).The washing of hybridization and 0.2x SSC under stringent hybridization condition can comprise 65 ℃.When using coding to be different from the pulsating proteinic nucleic acid of the proteic protein of wild-type sirtuin such as wild-type sirtuin albumen, protein is preferably bioactive, for example, and can be deacetylated.Unique needs be a part of in cell, expressing bioactive sirtuin.For example, be different from the protein of the wild-type SIRT1 of GenBank accession number NP_036370, preferably comprise its core texture.Core texture refers to the amino acid 62-293 of GenBank accession number NP_036370 sometimes, and it comprises that by the Nucleotide 237-932 coding of GenBank accession number NM_012238 NAD combination and substrate are in conjunction with the territory.The core domain of SIRT1 also can be meant about amino acid 261-447 of GenBank accession number NP_036370, it is by the Nucleotide 834-1394 coding of GenBank accession number NM_012238, be meant about amino acid 242-493 of GenBank accession number NP_036370, it is by the Nucleotide 777-1532 coding of GenBank accession number NM_012238, or referring to the amino acid 254-495 of GenBank accession number NP_036370, it is by Nucleotide 813-1538 coding of GenBank accession number NM_012238.Whether protein keeps biological function, and for example deacetylated ability can be determined according to methods known in the art.

In certain embodiments, the method for using sirtuin to regulate compound reduction, prevention or treatment disease or obstacle can also comprise the protein level that reduces sirtuin such as people SIRT1, SITR2 and/or SIRT3 or its homologue.Reducing the sirtuin protein level can realize according to methods known in the art.For example, target can be expressed in cell in siRNA, antisense nucleic acid or the ribozyme of sirtuin.Also can use dominance negative sirtuin mutant, for example mutant that can not be deacetylated.For example can use and be described in Luo etc., the H363Y mutant of the SIRT1 of (2001) Cell 107:137.Alternatively, the medicine that can use inhibition to transcribe.

The method of regulating the sirtuin protein level also comprises method and other methods known in the art of stabilization/stabilization removal of the method for the genetic transcription of regulating coding sirtuin, corresponding mRNAs.

Old and feeble/stress

In one embodiment, the invention provides by with cell with increase sirtuin protein level and/or active sirtuin of the present invention regulate compound contact prolong cell survival, prolong ability of cell proliferation, delay cell wear out, promote cell survival, delay in the cell cell aging, simulation heat restriction, increase cell to stress tolerance or prevent apoptotic method.In an exemplary embodiment, described method comprises cell is contacted with the sirtuin activating compounds.

Method described herein can be used to increase cell, particularly primary cell (for example, the cell that obtains from for example people's organism) and keep the amount of survival time cell cultures.The embryo does (ES) cell and multipotential cell and also can use from the cell of its differentiation to be increased sirtuin protein level and/or active sirtuin and regulates compound treatment and come to preserve cell or longer time of its filial generation culture.This cell also can be used for transplanting to object, for example, and after modifying in the body of formerly external back.

In one embodiment, the cell of expection prolonged preservation can use increases sirtuin protein level and/or active sirtuin adjusting compound treatment.Cell can be in suspension (for example, hemocyte, serum, biological growth medium etc.) or tissue or organ.For example, the blood of collecting from individuality for the purpose of blood transfusion can use increase sirtuin protein level and/or active sirtuin to regulate compound treatment and preserve the longer time of hemocyte.Additionally, the blood that is used for legal medical expert's purpose also can use increase sirtuin protein level and/or active sirtuin to regulate compound treatment.Other can avoid apoptotic cell with prolongs life or protection through processing and comprise the cell that is used to consume, and for example, come from inhuman mammiferous cell (for example meat) or vegetable cell (for example vegetables).

Increase sirtuin protein level and/or active sirtuin adjusting compound and also can be applied in the growth and process of growth of Mammals, plant, insect or microorganism, so that for example, change, delay or accelerated development and/or process of growth.

In another embodiment, increasing sirtuin protein level and/or active sirtuin regulates compound and also can be used to handle and be used to transplant or the cell of cell therapy, comprise, for example, solid tissue's transplanting, organ transplantation, cell suspension, stem cell, medullary cell etc.Cell or tissue can be that autotransplantation, heteroplastic transplantation, isotransplantation or culture transferring are transplanted.Using sirtuin to regulate the compound treatment cell or tissue can be before object administration/implantation, in administration/implantation and/or after administration/implantation.Cell or tissue can remove preceding from the donor individuality or cell or tissue removes from the donor individuality in earlier external back, the back body that exsomatizes or after implanting acceptor and handles.For example, donor or acceptor individuality can use sirtuin to regulate the hypotype that compound treatment maybe can have the cell/tissue that uses increase sirtuin protein level and/or active sirtuin adjusting compound treatment partly capapie.In certain embodiments, cell or tissue (or donor or acceptor individuality) can additionally use the another kind of medicine processing that is used to prolong transplanting survival, described another kind of medicine for example is immunosuppressor, cytokine, angiogenesis factor etc.

In other embodiments, cell can use increases sirtuin protein level and/or active sirtuin adjusting compound treatment in vivo, for example increases its life-span or prevention apoptosis.For example, by using increase sirtuin protein level and/or active sirtuin adjusting compound treatment skin or epidermic cell to protect skin to avoid aging (for example, producing wrinkle, forfeiture elasticity etc.).In an exemplary embodiment, skin contacts with the medicine or the cosmetic composition that contain increase sirtuin protein level and/or active sirtuin adjusting compound.The exemplary skin worry that can handle according to method described herein or skin conditions comprises relevant with inflammation, sun damage or naturally-aged or by its obstacle that causes or disease.For example, composition is used for prevention or treats damage, discoid lupus erythematosus, dermatomyositis, psoriatic, skin carcinoma and the naturally-aged effect that contact dermatitis (comprising irritant contact dermatitis and allergic contact dermatitis), atopic dermatitis (also being known as allergic eczema), actinic keratosis, keratinization obstacle (comprising eczema), epidermolysis bullosa (comprising penfigus), exfoliative dermatitis, seborrheic dermatitis, erythema (comprising erythema multiforme and erythema nodosum), daylight or other light sources cause.In another embodiment, increase sirtuin protein level and/or active sirtuin and regulate that compound can be used for the treatment of wound and/or burn promotes healing, comprise, for example, once, two degree or third degree burn and/or heat, chemistry or electric injury.As further described herein, under the effective dosage regimen background that produces desired effects, preparation can be with topical administration skin or mucosal tissues such as ointment, lotion, emulsifiable paste, microemulsion, gel, solution.

Comprising one or more topical formulations that increase sirtuin protein level and/or active sirtuin adjusting compound also can be as for example prophylactic compositions of chemoprophylaxis.When in the chemoprophylaxis method, using, in special individuality at the easily infected skin of any visible patient's condition pre-treatment.

Sirtuin regulate compound can the part or general be delivered to object.In one embodiment, sirtuin regulates compound is delivered to object partly by injection, topical formulations etc. tissue or organ.

In another embodiment, increase that sirtuin protein level and/or active sirtuin regulate that compound can be used for the treatment of or object of prevention in the cell aging disease or the patient's condition of inducing or aggravating; Reduce the method for the old and feeble rate of object, for example, after aging begins; Prolong the method for object lifetime; The disease that treatment or prevention are relevant with the life-span or the method for the patient's condition; Treatment or prevention relate to the disease of ability of cell proliferation or the method for the patient's condition; With treatment or prevention cell injury or the dead disease that causes or the method for the patient's condition.In certain embodiments, this method does not work by reducing the disease incidence rate that shortens object lifetime.In certain embodiments, this method not by reduce disease for example the lethality rate that causes of cancer work.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound can give object usually increases its cell survival and protects its cell to anti-stress and/or to anti-apoptotic.The applicant believes that using compounds for treating object described herein stress be similar to making object experience hormesis as being of value to organic gentleness, and can prolong its life-span.

Increase sirtuin protein level and/or active sirtuin adjusting compound and can give object pre-anti-aging and old and feeble relevant result or disease, for example apoplexy, heart trouble, heart failure, sacroiliitis, hypertension and Alzheimer's.Other treatable patient's condition for example comprise, with the aging relevant eye obstacle of eyes, for example, cataract, glaucoma and macular degeneration.Increase sirtuin protein level and/or active sirtuin adjusting compound also can give for example relevant with the necrocytosis diseases such as chronic disease of object treatment and protect cell to avoid necrocytosis.Exemplary disease comprises and neutrophil cell dead relevant disease, neuron dysfunction or myocyte's death or dysfunction, for example Parkinson's disease, Alzheimer's, multiple sclerosis, amniotropic lateral sclerosis and muscular dystrophy; AIDS; Fulminant hepatitis; With the relevant disease of brain degeneration, for example Ke-Ya Shi disease, retinitis pigmentosa and cerebellar degeneration; Myelodysplasia is aplastic anemia for example; Ischemic disease is myocardial infarction and apoplexy for example; Hepatopathy is alcoholic liver, hepatitis B and hepatitis C for example; Joint disease is osteoarthritis for example; Atherosclerosis; Alopecia; The skin loss that ultraviolet ray causes; Lichen planus; Skin atrophy; Cataract and transplant rejection.Necrocytosis can be caused by operation, pharmacological agent, chemistry contact or radiation contact.

Increase sirtuin protein level and/or active sirtuin and regulate the object that compound also can suffer from the damage of acute illness such as organ or tissue, for example, suffer from the object of apoplexy or myocardial infarction or suffer from the object of Spinal injury.Increase sirtuin protein level and/or active sirtuin adjusting compound and also can be used to repair alcoholic liver.

Cardiovascular disorder

In another embodiment, object increase sirtuin protein level and/or the active sirtuin that the invention provides by needing regulates the method that compound treats and/or prevents cardiovascular disorder.

The cardiovascular disorder of using increase sirtuin protein level and/or active sirtuin adjusting compound to treat or to prevent comprises myocardosis or myocarditis; For example idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced myocardosis, ischemic cardiomyopathy and hypertension myocardosis.What use that Compounds and methods for described herein also can treat or prevent is the artery congee sample obstacle of main blood vessel (great vessels disease) as Aorta, coronary artery, carotid artery, cerebral arteries, the Renal artery, iliac artery, femoral artery He popliteal artery.Other vascular disease that can treat or prevent comprise with platelet aggregation, retina arteriole, glomerulus arteriole, vasa nervorum, heart arteriole, eye follows capillary bed, kidney, heart and the maincenter disease relevant with peripheral nervous system.Increase sirtuin protein level and/or active sirtuin and regulate the HDL level that compound also can be used for increasing individual blood plasma.

Use increase sirtuin protein level and/or active sirtuin to regulate treatable other obstacles of compound and comprise for example crown intervention back restenosis, with the obstacle relevant with the low density cholesterol horizontal abnormality with high-density.

In one embodiment, increasing sirtuin protein level and/or active sirtuin regulates the part that compound can be used as with other cardiovascular agent combined therapies and gives, the other treatment cardiovascular agent comprises, for example, antiarrhythmic drug, antihypertensive drug, calcium channel blocker, the heart stop rich liquid, cardiac tonic, fibrinolytic agent, hardening solution, vasoconstrictor, vasodilator, nitric oxide donors, potassium channel antagonists, sodium channel inhibitor, statins or naturiuretic medicine.

In one embodiment, increasing sirtuin protein level and/or active sirtuin regulates the part that compound can be used as with other anti-arrhythmia drug regimen treatments and gives.Anti-arrhythmia medicine is divided into four main groups according to its mechanism of action usually: I type, sodium-ion channel blocking-up; The II type, the Beta-3 adrenergic blocking-up; The III type, repolarization prolongs; With the IV type, the calcium channel blocking-up.The anti-arrhythmia medicine of I type comprises lignocaine, Moracizine, mexiletine, tocainide, procainamide, encainide, flecainide, tocainide, Phenytoin Sodium Salt, Propafenone, Quinidine, disopyramide and flecainide.The anti-arrhythmia cartridge bag of II type is drawn together Proprasylyte and esmolol.The III type comprises the medicine by the effect of over reach current potential time-histories, for example, amiodarone, artilide, bretylium, the non-ammonium of chlorine, isobutilide, sotalol, Azimilide, P162a, Dronedarone, Ersentilide, ibutilide, tedisamil and trecetilide.The anti-arrhythmia cartridge bag of IV type is drawn together verapamil, diltiazem

(diltaizem), purple foxglove, vidarabine, nickelous chloride and magnesium ion.

In another embodiment, increasing sirtuin protein level and/or active sirtuin regulates the part that compound can be used as with other cardiovascular agent combined therapy and gives.The example of cardiovascular agent comprises vasodilator, for example, and the bent piperazine of hydrazine; Angiotensin-convertion enzyme inhibitor, for example, captopril; Antianginal drug, for example, sorbide nitrate, trinitrin and four pentaerythritol tetranitrates; Antiarrhythmics, for example, Quinidine, procainamide and lignocaine; Potent cardiac glycosides, for example, digoxin and digoxigenin; Calcium antagonist, for example, verapamil and nifedipine; Diuretic(s), for example thiazides and related compound, for example, Hydrex, chlorothiazide, chlorthalidone, hydrochlorothiazide and other diuretic(s), for example, Furosemide and triamterene, and tranquilizer, for example, nitrazepam, flurazepam and diazepam.

Other exemplary cardiovascular agentes comprise; for example; cyclooxygenase-2 inhibitors is acetylsalicylic acid or indomethacin for example; anticoagulant such as clopidogrel; ticlopidine or acetylsalicylic acid; fibrinogen antagonist agent or diuretic(s) be chlorothiazide for example; hydrochlorothiazide; flumethiazide; Hydroflumethiazide; Hydrex; Methyclothiazide; trichlormethiazide; polythiazide or benzthiazide and Ethacrynic Acid tricrynafen; chlorthalidone; Furosemide; musolimine; bumetanide; triamterene; the salt of guanamprazine and spironolactone and these compounds; angiotensin-convertion enzyme inhibitor is captopril for example; zofenopril; fosinopril; enalapril; ceranopril; cilazopril; delapril; pentopril; quinapril; Ramipril; the salt of lisinopril and these compounds; the Angiotensin II antagonist is losartan for example; irbesartan or valsartan; thrombolytic agent is tissue plasminogen activator (tPA) for example; Recomposed tPA; streptokinase; urokinase; uPA; with fennel acidylate Profibrinolysin streptokinase activator complex body (APSAC; Eminase; the Beecham laboratory); or animal sialisterium plasminogen activator, calcium channel blocker is verapamil for example; nifedipine or diltiazem

, the thromboxane receptor antagonist is Ifetroban, prostacyclin analogs or phosphodiesterase inhibitor for example.If with fixed dosage preparation, this combined prod uses The compounds of this invention in above-mentioned dosage range and other pharmaceutical active medicines in the dosage range of its approval.

Also have other exemplary cardiovascular agentes to comprise, for example, vasodilator, for example, bencyclane, CN, citicoline, Cyclelate, Vasociclate (cyclonicate), ebumamonine, phenoxezyl, flunarizine, Ibudilast, ifenprodil, lomerizine, naphlole, nikamate, nosergoline, nimodipine, Papaverine, pentifylline, nofedoline, vincamine, vinpocetine, vichizyl, pentoxifylline, prostacyclin derivatives (for example prostaglandin E1 and prostacyclin I2), blockade of endothelin receptors medicine (for example bosentan), diltiazem

, Nicoril and pannonit.The example of brain-protection drugs comprises free-radical scavengers (for example pressing down Da Lafeng, vitamin-E and vitamins C), glutaminate antagonist, AMPA antagonist, kainate antagonist, nmda antagonist, GABA antagonist, somatomedin, opioid antagonists, phosphoric acid Yelkin TTS precursor, serotonin agonist, Na ⁺/ Ca ²⁺Passage Depressant and K ⁺The channel opener medicine.The example of brain metabolism energizer comprises amantadine, tiapride and γ-An Jidingsuan.The example of anti-coagulant comprises heparin (for example heparin sodium, clarin, dalteparin sodium, reach calciparine, Parnaparin Sodium, Reviparin Sodium and Danaparoid sodium), warfarin, enoxaparin, argatroban, batroxobin and Trisodium Citrate.The example of antiplatelet drug comprises Ticlopidine Hydrochloride, Dipyridamole, Cilostazole, ethyl icosapentate, Sarpogrelatehydrochloride, draws hydrochloric acid

, trapidil, nonsteroidal antiinflammatory agent (for example acetylsalicylic acid), Beraprost Sodium, Iloprost and indobufene.The example of thrombolysis medicine comprises urokinase, tissue-type plasminogen activator (for example alteplase, Tisokinase, Nateplase, pamiteplase, Monteplase and rateplase) and nasaruplase.The example of antihypertensive drug comprises angiotensin converting enzyme inhibitor (captopril for example, alacepril, lisinopril, imidapril, quinapril, temocapril, delapril, benazepril, Yipingshu, Trolapril, enalapril, SQ-29852, fosinopril, imadapril, mobertpril, perindopril, Ramipril, spirapril and Tyrylen), Angiotensin II (losartan for example, Candesartan, valsartan, Eprosartan and irbesartan), calcium channel blocker (Aranidipine for example, efonidipine, nicardipine, bamidipine, benidipine, Manidipine, cilnidipineb, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine, diltiazem

, Bepridil, clentiazem Phenelzine, galopamil, Mibefradil, prenylamine, sesamodil, terodiline, verapamil, cilnidipineb, elgodipine, Isradipine, Lacidipine (62, lercanidipine, nimodipine, CN, flunarizine, lidoflazine, lomerizine, bencyclane, Pagano-Cor and perhexiline), receptor, blocking agent (Proprasylyte, pindolol, indenolol, carteolol, bunitrolol, atenolol USP 23, acebutolol, metoprolol, timolol, nipradolol, penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol, celiprolol, Bopindolol, bevantolol, Trate, alprenolol, amosulalol, Arottnolol, befunolol, bucumolol, bufetolol, buferalol, bupranolol, butylidyne, butofilolol, Carazolol, cetamolol, cloranolol, Sch-19927, epanolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol, nevibolol, oxprenolol, practolol, Pronethalol, sotalol, sufinalol, talinolol, Tertatolol, toliprolol, xybenolol and esmolol), alpha-receptor blocking agent (amosulalol for example, Prazosin, terazosin, Doxazosin, bunazosin, urapidil, phentolamine, Arottnolol, dapiprazole, fenspiride, Indoramine, Trate, naftopidil, Varson, tamsulosin, tolazoline, trimazosin and Yohimbine), sympathetic inhibitor (clonidine for example, guanfacine, guanabenz, methyldopa and serpentine), hydralazine, todralazine, budralazine and cadralazine.The example of anti-anginal drug comprises nitrate medicine (Isopentyl nitrite for example, pannonit and Isosorbide), receptor, blocking agent (Proprasylyte for example, pindolol, indenolol, carteolol, bunitrolol, atenolol USP 23, acebutolol, metoprolol, timolol, nipradolol, penbutolol, nadolol, tilisolol, carvedilol, bisoprolol, betaxolol, celiprolol, Bopindolol, bevantolol, Trate, alprenolol, amosulalol, Arottnolol, befunolol, bucumolol, bufetolol, bufetolol, bupranolol, butylidyne, butofilolol, Carazolol, cetamolol, cloranolol, Sch-19927, epanolol, levobunolol, mepindolol, metipranolol, moprolol, nadoxolol, nevibolol, oxprenolol, practolol, Pronethalol, sotalol, sufinalol, talinolol, Tertatolol, toliprolol, andxybenolol), calcium channel blocker (Aranidipine for example, efonidipine, nicardipine, bamidipine, benidipine, Manidipine, cilnidipineb, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, amlodipine, diltiazem , Bepridil, clentiazem , Phenelzine, galopamil, mibefradil, prenylamine, sesamodil, terodiline, verapamil, cilnidipineb, elgodipine, Isradipine, Lacidipine (62, lercanidipine, nimodipine, CN, flunarizine, lidoflazine, lomerizine, bencyclane, Pagano-Cor and perhexiline) trimetazidine, Dipyridamole, Pagano-Cor, draw , trapidil, Nicoril, according to promise liver and acetylsalicylic acid.The example of diuretic(s) comprises thiazide diuretic (for example hydrochlorothiazide, Methyclothiazide, trichlormethiazide, behyd and Pentylhydroflumethiazide), loop diuretic (for example Furosemide, Ethacrynic Acid, bumetanide, piretanide, azosemide and torasemide), K ⁺Conservative diuretic(s) (spironolactone, triamterene and canrenoate potassium), osmotic pressure diuretic(s) (for example Isosorbide, D-N.F,USP MANNITOL and glycerine), nonthiazide diuretic(s) (for example meticrane, tripamide, chlorthalidone and mefruside) and acetazolamide.The example of cardiotonic drug comprises digitalis preparation (digoxigenin for example; digoxin; Metildigoxin; Deslanoside; vesnarinone; lanatoside C and Proscillaridin); xanthine preparation (aminophylline for example; Zy 15061; diprophylline and cordabromin); catecholamine preparation (Dopamine HCL for example; dobutamine and Docarpamine); PDE III inhibitor (amrinone for example; olprinone and milrinone); denopamine; Ubidecarenone; pimobendan; Simdax; taurine; vesnarinone; Carperitide and colforsin.The example of antiarrhythmic drug comprises ajmaline, pirmenol, procainamide, cibenzoline, disopyramide, Quinidine, aprindine, mexiletine, lignocaine, quinizine, pilsicainide, Propafenone, flecainide, atenolol USP 23, acebutolol, sotalol, Proprasylyte, metoprolol, pindolol, amiodarone, Nifekalant, diltiazem , Bepridil and verapamil.The example of antihyperlipidemic comprises Zarator, Simvastatin, Pravastatin sodium, fluvastatin sodium, S-8527, clofibrate, simfibrate, fenofibrate, bezafibrate, glyoxal ethyline and 1-chloro-2, polymkeric substance of 3-propylene oxide (colestimide) and Colestyramine.The example of immunosuppressor comprises azathioprine, mizoribine, Ciclosporin A, tacrolimus, gusperimus and Rheumatrex.

Necrocytosis/cancer

Increase sirtuin protein level and/or active sirtuin adjusting compound and can give the object that nearest acceptance maybe may be accepted doses radiation or toxin.In one embodiment, the dosage of radiation or toxin for example, is operated in the radiation dyestuff administration of Nuclear power plants, flight aircraft, X ray, cat scan or imaging of medical as accepting with work part relevant or medical procedure.In such embodiment, compound gives as preventive measures.In another embodiment, radiation or toxin contact are accepted unintentionally, and for example, the result of industrial accident, the war of living in natural radiation position, the attack of terrorism or comprising radiation or toxicant attack.In this case, compound is preferably given the follow-up developments that suppressed apoptosis and acute radiation syndrome as quickly as possible after contact.

Sirtuin regulates compound and also can be used for the treatment of and/or preventing cancer.In certain embodiments, increasing sirtuin protein level and/or active sirtuin adjusting compound can be used for the treatment of and/or preventing cancer.The reduction of the obstacle incidence that energy limited is relevant with the aging that comprises cancer interrelate (referring to for example, Bordone and Guarente, Nat.Rev.Mol.Cell Biol. (2005 epub); Guarente and Picard, Cell120:473-82 (2005); Berrigan, etc., Carcinogenesis 23:817-822 (2002); With Heilbronnand Ravussin, Am.J.Clin.Nutr.78:361-369 (2003)).Additionally, shown come from zymic Sir2 protein to the life-span by glucose limitation prolong be essential (referring to for example, Lin etc., Science 289:2126-2128 (2000); Anderson etc., Nature 423:181-185 (2003)), a kind of saccharomyces model of energy limited.Correspondingly, sirtuin protein level and/or active increase may be to the aging that treats and/or prevents cancer for example the incidence thing of relevant obstacle useful.In other embodiments, reducing sirtuin protein level and/or active sirtuin adjusting compound can be used for the treatment of or preventing cancer.For example; suppress compound and can be used to stimulate for example substrate acetylize of p53, increase apoptosis thus, and reduce cell and organic life-span; make them to stress be more responsive, and/or increase cell or organic radiosensitivity and/or chemosensitivity.Therefore, suppress compound and can be used for for example treating cancer.Can use sirtuin to regulate the cancer of the exemplary cancer of compounds for treating as brain and kidney; The hormone-dependent type cancer comprises mammary gland, prostate gland, testis and ovarian cancer; Lymphoma and leukemia.In the cancer relevant with solid tumor, regulating compound can directly deliver medicine in the tumour.The hemocyte cancer, for example leukemia can be treated in blood flow or marrow by regulating compound administration.The benign cell growth also can be treated, for example wart.Treatable other diseases comprises autoimmune disorder, for example, systemic lupus erythematosus, scleroderma and sacroiliitis, wherein the autoimmunization cell should be removed.Virus infection, for example pernicious the and optimum obstacle that bleb, HIV, adenovirus and HTLV-1 are relevant also can be regulated compounds for treating by giving sirtuin.Alternatively, cell can be taken from through handling in the first external back body removing the object of some undesirable cell such as cancer cells, and is back to identical or different object.

Can with the adjusting compound with antitumour activity described herein (for example, the compound of cell death inducing reduces the compound in life-span or makes the compound of cell to stress sensitive) chemotherapeutic that gives together comprises: aminoglutethimide, amsacrine, Anastrozole, Asparaginase, bcg, bicalutamide, bleomycin, buserelin, busulfan, camptothecine, capecitabine, carboplatin, carmustine, Chlorambucil, cis-platinum, carat Qu Bin, clodronate, colchicine, endoxan, cyproterone, cytosine arabinoside, Dacarbazine, dactinomycin, daunorubicin, Retalon, stilboestrol, docetaxel, Dx, epirubicin, estradiol, estramustine, Etoposide, Exemestane, filgrastim, fludarabine, fluohydrocortisone, Fluracil, Fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, Interferon, rabbit, Rinotecan, ironotecan, letrozole, Calciumlevofolinate, leuprorelin acetate, LEVAMISOLE HCL, lomustine, mustargen, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, Nilutamide, R 17934, Sostatin, oxaliplatin, taxol, Pamidronate, pentostatin, Plicamycin, porfimer, Procarbazine, Raltitrexed, Mabthera, streptozocin, Suramine, tamoxifen, replace not azoles ammonia, teniposide, testosterone, Tioguanine, plug is for group, titanocene dichloride, Hycamtin, trastuzumab, vitamin A acid, vinealeucoblastine(VLB), vincristine(VCR), vindesine and vinorelbine.

These chemotherapeutics can be divided into for example following group according to their mechanism of action: metabolic antagonist/anticarcinogen, for example pyrimidine analogue (5 FU 5 fluorouracil, Ro 2-9757 deoxynucleoside, capecitabine, gemcitabine and cytosine arabinoside) and purine analogue, folate antagonist and relevant inhibitor (mercaptopurine, Tioguanine, pentostatin and 2-chlorodeoxyadenosine (carat Qu Bin)); Antiproliferative/antimitotic drug, comprise for example vincaleucoblastine (vinealeucoblastine(VLB) of natural product, vincristine(VCR) and vinorelbine), the microtubule cracking agent is Taxan (taxol for example, Docetaxel), vincristin, vinealeucoblastine(VLB), R 17934, esperamicin and nvelbine, epidipodophyllotoxins (teniposide), dna damage agent (actinomycin, amsacrine, anthracycline antibiotics, bleomycin, busulfan, camptothecine, carboplatin, Chlorambucil, cis-platinum, endoxan, endoxan, dactinomycin, daunorubicin, Docetaxel, Dx, epirubicin, altretamine oxaliplatin (hexamethylmelamineoxaliplatin), ifosfamide, melphalan, merchlorethamine, mitomycin, mitoxantrone, Nitrosourea, taxol, Plicamycin, Procarbazine, teniposide, thiophene is for group and Etoposide (VP16)); Microbiotic is dactinomycin (Actinomycin D), daunorubicin, Dx (Zorubicin), idarubicin, anthracycline antibiotics, mitoxantrone, bleomycin, Plicamycin (Plicamycin) and mitomycin for example; Enzyme (systematically metabolism L-aspartic acid and depriving does not have synthetic oneself the L-Asparaginase of cell of aspartic acid of ability); Antiplatelet drug; Antiproliferative/antimitotic alkylating agent is mustargen (mustargen, endoxan and analogue, melphalan, Chlorambucil), aziridine and Sulpyrine (altretamine and thiotepa), alkylsulfonate-busulfan, Nitrosourea (carmustine (BCNU) and analogue, streptozocin), trazenes-dacarbazine (DTIC) for example; Antiproliferative/antimitotic metabolic antagonist is folacin (Rheumatrex) for example; Platinum coordination complex (cis-platinum, carboplatin), Procarbazine, hydroxyurea, mitotane, aminoglutethimide; Hormone, hormone analogs (oestrogenic hormon, tamoxifen, goserelin, bicalutamide, Nilutamide) and aromatase inhibitor (letrozole, Anastrozole); Antithrombotics (heparin, synthetic heparinate and other thrombin inhibitorss); Fibrinolytic agent (for example tissue plasminogen activator, streptokinase and urokinase), acetylsalicylic acid, cox 2 inhibitor, Dipyridamole, ticlopidine, clopidogrel, ReoPro; Anti-migration medicine; Antisecretory drug (breveldin); Immunosuppressor (Ciclosporin A, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenlate mofetil); Anti-angiogenic compounds (TNP-470, genistein) and growth factor receptor inhibitors (vascular endothelial growth factor (VEGF) inhibitor, fibroblast somatomedin (FGF) inhibitor, Urogastron (EGF) inhibitor); Angiotensin receptor blocker; Nitric oxide donors; Antisense oligonucleotide; Antibody (trastuzumab); Cell cycle inhibitor and differentiating inducer (vitamin A acid); The mTOR inhibitor, topoisomerase enzyme inhibitor (Dx (Zorubicin), amsacrine, camptothecine, daunorubicin, dactinomycin, eniposide, epirubicin, Etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, Hycamtin, irinotecan), cortin (cortisone, dexamethasone, hydrocortisone, methyl meticortelone, prednisone and Prenylcysteine); Growth factor signal transduction kinase inhibitor; Mitochondria dysfunction inductor and caspase activator; The chromatin cracking agent.

These chemotherapeutics can be with described herein as inducing cell death or reduce the life-span or increase and sirtuin that stress susceptibility is regulated compound use and/or make up other chemotherapeutic agents.Develop many combined therapies, included but not limited to listed those in the table 1.

The example combinations treatment of table 1 treatment cancer

Title	Medicine
Title	Medicine	ABV	Dx, bleomycin, vinealeucoblastine(VLB)
ABVD	Dx, bleomycin, vinealeucoblastine(VLB), Dacarbazine	ABV	Dx, bleomycin, vinealeucoblastine(VLB)
ABVD	Dx, bleomycin, vinealeucoblastine(VLB), Dacarbazine	AC (mammary gland)	Dx, endoxan
AC (sarcoma)	Dx, cis-platinum	AC (mammary gland)	Dx, endoxan
AC (sarcoma)	Dx, cis-platinum	AC (neuroblastoma)	Endoxan, Dx
ACE	Endoxan, Dx, Etoposide	AC (neuroblastoma)	Endoxan, Dx
ACE	Endoxan, Dx, Etoposide	ACe	Endoxan, Dx
AD	Dx, Dacarbazine	ACe	Endoxan, Dx
AD	Dx, Dacarbazine	AP	Dx, cis-platinum
ARAC-DNR	Cytosine arabinoside, daunorubicin	AP	Dx, cis-platinum
ARAC-DNR	Cytosine arabinoside, daunorubicin	B-CAVe	Bleomycin, lomustine, Dx, vinealeucoblastine(VLB)
BCVPP	Carmustine, endoxan, vinealeucoblastine(VLB), Procarbazine, prednisone	B-CAVe	Bleomycin, lomustine, Dx, vinealeucoblastine(VLB)
BCVPP		BEACOPP	Bleomycin, Etoposide, Dx, endoxan, vincristine(VCR), Procarbazine, prednisone, filgrastim
BEP	Bleomycin, Etoposide, cis-platinum	BEACOPP

Title	Medicine
Title	Medicine	BIP	Bleomycin, cis-platinum, ifosfamide, mesna
BOMP	Bleomycin, vincristine(VCR), cis-platinum, mitomycin	BIP	Bleomycin, cis-platinum, ifosfamide, mesna
BOMP	Bleomycin, vincristine(VCR), cis-platinum, mitomycin	CA	Cytosine arabinoside, asparaginase
CABO	Cis-platinum, Rheumatrex, bleomycin, vincristine(VCR)	CA	Cytosine arabinoside, asparaginase
CABO	Cis-platinum, Rheumatrex, bleomycin, vincristine(VCR)	CAF	Endoxan, Dx, Fluracil
CAL-G	Endoxan, daunorubicin, vincristine(VCR), prednisone, aspartoyl enzyme	CAF	Endoxan, Dx, Fluracil
CAL-G		CAMP	Endoxan, Dx, Rheumatrex, Procarbazine
CAP	Endoxan, Dx, cis-platinum	CAMP	Endoxan, Dx, Rheumatrex, Procarbazine
CAP	Endoxan, Dx, cis-platinum	CaT	Carboplatin, taxol
CAV	Endoxan, Dx, vincristine(VCR)	CaT	Carboplatin, taxol
CAV	Endoxan, Dx, vincristine(VCR)	CAVE ADD	CAV and Etoposide
CA-VP16	Endoxan, Dx, Etoposide	CAVE ADD	CAV and Etoposide
CA-VP16	Endoxan, Dx, Etoposide	CC	Endoxan, carboplatin
CDDP/VP-16	Cis-platinum, Etoposide	CC	Endoxan, carboplatin
CDDP/VP-16	Cis-platinum, Etoposide	CEF	Endoxan, epirubicin, Fluracil
CEPP(B)	Endoxan, Etoposide, prednisone, be with or without/bleomycin	CEF	Endoxan, epirubicin, Fluracil
CEPP(B)		CEV	Endoxan, Etoposide, vincristine(VCR)
CF	Cis-platinum, Fluracil or carboplatin, Fluracil	CEV	Endoxan, Etoposide, vincristine(VCR)
CF	Cis-platinum, Fluracil or carboplatin, Fluracil	CHAP	Endoxan or endoxan, altretamine, Dx, cis-platinum
ChlVPP	Chlorambucil, vinealeucoblastine(VLB), Procarbazine, prednisone	CHAP	Endoxan or endoxan, altretamine, Dx, cis-platinum
ChlVPP		CHOP	Endoxan, Dx, vincristine(VCR), prednisone
CHOP-BLEO	Bleomycin is added among the CHOP	CHOP	Endoxan, Dx, vincristine(VCR), prednisone
CHOP-BLEO	Bleomycin is added among the CHOP	CISCA	Endoxan, Dx, cis-platinum
CLD-BOMP	Bleomycin, cis-platinum, vincristine(VCR), mitomycin	CISCA	Endoxan, Dx, cis-platinum
CLD-BOMP	Bleomycin, cis-platinum, vincristine(VCR), mitomycin	CMF	Rheumatrex, Fluracil, endoxan
CMFP	Endoxan, Rheumatrex, Fluracil, prednisone	CMF	Rheumatrex, Fluracil, endoxan
CMFP	Endoxan, Rheumatrex, Fluracil, prednisone	CMFVP	Endoxan, Rheumatrex, Fluracil, vincristine(VCR), prednisone
CMV	Cis-platinum, Rheumatrex, vinealeucoblastine(VLB)	CMFVP	Endoxan, Rheumatrex, Fluracil, vincristine(VCR), prednisone
CMV	Cis-platinum, Rheumatrex, vinealeucoblastine(VLB)	CNF	Endoxan, mitoxantrone, Fluracil
CNOP	Endoxan, mitoxantrone, vincristine(VCR), prednisone	CNF	Endoxan, mitoxantrone, Fluracil
CNOP	Endoxan, mitoxantrone, vincristine(VCR), prednisone	COB	Cis-platinum, vincristine(VCR), bleomycin

Title	Medicine
Title	Medicine	CODE	Cis-platinum, vincristine(VCR), Dx, Etoposide
COMLA	Endoxan, vincristine(VCR), methotrexate, Calciumlevofolinate, cytosine arabinoside	CODE	Cis-platinum, vincristine(VCR), Dx, Etoposide
COMLA		COMP	Endoxan, vincristine(VCR), Rheumatrex, prednisone
The Cooper therapy	Endoxan, Rheumatrex, Fluracil, vincristine(VCR), prednisone	COMP	Endoxan, vincristine(VCR), Rheumatrex, prednisone
The Cooper therapy	Endoxan, Rheumatrex, Fluracil, vincristine(VCR), prednisone	COP	Endoxan, vincristine(VCR), prednisone
COPE	Endoxan, vincristine(VCR), cis-platinum, Etoposide	COP	Endoxan, vincristine(VCR), prednisone
COPE	Endoxan, vincristine(VCR), cis-platinum, Etoposide	COPP	Endoxan, vincristine(VCR), Procarbazine, prednisone
CP (chronic lymphocytic leukemia)	Chlorambucil, prednisone	COPP	Endoxan, vincristine(VCR), Procarbazine, prednisone
CP (chronic lymphocytic leukemia)	Chlorambucil, prednisone	CP (ovarian cancer)	Endoxan, cis-platinum
CT	Cis-platinum, taxol	CP (ovarian cancer)	Endoxan, cis-platinum
CT	Cis-platinum, taxol	CVD	Cis-platinum, vinealeucoblastine(VLB), Dacarbazine
CVI	Carboplatin, Etoposide, ifosfamide, mesna	CVD	Cis-platinum, vinealeucoblastine(VLB), Dacarbazine
CVI	Carboplatin, Etoposide, ifosfamide, mesna	CVP	Endoxan, vincristine(VCR), prednisone
CVPP	Lomustine, Procarbazine, prednisone	CVP	Endoxan, vincristine(VCR), prednisone
CVPP	Lomustine, Procarbazine, prednisone	CYVADIC	Endoxan, vincristine(VCR), Dx, Dacarbazine
DA	Daunorubicin, cytosine arabinoside	CYVADIC	Endoxan, vincristine(VCR), Dx, Dacarbazine
DA	Daunorubicin, cytosine arabinoside	DAT	Daunorubicin, cytosine arabinoside, Tioguanine
DAV	Daunorubicin, cytosine arabinoside, Etoposide	DAT	Daunorubicin, cytosine arabinoside, Tioguanine
DAV	Daunorubicin, cytosine arabinoside, Etoposide	DCT	Daunorubicin, cytosine arabinoside, Tioguanine
DHAP	Cis-platinum, cytosine arabinoside, dexamethasone	DCT	Daunorubicin, cytosine arabinoside, Tioguanine
DHAP	Cis-platinum, cytosine arabinoside, dexamethasone	DI	Dx, ifosfamide
The DTIC/ tamoxifen	Dacarbazine, tamoxifen	DI	Dx, ifosfamide
The DTIC/ tamoxifen	Dacarbazine, tamoxifen	DVP	Daunorubicin, vincristine(VCR), prednisone
EAP	Etoposide, Dx, cis-platinum	DVP	Daunorubicin, vincristine(VCR), prednisone
EAP	Etoposide, Dx, cis-platinum	EC	Etoposide, carboplatin
EFP	Etoposide, Fluracil, cis-platinum	EC	Etoposide, carboplatin
EFP	Etoposide, Fluracil, cis-platinum	ELF	Etoposide, Calciumlevofolinate, Fluracil
EMA86	Mitoxantrone, Etoposide, cytosine arabinoside	ELF	Etoposide, Calciumlevofolinate, Fluracil
EMA86	Mitoxantrone, Etoposide, cytosine arabinoside	EP	Etoposide, cis-platinum
EVA	Etoposide, vinealeucoblastine(VLB)	EP	Etoposide, cis-platinum
EVA	Etoposide, vinealeucoblastine(VLB)	FAC	Fluracil, Dx, endoxan
FAM	Fluracil, Dx, mitomycin	FAC	Fluracil, Dx, endoxan

Title	Medicine
Title	Medicine	FAMTX	Rheumatrex, Calciumlevofolinate, Dx
FAP	Fluracil, Dx, cis-platinum	FAMTX	Rheumatrex, Calciumlevofolinate, Dx
FAP	Fluracil, Dx, cis-platinum	F-CL	Fluracil, Calciumlevofolinate
FEC	Fluracil, endoxan, epirubicin	F-CL	Fluracil, Calciumlevofolinate
FEC	Fluracil, endoxan, epirubicin	FED	Fluracil, Etoposide, cis-platinum
FL	Flutamide, leuprorelin acetate	FED	Fluracil, Etoposide, cis-platinum
FL	Flutamide, leuprorelin acetate	FZ	Flutamide, goserelin acetate implant
HDMTX	Rheumatrex, Calciumlevofolinate	FZ	Flutamide, goserelin acetate implant
HDMTX	Rheumatrex, Calciumlevofolinate	Hexa-CAF	Altretamine, endoxan, Rheumatrex, Fluracil
ICE-T	Ifosfamide, carboplatin, Etoposide, taxol, mesna	Hexa-CAF	Altretamine, endoxan, Rheumatrex, Fluracil
ICE-T	Ifosfamide, carboplatin, Etoposide, taxol, mesna	IDMTX/6-MP	Rheumatrex, mercaptopurine, Calciumlevofolinate
IE	Ifosfamide, Etoposide, mesna	IDMTX/6-MP	Rheumatrex, mercaptopurine, Calciumlevofolinate
IE	Ifosfamide, Etoposide, mesna	Ifo VP	Ifosfamide, Etoposide, mesna
IPA	Ifosfamide, cis-platinum, Dx	Ifo VP	Ifosfamide, Etoposide, mesna
IPA	Ifosfamide, cis-platinum, Dx	M-2	Vincristine(VCR), carmustine, endoxan, prednisone, melphalan
MAC-III	Rheumatrex, Calciumlevofolinate, dactinomycin, endoxan	M-2
MAC-III	Rheumatrex, Calciumlevofolinate, dactinomycin, endoxan	MACC	Rheumatrex, Dx, endoxan, lomustine
MACOP-B	Rheumatrex, Calciumlevofolinate, Dx, endoxan, vincristine(VCR), bleomycin, prednisone	MACC	Rheumatrex, Dx, endoxan, lomustine
MACOP-B		MAID	Mesna, Dx, ifosfamide, Dacarbazine
m-BACOD	Bleomycin, Dx, endoxan, vincristine(VCR), dexamethasone, Rheumatrex, Calciumlevofolinate	MAID	Mesna, Dx, ifosfamide, Dacarbazine
m-BACOD		MBC	Rheumatrex, bleomycin, cis-platinum
MC	Mitoxantrone, cytosine arabinoside	MBC	Rheumatrex, bleomycin, cis-platinum
MC	Mitoxantrone, cytosine arabinoside	MF	Rheumatrex, Fluracil, Calciumlevofolinate
MICE	Ifosfamide, carboplatin, Etoposide, mesna	MF	Rheumatrex, Fluracil, Calciumlevofolinate
MICE	Ifosfamide, carboplatin, Etoposide, mesna	MINE	Mesna, ifosfamide, mitoxantrone, Etoposide
mini-BEAM	Carmustine, Etoposide, cytosine arabinoside, melphalan	MINE	Mesna, ifosfamide, mitoxantrone, Etoposide
mini-BEAM	Carmustine, Etoposide, cytosine arabinoside, melphalan	MOBP	Bleomycin, vincristine(VCR), cis-platinum, mitomycin
MOP	Mustargen, vincristine(VCR), Procarbazine	MOBP	Bleomycin, vincristine(VCR), cis-platinum, mitomycin
MOP	Mustargen, vincristine(VCR), Procarbazine	MOPP	Mustargen, vincristine(VCR), Procarbazine, prednisone
MOPP/ABV	Mustargen, vincristine(VCR), Procarbazine, prednisone, Dx, bleomycin, vinealeucoblastine(VLB)	MOPP	Mustargen, vincristine(VCR), Procarbazine, prednisone
MOPP/ABV		MP (multiple myeloma)	Melphalan, prednisone

Title	Medicine
Title	Medicine	MP (prostate cancer)	Mitoxantrone, prednisone
MTX/6-MO	Rheumatrex, mercaptopurine	MP (prostate cancer)	Mitoxantrone, prednisone
MTX/6-MO	Rheumatrex, mercaptopurine	MTX/6-MP/VP	Rheumatrex, mercaptopurine, vincristine(VCR), prednisone
MTX-CDDPAdr	Rheumatrex, Calciumlevofolinate, cis-platinum, Dx	MTX/6-MP/VP	Rheumatrex, mercaptopurine, vincristine(VCR), prednisone
MTX-CDDPAdr	Rheumatrex, Calciumlevofolinate, cis-platinum, Dx	MV (mammary cancer)	Mitomycin, vinealeucoblastine(VLB)
MV (acute myelocytic leukemia)	Mitoxantrone, Etoposide	MV (mammary cancer)	Mitomycin, vinealeucoblastine(VLB)
MV (acute myelocytic leukemia)	Mitoxantrone, Etoposide	The M-VAC Rheumatrex	Vinealeucoblastine(VLB), Dx, cis-platinum
The MVP mitomycin	Vinealeucoblastine(VLB), cis-platinum	The M-VAC Rheumatrex	Vinealeucoblastine(VLB), Dx, cis-platinum
The MVP mitomycin	Vinealeucoblastine(VLB), cis-platinum	MVPP	Mustargen, vinealeucoblastine(VLB), Procarbazine, prednisone
NFL	Mitoxantrone, Fluracil, Calciumlevofolinate	MVPP
NFL	Mitoxantrone, Fluracil, Calciumlevofolinate	NOVP	Mitoxantrone, vinealeucoblastine(VLB), vincristine(VCR)
OPA	Vincristine(VCR), prednisone, Dx	NOVP	Mitoxantrone, vinealeucoblastine(VLB), vincristine(VCR)
OPA	Vincristine(VCR), prednisone, Dx	OPPA	Third carbazine is added among the OPA
PAC	Cis-platinum, Dx	OPPA	Third carbazine is added among the OPA
PAC	Cis-platinum, Dx	PAC-I	Cis-platinum, Dx, endoxan
PA-CI	Cis-platinum, Dx	PAC-I	Cis-platinum, Dx, endoxan
PA-CI	Cis-platinum, Dx	PC	Taxol, carboplatin or taxol, cis-platinum
PCV	Lomustine, Procarbazine, vincristine(VCR)	PC	Taxol, carboplatin or taxol, cis-platinum
PCV	Lomustine, Procarbazine, vincristine(VCR)	PE	Taxol, estramustine
PFL	Cis-platinum, Fluracil, Calciumlevofolinate	PE	Taxol, estramustine
PFL	Cis-platinum, Fluracil, Calciumlevofolinate	POC	Prednisone, vincristine(VCR), lomustine
ProMACE	Prednisone, Rheumatrex, Calciumlevofolinate, Dx, endoxan, Etoposide	POC	Prednisone, vincristine(VCR), lomustine
ProMACE		ProMACE/cytaBOM	Prednisone, Dx, endoxan, Etoposide, cytosine arabinoside, bleomycin, vincristine(VCR), Rheumatrex, Calciumlevofolinate, sulfamethoxazole
PRoMACE/MOPP	Prednisone, Dx, endoxan, Etoposide, mustargen, vincristine(VCR), Procarbazine, Rheumatrex, Calciumlevofolinate	ProMACE/cytaBOM
PRoMACE/MOPP		Pt/VM	Cis-platinum, teniposide
PVA	Prednisone, vincristine(VCR), aspartoyl enzyme	Pt/VM	Cis-platinum, teniposide
PVA	Prednisone, vincristine(VCR), aspartoyl enzyme	PVB	Cis-platinum, vinealeucoblastine(VLB), bleomycin
PVDA	Prednisone, vincristine(VCR), daunorubicin, aspartoyl enzyme	PVB	Cis-platinum, vinealeucoblastine(VLB), bleomycin
PVDA		SMF	Streptozocin, mitomycin, Fluracil
TAD	Mustargen, Dx, vinealeucoblastine(VLB), vincristine(VCR), bleomycin,	SMF	Streptozocin, mitomycin, Fluracil

Title	Medicine
Title	Medicine		Etoposide, prednisone
TCF	Taxol, cis-platinum, Fluracil		Etoposide, prednisone
TCF	Taxol, cis-platinum, Fluracil	TIP	Taxol, ifosfamide, mesna, cis-platinum
TIT	Rheumatrex, cytosine arabinoside, hydrocortisone	TIP	Taxol, ifosfamide, mesna, cis-platinum
TIT	Rheumatrex, cytosine arabinoside, hydrocortisone	Topo/CTX	Endoxan, Hycamtin, mesna
VAB-6	Endoxan, dactinomycin, vinealeucoblastine(VLB), cis-platinum, bleomycin	Topo/CTX	Endoxan, Hycamtin, mesna
VAB-6		VAC	Vincristine(VCR), dactinomycin, endoxan
VACAdr	Vincristine(VCR), endoxan, Dx, dactinomycin, vincristine(VCR)	VAC	Vincristine(VCR), dactinomycin, endoxan
VACAdr		VAD	Vincristine(VCR), Dx, dexamethasone
VATH	Vinealeucoblastine(VLB), Dx, plug are for group, Fluoxymesterone	VAD	Vincristine(VCR), Dx, dexamethasone
VATH		VBAP	Vincristine(VCR), carmustine, Dx, prednisone
VBCMP	Vincristine(VCR), carmustine, melphalan, endoxan, prednisone	VBAP	Vincristine(VCR), carmustine, Dx, prednisone
VBCMP		VC	Vinorelbine, cis-platinum
VCAP	Vincristine(VCR), endoxan, Dx, prednisone	VC	Vinorelbine, cis-platinum
VCAP	Vincristine(VCR), endoxan, Dx, prednisone	VD	Vinorelbine, Dx
VelP	Vinealeucoblastine(VLB), cis-platinum, ifosfamide, mesna	VD	Vinorelbine, Dx
VelP	Vinealeucoblastine(VLB), cis-platinum, ifosfamide, mesna	VIP	Etoposide, cis-platinum, ifosfamide, mesna
VM	Mitomycin, vinealeucoblastine(VLB)	VIP	Etoposide, cis-platinum, ifosfamide, mesna
VM	Mitomycin, vinealeucoblastine(VLB)	VMCP	Vincristine(VCR), melphalan, endoxan, prednisone
VP	Etoposide, cis-platinum	VMCP	Vincristine(VCR), melphalan, endoxan, prednisone
VP	Etoposide, cis-platinum	V-TAD	Etoposide, Tioguanine, daunorubicin, cytosine arabinoside
5+2	Cytosine arabinoside, daunorubicin, mitoxantrone	V-TAD	Etoposide, Tioguanine, daunorubicin, cytosine arabinoside
5+2	Cytosine arabinoside, daunorubicin, mitoxantrone	7+3	Cytosine arabinoside and/daunorubicin or idarubicin or mitoxantrone
" 8 close 1 "	Methylprednisolone, vincristine(VCR), lomustine, Procarbazine, hydroxyurea, cis-platinum, cytosine arabinoside, Dacarbazine	7+3

Except the chemotherapy of routine, the sirtuin of can inducing cell death or reducing the life-span described herein regulates compound and also can use with sense-rna, RNAi or other polynucleotide, suppress the expression of cellularity part, cellularity partly causes undesirable cell proliferation, is the target spot of conventional chemical treatment.Only illustrate, these target spots are somatomedin, growth factor receptors, cyclin, transcription factor or signal transduction kinases.

The combined therapy that comprises sirtuin adjusting compound and conventional chemical medicine may be more favourable than combined therapy known in the art, because combination allows the conventional chemical medicine in the effect bigger than performance under the low dosage.In a preferred embodiment, when being used in combination with sirtuin adjusting compound, the effective dose (ED of the combination of chemotherapeutic drug or conventional chemical curative ₅₀) at least than the ED of independent chemotherapeutic drug ₅₀Little 2 times, in addition more preferably little 5 times, 10 times or even 25 times.On the contrary, when regulating compound and be used in combination with sirtuin described herein, the therapeutic index of this chemotherapeutic drug or its combination (TI) the conventional chemical medicine therapy than independent at least is high 2 times, in addition more preferably high 5 times, 10 times or even 25 times.Neuronal disease/obstacle

In some aspects, increase sirtuin protein level and/or active sirtuin and regulate the patient that compound can be used for the treatment of the traumatic or mechanical injuries of suffering from neurodegenerative disease and central nervous system (CNS), spinal cord or peripheral nervous system (PNS).Neurodegenerative disease generally comprises the minimizing of human brain quality and volume, and this is because the atrophy and/or the death of brain cell, and this is more more abstruse and owing to aging than healthy people.Since the specific brain regions zone carry out sexual involution (for example, neurocyte dysfunction and death), neurodegenerative disease can be after long-term normal brain activity function progress gradually.Alternatively, neurodegenerative disease can be fallen ill fast, for example relevant with wound or toxin neurodegenerative disease.Cerebral degeneration's actual generation can be earlier and a lot of years of clinical manifestation.The example of neurodegenerative disease includes but not limited to alzheimer's disease (AD), Parkinson's disease (PD), Huntington Chorea (HD), amyotrophic lateral sclerosis (ALS; Lou Gehrig disease), the neuropathy and the hereditary ataxia of Diffuse Lewy body disease, tarantism-echinocytosis, primary lateral bundle sclerosis, eye disease (optic nerve inflammation), chemotherapy inductive neuropathy (for example, deriving from vincristine(VCR), taxol, bortezomib), diabetes-induced.Increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for the treatment of these obstacles and other obstacle described below.

AD is a CNS obstacle chronic, that can't cure and can not stop, and it takes place gradually, causes the decline of the loss of memory, abnormal behaviour, personality change and elaborative faculty.These lose and are correlated with the dead of particular type brain cell and being connected with the destruction of network enabled (for example, neurogliocyte) between it.AD is described as the reverse of growth in childhood.In suffering from the most people of AD, after symptom comes across 60 years old.The symptom of very early time comprises forfeiture, false judgment and the personality change of recent memory.Disease subsequently, the patient who suffers from AD can forget how to do simple working as washing one's hands.Finally, the patient who suffers from AD loses all inferential capabilities and becomes and relies on other people and carry out daily nursing.At last, disease makes patient become weak and is unable to leave the bed, and can develop the compossibility disease usually.

PD is a CNS obstacle chronic, that can't cure and can not stop, its take place gradually and cause uncontrolled body kinematics, stiff, tremble and dyskinesia.These motor system problems are dead relevant with the brain cell of the brain area that produces Dopamine HCL, and Dopamine HCL is the chemical substance that helps the control MA.In suffering from most of people of PD, after symptom comes across 50 years old.The initial symptom of PD is for to influence significantly trembling of four limbs, especially at hand or lip.PD characteristic symptom subsequently is stiff or bradykinesia, slow in action, stoop posture and damaging equilibrant.The for example loss of memory, dementia, depression, emotional change, dysphagia, unusual speech, sexual dysfunction and bladder and bowel problems of secondary symptom widely.These symptoms can begin to hinder conventional activity, for example control fork or read the newspaper.At last, the patient who the suffers from PD degree of depth that becomes is disabled and be unable to leave the bed.

ALS (motor neuron) is a CNS obstacle chronic, that can't cure and can not stop, and it attacks motor neuron, and motor neuron is for connecting the CNS part of brain and skeletal muscle.In ALS, motor neuron is rotten and final dead, though human brain normally keeps function and sensitivity completely, movement instruction can not arrive muscle.Great majority suffer from the people of ALS between 40 years old and 70 years old.At first weak motor neuron is the motor neuron of control arm or leg.Suffer from the human action inconvenience of ALS, they can drop article, fall, ambiguous speech and uncontrolledly laugh at or cry.Final limb muscle is stopped using and the beginning atrophy.It is weak that this myasthenia can become, and patient can need wheelchair or the activity of can not getting up that becomes.

The inducement major part of these nervous system diseases is still unknown.They are normally defined different diseases, but clearly show special similarity in primary process, and show that usually staggered symptom is more than accidental its single symptom of expection.Current disease definition can not be handled staggered problem suitably, needs the classification of new neurodegeneration obstacle.

HD is another kind of neurodegenerative disease, results from some regional procedural degeneration of neurone heredity of brain.This degeneration causes uncontrolled motion, intelligence forfeiture and affective disorder.HD is a familial disease.Dominant mutation by the wildness gene is transmitted to child by father and mother.Some early symptoms of HD are mood swings, depression, irritability or driving, study new things, remember thing or the difficulty of making decision.Along with disease is carried out, fix attention on the intelligence task difficulty that becomes more and more, patient is on the feed and swallow and can have any problem.

Tay Sachs disease and sandhoff disease are to lack the lysosome glycolipid that β-hexanone amine enzyme causes to store sick (Gravel etc., The Metabolic Basis of Inherited Disease, volume .Scriver etc., McGraw-Hill, New York, 2839-2879 page or leaf, 1995).In these two kinds of diseases, the substrate of GM2 Sphingolipids,sialo and β-glycolipid that hexanone amine enzyme is relevant is assembled in neural system and is caused acute neurodegenerative.In most of severe forms, the symptom morbidity starts from early stage infancy.The serious neurodegeneration course of disease takes place subsequently, and affected baby shows dyskinesia, epileptic seizures, visual loss and deafness.Death betides the year at 2-5 usually.Verified neurone forfeiture (Huang etc., Hum.Mol.Genet.6:1879-1885,1997) by apoptosis mechanism.

It is known that apoptosis plays an important role in immunity system AIDS pathogeny.But HIV-1 also induces nervous system disease.Shi etc., (J.Clin.Invest.98:1979-1990,1996) detect CNS in the external model and derive from the infection induced apoptosis of HIV-1 in patient's AIDS the cerebral tissue, found the infection induced extracorporeal neuron of HIV-1 and the Astrocytic apoptosis of initial stage brain culture.Also detect neurone and Astrocytic apoptosis in the cerebral tissue that derives from 10/11 patient AIDS, these patients comprise that 5/5 suffers from the patient of HIV-1 dementia and the patient of 4/5 non-dementia.

Four kinds of peripheral neurophaties relevant with HIV are arranged, and promptly esthesioneurosis, AIDP/CIPD, drug induced neuropathy are relevant with CMV.

The neuropathic general type relevant with AIDS is tip symmetry polyneuropathy (DSPN).This syndrome is the result of serious sex change, it is characterized by numbness and feels numb.DSPN seldom causes serious unusual, and it is slow that majority causes numbness or human hair combing waste fiber crops and ankle joint to reflect.It extensively takes place with how serious immunosuppression, and progress stably.Use tricyclics treatment relief of symptoms, but can not influence the potential nerve injury.

Known more common but more not serious neuropathy type is acute or chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP).In AIDP/CIDP, the fat membrane damage that covers nerve impulse is arranged.This neuropathy comprises inflammation, is similar to the muscle deterioration of the life-time service AZT that often thinks.This is the initial stage performance that HIV infects, and patient can not complain pain, but can not respond the mirrored text of standard.This neuropathy may be relevant with seroconversion, in this case its spontaneously dissolving sometimes.It can be used as the sign that HIV infects, and shows it is the opportunity that can consider antiviral therapy.It is autoimmunization that AIDP/CIDP may originate from.

Drug-induced or toxicity neuropathy can be very painful.With other drug for example, vincristine(VCR), Phenytoin Sodium Salt (antiepileptic drug), high dosage VITAMIN, vazadrine are the same with antifol, antiviral causes peripheral neurophaty usually.Peripheral neurophaty usually is used for the clinical trial of antiviral dose limitation side effect, and it means can not give more medicine.In addition, the use of this medicine can make neuropathy worsen but not alleviate.Usually, these drug-induced neuropathy are reversible after drug withdrawal.

CMV can cause some nervous syndromes among the AIDS, comprises encephalitis, myelitis and polyradiculopathy.

Neurone forfeiture also is the prominent feature of prion disease, people's Creutzfeldt-Jakob disease for example, ox BSE (mad cow disease), sheep itch of sheep and goat (Scrapie Disease) and cat spongiform encephalopathy (FSE).Increase sirtuin protein level and/or active sirtuin regulate compound to treatment or prevention because these neurone forfeitures of causing of disease formerly are useful.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for the treatment of or prevent any disease or obstacle that comprises the axon disease.Tip axon disease is a kind of peripheral neurophaty, results from more neuronic metabolism of peripheral nervous system (PNS) or toxicity obstacle.It is neural to metabolism or the prevailing reaction of toxicity obstacle, can by for example diabetes, renal failure, deletion syndrome for example the effect of metabolism such as malnutrition and alcoholism disease and toxin or medicine cause.The sick modal cause of tip axon is diabetes, and modal tip axon disease is a diabetic neuropathy.The part of the tip of aixs cylinder is at first degenerated usually, and axonal atrophy neuralward cell paste slowly extends.If noxious stimulation is removed, regeneration is possible, although prognosis reduces according to duration of stimulation and severity.Those people that suffer from tip axon disease show symmetrical glove-stocking sensorimotor obstacle usually.Degree of depth tendon reflex and autonomic nervous system (ANS) function also can be lost or be reduced in the invasion and attack zone.

Diabetic neuropathy is the neurological disorder relevant with diabetes.These disease conditions result from the diabetes microvascular lesions usually, comprise the little blood vessel (vasa nervorum) that supply is neural.The relatively common patient's condition relevant with diabetic neuropathy comprises cranial nerve,third; Mononeuropathy; Mononeuritis multiplex; Diabetic muscular dystrophy; The pain polyneuropathy; Autonomic neuropathy; With the ventral thoracic nerve disease.The clinical manifestation of diabetic neuropathy comprises, for example, the sensorimotor polyneuropathy for example numbness, anesthesia, insensitive and night pain; Autonomic neuropathy is delayed gastric emptying or gastroparesis for example; Mononeuropathy with for example eye movement of cranium neuropathy (the 3rd) neuropathy or chest or spinal nerves.

Peripheral neurophaty is the medical terminology that is used for the peripheral nervous system nerve injury, and it can be caused by the side effect of sacred disease or systemic disease.Peripheral neurophaty its performance with cause on different, can affect the nerves or MNJ.The main inducing of peripheral neurophaty comprises epileptic seizures, nutritive deficiency and HIV, though diabetes are most probable inducements.The mechanical pressure, tumour, neural internal hemorrhage, the exposure health that rest on a position long time also can cause peripheral neurophaty in for example radiation of extreme condition, low temperature or poisonous substance.

In an exemplary embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for the treatment of or prevent multiple sclerosis (MS), comprise recurrent MS and monosymptom MS and other demyelination patient's condition, for example, chronic inflammatory demyelinating polyneuropathy or associated symptom.

MS is the disease chronic, that central nervous system usually disables.Such possibility is pointed in various evidences concentrated area, and promptly this disease is that obstacle by immunologic function causes, though the inducement of this obstacle is not also determined.This obstacle makes immune cell attack myelin, and myelin is the fat that comprises around the insulation sheaths of the neural axon that is arranged in central nervous system (" CNS ").When myelin is impaired, electricimpulse can not be in brain and spinal cord along the nerve fiber approach rapidly or normal conduction.This causes in the aixs cylinder obstacle of the breaking of normal electroconductibility, fatigue and vision, strength, coordination, balance, sensation and bladder and intestinal function.

Like this, MS is a neurological disorder now common and that know, it is characterized in that betiding the inflammation patch and the demyelination at any position of CNS, still, does not almost always have relative peripheroneural participation.Demyelination produces with cracking in the isolator of electric rope or tears similar situation.That is, when insulation sheaths was broken, circuit was understood short circuit, and coupled electric installation is understood discontinuous operation or do not worked.This sheath damage around nerve fiber causes passing the neural short circuit of brain and spinal cord and thereby causes the MS symptom.Further finding that patch appears in this demyelination, and is opposite along whole C NS.In addition, this demyelination may be intermittent.Therefore, this patch scatters on time and space.

Believing that morbidity comprises the local failure of hemato encephalic barrier, it causes limitation immunity and inflammatory response, and with to myelin and neuronic follow-up damage.

Clinically, MS is present in both sexes and takes place at any age.But it is the most common to find expression in relatively young grownup, usually with single focal lesion, and for example optic nerve injury, mono-anesthesia's (sensory deprivation) or paresthesia (the local forfeiture of sensation) or myasthenia.In addition, dizzy, diplopia, topalgia, pain uncontrolled and arm and leg can betide cervical flexure, and a large amount of different types of uncommon symptom.

The initial attack of MS is normally temporary transient, and it can be several weeks, several months or several years further attacking before taking place.Some know from experience enjoy in a lot of years stable, do not have a situation of symptom relatively, and the course of disease of knowing from experience the deterioration that experience continues of some other misfortune, and final complete paralysis.The most usually, have a series of mitigation and a recurrence, wherein recurrence can make patient than what were worse in the past.Recurrence can be caused by stress event, virus infection or poisonous substance.Wherein, the body temperature of rising for example heating can make worse off, or can make improving situation by for example cooling bath reduction temperature.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for the treatment of neural wound, comprise because the wound of disease, damage (comprising surgical operation) or environment wound (for example, neurotoxin, alcoholism etc.).

Increase sirtuin protein level and/or active sirtuin and regulate the symptom that compound also can be used for preventing, treating and alleviate various PNS obstacles, for example symptom what follows.PNS is by leading to or forming from the nerve of the nervous ramification of spinal cord and CNS.Peripheral nerve is handled the function of health different series, comprises sensation, motion and autorhymicity function.When individuality suffered from peripheral neurophaty, the PNS nerve was damaged.The nerve injury meeting results from multiple reason, for example disease, physical injury, poisoning or malnutrition.These medicines both can influence esodic nerve also can influence exodic nerve.The reason that depends on damage, neurocyte aixs cylinder, its protection myelin or the two can be damaged or destroy.

Term " peripheral neurophaty " comprises a large amount of obstacles, the nerve-peripheral nerve outside its midbrain and the spinal cord-damage.Peripheral neurophaty is also referred to as the peripheral nerve inflammation, if perhaps relate to many nerves, can use term polyneuropathy or polyneuritis.

Peripheral neurophaty is the obstacle that extensively distributes, and has many underlying causes.In these reasons some are common, diabetes for example, and other are very rare, for example, acrylamide poisoning and some genetic diseases.The prevailing global reason of peripheral neurophaty is a leprosy.Leprosy is caused that by the bacterium Mycobacterium leprae it attacks affected people's peripheral nerve.

Leprosy is very rare in the U.S., and in the U.S., diabetes are prevailing known reasons of peripheral neurophaty.According to estimates, surpass 1,000 7 hundred ten thousand people at US and European and suffer from the relevant polyneuropathy of diabetes.Many neuropathy are idiopathic; Do not find known reason.Prevailing heredity peripheral neurophaty is a charcot-Marie-Tooth atrophy in the U.S., and it influences about 125,000 people.

The peripheral neurophaty another kind of comparatively knowing is a Guillain-Barr é syndrome, it results from the complication relevant with virus disease, for example cytomegalovirus, Epstein-Barr virus and human immunodeficiency virus (HIV) or infectation of bacteria comprise campylobacter jejuni and Lyme disease.Whole world sickness rate is annual approximately per 100,000 philtrums, 1.7 examples.The well-known reason of other of peripheral neurophaty comprises chronic alcoholism, varicella zoster virus infection, botulism and poliomyelitis.Peripheral neurophaty can develop as primary symptom, or it is owing to other disease.For example, peripheral neurophaty just for example amyloid neuropathy, some cancer or genetic nerve learn a kind of symptom of the disease of obstacle, this disease can influence PNS and CNS, and other bodily tissues.

Increasing medicable other PNS diseases of sirtuin protein level and/or active sirtuin adjusting compound comprises: the Brachial Plexus neuropathy (disease of the peripheral nerve part of nape root and the first chest root, nerve trunk, bundle and brachial plexus.Clinical manifestation comprises regional pain, paresthesia; Myasthenia and upper limbs are felt to go down.These diseases are relevant with wound, comprise maternal infuries; Thoracic outlet syndrome; Vegetation, neuritis, radiotherapy; And other diseases.Referring to Adams etc., Principles of Neurology, the 6th edition, 1351-2 page or leaf); Diabetic neuropathy (periphery relevant, self-discipline and cranial nerve symptom) with diabetes.These patient's condition normally cause because of the diabetic microvascular lesions, comprise the little blood vessel (vasa nervorum) that supply is neural.The relatively common patient's condition relevant with diabetic neuropathy comprises: third cranial nerve paralysis; Mononeuropathy; Mononeuritis multiplex; Diabetic muscular dystrophy; The painful polyneuropathy; Autonomic neuropathy; With ventral thoracic nerve disease (referring to Adam etc., Principles of Neurology, the 6th edition, 1325 pages); Mononeuropathy (be different from diffuse type peripheral nerve dysfunction or with disproportionate single peripheroneural disease or the wound of relating to of its sign).Mononeuritis multiplex is meant the disease that is characterized as multiple isolated nerve injury.Mononeuropathy may be due to reason widely, comprises local asphyxia; Trauma injuries; Compressing; Connective tissue disease; Accumulation wound obstacle; And other diseases; Neurodynia (along the path of periphery or cranial nerve or the fierceness that takes place of distributing or ache); The peripheral nervous system vegetation vegetation of peripheral nerve tissue (result from).This comprises neurofibroma; Schwannoma; GCT; With pernicious periphery sheath knurl (referring to DeVita Jr etc., Cancer:Principles and Practice of Oncology, the 5th edition, 1750-1 page or leaf); And nerve compression syndromes (because of the nerve of inside or external cause or the mechanical pressure of nerve root).These can cause owing to for example myelin dysfunction or aixs cylinder loss, to the block of nerve impulse.Neural and schwann's sheath damage can be by local asphyxia; Inflammation; Or direct mechanical effect; Neuritis (general term of indication periphery or cranial nerve inflammation) causes.Clinical manifestation can comprise pain; Paresthesia; Peralytic dementia; Or oxypathy; Polyneuropathy (multiple peripheral neurophaty).Multi-form classification according to the types of nerve that influence (for example is, sensation, motion or self-discipline), the distribution of nerve injury (for example, tip to proximal), formerly send out neural part affected (for example, demyelination to aixs cylinder), nosetiology or mode of inheritance.

In another embodiment, the sirtuin activating compounds can be used for the treatment of or prevent the neuropathy of chemotherapy-induced.Sirtuin regulate compound can prior to before the chemotherapeutic drug administration, in the chemotherapeutic drug administration and/or the chemotherapeutic drug administration begin the back administration.If the sirtuin activating compounds begins the back administration in the chemotherapeutic drug administration, the sirtuin activating compounds prior to or wish in the neuropathy symptom administration at the beginning of chemotherapy-induced.

Any part of chemotherapeutic agent meeting injured nerve system.Fortunately, encephalopathic and myelopathy are very rare.Peripheral nerve injury is more common, can become the side effect of the treatment of suffering from cancer such as lymphadenomatous people experience.Most of neuropathy influence sensory nerve but not motorius.Therefore, common symptom is tingle, numbness or balance.The longest nerve looks like the most responsively in the body, so most patient can be reported numbness or at their hand and pin numb.

With the common maximally related chemotherapeutic drug of neuropathy be vincaleucoblastine (at first derived from a kind of cancer therapy drug of a kind of Vinca plant-Vinca plant genus) and the medicine that contains platinum that is called cis-platinum.Vincaleucoblastine comprises medicine vinealeucoblastine(VLB), vincristine(VCR) and vindesine.Many lymphadenomatous combined therapies for example CHOP and CVP comprise vincristine(VCR), and it is the most normal known medicine that causes this problem.In fact, the dosage that can give of neuropathic just risk restriction vincristine(VCR).

That has carried out studies show that most patient because the vincristine(VCR) treatment can be lost the tingle to a certain degree (paresthesia) that some shank reflects and can experience finger and toe.Neuropathy does not usually show its symptom but appearance after several weeks usually in the beginning of treatment.Drug withdrawal is dispensable when symptom takes place at first, if but the neuropathy progress, this is necessary.Patient reports that to their doctor this symptom is very important, because if the drug deactivated nerve injury is most reversible.If anesis, most of doctors reduce dosage or the vincaleucoblastine of the other form of migrating, for example vinealeucoblastine(VLB) or the vindesine of vincristine(VCR) through regular meeting.By accident, the nerve of supply intestines can be influenced, causes stomachache and constipation.

In another embodiment, the sirtuin activating compounds can be used for the treatment of or prevent polyglutamic acid amides disease (ployglutamine disease).Huntington Chorea (HD) and 1 type spinocebellar ataxia (SCA1) are just by two examples that comprise the class genetic diseases that dynamic mutation that triplet (triplet) sequence repeats to expand causes.About this common mechanism, these diseases are called the trinucleotide polyphone and repeat disease.Known at least 14 kinds of this diseases are that influence is human.Wherein 9 kinds, comprise SCA1 and Huntington Chorea, have CAG as tumor-necrosis factor glycoproteins (seeing table 2).Since the CAG amino acids coding is called glutamine, these 9 kinds of trinucleotide series connection repeat the disease unification and are called polyglutamic acid amides disease (ployglutamine disease).

Although the gene that different polyglutamic acid amides diseases relates to does not almost have common ground, the disease that they cause is followed the obviously similar course of disease.Every kind of genius morbi for not on the same group neurocyte carry out sexual involution.The cardinal symptom of these diseases is similar, though inequality, influence the middle-aged people usually.Since symptom is similar, the sick leave of polyglutamic acid amides is surely by the development of common cellularity mechanism.In in recent years, scientist is explaining that this mechanism is what very big progress arranged on.

On some threshold value, multiple glutamine number is many more in protein, and disease takes place more early, and symptom is serious more.This shows that unusual long glutamine bundle makes their host protein toxic to neurocyte.

In order to verify this hypothesis, scientist has made and has expressed the genetic engineering mouse with long polyglutamic acid amides bundle protein matter.No matter whether mouse expresses whole length protein or be that proteic those contain the part of polyglutamate bundle, they develop the symptom of polyglutamic acid amides disease.This shows long polyglutamic acid amides bundle self-inflicted injury cell, and is not a part that causes the functional protein of its damage.

For example, the symptom of SCA1 is considered to not to be directly caused by normal ataxin-1 afunction, but cause by the interaction between ataxin-1 and the another kind of protein that is called LANP.Thereby connecting each other to its existence neurocyte, LANP needs.When mutant ataxin-1 protein was assembled in neurocyte, it " caught " LANP protein, disturbs its normal function.Soon, as if the LANP afunction causes the neurocyte dysfunction.

The general introduction of table 2 polyglutamic acid amides disease

Disease	The gene title	Chromosomal localization	Mode of inheritance	Protein	Normal tumor-necrosis factor glycoproteins length	Disease tumor-necrosis factor glycoproteins length
Disease	The gene title	Chromosomal localization	Mode of inheritance	Protein	Normal tumor-necrosis factor glycoproteins length	Disease tumor-necrosis factor glycoproteins length	Spinal cord bulbar muscular atrophy disease (Kennedy disease)	AR	Xq13-21	The chain recessiveness of x-	Androgen receptor (AR)	9-36	38-62
HD	HD	4p16.3	Autosomal dominant	Huntington protein	6-35	36-121		AR	Xq13-21	The chain recessiveness of x-	Androgen receptor (AR)	9-36	38-62
HD	HD	4p16.3	Autosomal dominant	Huntington protein	6-35	36-121	Dentatorubral-pallidoluysian atrophy (Haw River syndrome)	DRPL A	12p13.31	Autosomal dominant	atrophin-1	6-35	49-88
1 type spinocebellar ataxia	SCA1	6p23	Autosomal dominant	ataxin-1	6-44	39-82	Dentatorubral-pallidoluysian atrophy (Haw River syndrome)	DRPL A	12p13.31	Autosomal dominant	atrophin-1	6-35	49-88
1 type spinocebellar ataxia	SCA1	6p23	Autosomal dominant	ataxin-1	6-44	39-82	2 type spinocebellar ataxias	SCA2	12q24.1	Autosomal dominant	ataxin-2	15-31	36-63
3 type spinocerebellum mutual aids	SCA3	14q32.1	Normal dyeing	ataxin-3	12-40	55-84	2 type spinocebellar ataxias	SCA2	12q24.1	Autosomal dominant	ataxin-2	15-31	36-63

Disease	The gene title	Chromosomal localization	Mode of inheritance	Protein	Normal tumor-necrosis factor glycoproteins length	Disease tumor-necrosis factor glycoproteins length
Disease	The gene title	Chromosomal localization	Mode of inheritance	Protein	Normal tumor-necrosis factor glycoproteins length	Disease tumor-necrosis factor glycoproteins length	Imbalance (Machado-Joseph disease)			Body dominance
6 type spinocebellar ataxias	SCA6	19p13	Autosomal dominant	α 1A voltage-dependent ca channel subunit	4-18	21-33	Imbalance (Machado-Joseph disease)			Body dominance
6 type spinocebellar ataxias	SCA6	19p13	Autosomal dominant	α 1A voltage-dependent ca channel subunit	4-18	21-33	7 type spinocebellar ataxias	SCA7	3p12-13	Autosomal dominant	ataxin-7	4-35	37-306
17 type spinocebellar ataxias	SCA1 7	6q27	Autosomal dominant	TATA is conjugated protein	25-42	45-63	7 type spinocebellar ataxias	SCA7	3p12-13	Autosomal dominant	ataxin-7	4-35	37-306

Many transcription factors in the neurone inclusion of various disease, have also been found.These transcription factors are possible with comprising the protein interaction of polyglutamic acid amides and being hunted down in the neurone inclusion.This may stop transcription factor to open and close gene according to the cell needs again.Another kind of view is that to be attacked the acetylize of histone in the cell low excessively.This has caused the hypothesis of I/II class histone deacetylase (HDAC I/II) inhibitor, and its known increase histone deacetylation may be the new therapy (U.S. Patent application 10/476,627 of polyglutamic acid amides disease; " treat the method for neurodegeneration, spirituality and other disease with deacetylase inhibitors ").

In another embodiment, the invention provides the neuropathic method of treatment or prevention and ischemic injury or disease-related, for example, coronary heart disease (comprising congestive heart failure and myocardial infarction), apoplexy, wind-puff, hemorrhagic shock, peripheral vascular disease (upper limbs and lower limb) and transplanting associated injury.

In certain embodiments, the invention provides the cytotropic blood flow of treatment central nervous system cell convection current and reduce next pre-antisitic defect.Usually the severity major part of the damage that can prevent depends on that the blood flow that flows to cell reduces the time length of degree and minimizing.For instance, in the mankind, be about 60-70mL/100g cerebral tissue/min to the dabbling normal amount of cerebral gray matter.When blood flow drops to when being lower than about 8-10mL/100g cerebral tissue/min, the death of central nervous system cell can take place usually, and (for example, the 20-35mL/100g cerebral tissue/min), tissue keeps survival but the unable to get up effect when high level slightly.In one embodiment, can prevent apoptotic or downright bad necrocytosis.In further another embodiment, can prevent the damage of local asphyxia mediation, for example cell toxicant oedema or central nervous system tissue's anoxenia.In each embodiment, central nervous system cell can be cord cell or brain cell.

Comprise that on the other hand giving object sirtuin activating compounds treats the central nervous system local asphyxia patient's condition.Some central nervous system local asphyxia patient's condition can be treated by sirtuin activating compounds described herein.In one embodiment, the local asphyxia patient's condition is an apoplexy, and it causes the ischemic central nervous system injury of any kind, for example apoptotic or downright bad necrocytosis, cell toxicant oedema or central nervous system tissue's anoxic.Apoplexy can influence any zone of brain or cause any cause of disease that apoplexy takes place to cause by known usually.In selectable this embodiment, apoplexy is the brain stem apoplexy.In general, the brain stem apoplexy attacks the brain stem of for example breathing of the unconscious life support function of control, blood pressure and heartbeat.In another selectable this embodiment, apoplexy is little cerebral apoplexy.Usually, the cerebellum zone of the brain of wind effect control balance and coordination in the cerebellum.In another embodiment, apoplexy is a cerebral embolism.Generally, cerebral embolism can influence any zone of brain, is normally caused by the obstruction of artery of angiemphraxis.In another was selected, apoplexy was a hemorrhagic apoplexy.The picture ishemic stroke, hemorrhagic apoplexy can influence any zone of brain, normally by with in the brain or hemorrhage on every side (hemorrhage) angiorrhexis that is feature cause.In further embodiment, apoplexy is the thrombus apoplexy.Usually, the thrombus apoplexy is caused by cumulative clogged with deposits blood vessel.

In another embodiment, the ischemic patient's condition can result from and betide the outer subject's body part of central nervous system, but still causes the obstacle that reduces to the central nervous system blood flow.These obstacles can include, but are not limited to the peripheral blood vessel obstacle, venous thrombosis, pulmonary infarction, arrhythmia (for example, atrial fibrillation), myocardial infarction, transient ischemic attack, unstable angina or sicklemia.In addition, the central nervous system ischemic patient's condition can take place owing to object experience surgical operation.For instance, object can experience heart operation, lung operation, spinal operation, brain operation, vascular surgery, abdominal operation or organ transfer operation.Organ transfer operation can comprise heart, lung, pancreas, kidney or liver transplantation operation.In addition, the central nervous system ischemia patient's condition can take place owing to the wound or the damage of the outer body portion of object central nervous system.For instance, wound or damage can cause the hemorrhage of total blood volume in to a certain degree the remarkable minimizing subject.Because the total amount of this minimizing, the volume of blood flow that flows to central nervous system reduces simultaneously.In further example, wound or damage also can cause limiting the angiemphraxis formation that flows to the neural system blood flow.

Certainly, can expect that the sirtuin activating compounds can be used for the treatment of the central nervous system ischemic patient's condition and no matter the cause of the patient's condition.In another embodiment, the ischemic patient's condition results from angiemphraxis.Angiemphraxis can be the obstruction of any kind, but normally cerebral thrombosis or embolism.In further embodiment, the ischemic patient's condition results from hemorrhage.Hemorrhage can be the hemorrhage of any kind, but normally hematencephalon or subarachnoid hemorrhage.In another embodiment, the ischemic patient's condition can result from angiostenosis.In general, blood vessel can be because vasoconstriction and narrow when betiding vasospasm for example.In another embodiment, the ischemic patient's condition results from the damage of brain or spinal cord.

Another aspect can administration sirtuin activating compounds reduces the infarct size at local asphyxia center after the central nervous system ischemic patient's condition.In addition, the sirtuin activating compounds valuably administration reduce ischemic penumbra after the central nervous system ischemic patient's condition or move the area of shape band.

In one embodiment, the medicinal composition therapy comprises medicine or the compound that is used for the treatment of or prevents the neurodegenerative disease or the secondary patient's condition relevant with these patient's condition.Therefore, the medicinal composition therapy comprises one or more sirtuin activators and one or more anti-neurodegenerative medicines.For example, one or more sirtuin activating compounds can with one or more combinations in significant quantity following: L-DOPA; Dopamine agonist; Adenosine A ₂The A receptor antagonist; The COMT inhibitor; The MAO inhibitor; The N-NOS inhibitor; The sodium channel antagonist; Selective N-methyl D aspartic acid (NMDA) receptor antagonist; AMPA/ kainate receptor antagonist; Calcium-channel antagonists; The GABA-A receptor stimulant; Acetylcholinesterase depressant; Matrix metallo-proteinase inhibitor; The PARP inhibitor; P38MAP kinases or c-jun-N-terminal kinase inhibitor; TPA; The NDA antagonist; Beta-interferon; Somatomedin; The L-glutamic acid inhibitor; And/or the part of cell therapy.

Exemplary nmda receptor antagonist comprises (+)-(1S, 2S)-1-(4-hydroxyl-phenyl)-2-(4-hydroxy-4-phenyl piperidine subbase)-1-propyl alcohol, (1S, 2S)-1-(4-hydroxy 3-methoxybenzene base)-2-(4-hydroxy-4-phenyl piperidine subbase)-1-propyl alcohol, (3R, 4S)-and 3-(4-(4-fluorophenyl)-4-hydroxy piperidine-1-base-)-chroman-4,7-glycol, methylsulfonic acid (1R ^*, 2R ^*)-1-(4-hydroxy-3-methyl phenyl)-2-(4-(4-fluoro-phenyl)-4-methyl piperidine-1-yl)-propane-1-alcohol ester or its pharmaceutically-acceptable acid addition.

Exemplary dopamine agonist comprises levodopa; The L-dopa decarboxylase inhibitor is carbidopa or benserazide, bromocriptine, dihydroergocryptine, etisulergine, AF-14, alaptide, pergolide, trivastal for example; The d1 dopamine receptor agonist is A-68939, A-77636, dihydrexine and SKF-38393 for example; The d2 dopamine receptor agonist is carbergoline for example, methylergol carbamide, N-0434, Nazagolide, PD-118440, pramipexole, quinpirole and ropinirole; The moving agent of Dopamine HCL/beta-adrenergic receptor kinase 1 is DPDMS and dopexamine for example; Dopamine HCL/5-HT uptake inhibitor/5-HT-1A agonist is Roxindole for example; Dopamine HCL/opioid receptor agonist is NIH-10494 for example; α 2-1 adrenergic antagonists/dopamine agonist is terguride for example; α 2-1 adrenergic antagonists/dopamine D 2 agonist is ergoline and talipexole for example; The dopamine uptake inhibitor is GBR-12909, GBR-13069, GYKI-52895 and NS-2141 for example; The monoamine oxidase-B inhibitor is selegiline, N-(2-butyl)-N-methyl propargyl amine, N-methyl N-(2-amyl group) propargyl amine, AGN-1133, ergot derivative, lazabemide, LU-53439, MD-280040 and mofegiline for example; With COMT inhibitor CGP-28014 for example.

Exemplary acetylcholinesterase depressant comprises how neat many piperazines are, 1-(2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(2-phenyl-1H-benzoglyoxaline-5-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(1-ethyl-2-methyl isophthalic acid H-benzoglyoxaline-5-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(2-methyl-6-benzothiazolyl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(2-methyl-6-benzothiazolyl)-3-[1-[(2-methyl-4-thiazolyl) methyl]-the 4-piperidyl]-1-acetone; 1-(5-methyl-benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl) 4-piperidyl]-1-acetone; 1-(6-methyl-benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(3,5-dimethyl-benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(cumarone-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(1-benzenesulfonyl-6-methyl-indoles-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-methyl-indoles-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(1-benzenesulfonyl-5-amino-indoles-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-amino-indoles-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; And 1-(5-acetylaminohydroxyphenylarsonic acid indoles-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone.1-(6-quinolyl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-indyl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-benzo thiophene phenyl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-quinazolyl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-benzoxazolyl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-benzofuryl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-methyl-benzimidazolyl-2 radicals-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-methyl-benzimidazolyl-2 radicals-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-chloro-benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-azaindole 2-yl)-3-[1-(phenmethyl) 4-piperidyl]-1-acetone; 1-(6-azepine benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(1H-2-oxo-pyrrolo-[2 ', 3 ', 5,6] benzo [b] thieno--2-yl)-3-[1-(phenmethyl) 4-piperidyl]-1-acetone; 1-(6-methyl-benzothiazole-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-methoxyl group-indoles-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-methoxyl group-benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(6-acetylaminohydroxyphenylarsonic acid benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl)-4-piperidyl]-1-acetone; 1-(5-acetylaminohydroxyphenylarsonic acid benzo [b] thiophene phenol-2-yl)-3-[1-(phenmethyl-)-4-piperidyl]-1-acetone; 6-hydroxyl-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 5-methyl-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-methoxyl group-3[2-[1 (phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-ethanamide-3-[2-[1-(phenmethyl)-4-piperidyl]-ethyl]-1, the 2-benzoisoxazole; 6-amino-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-(4-morpholinyl)-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 5,7-dihydro-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2-benzoisoxazole-6-ketone; 3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzisothiazole; 3-[2-[1-(phenmethyl)-4-piperidyl] vinyl]-1, the 2-benzoisoxazole; 6-phenylamino-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1,2 ,-benzoisoxazole; 6-(2-thiazolyl)-3-[2-[1-(phenmethyl-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-(2-oxazolyl)-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1, the 2-benzoisoxazole; 6-pyrrolidyl-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-1 ,-2-benzoisoxazole; 5,7-dihydro-5,5-dimethyl-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-6H-pyrrolo-[4,5-f]-1,2-benzoisoxazole-6-ketone; 6,8-dihydro-3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-7H-pyrrolo-[5,4-g]-1,2-benzoisoxazole-7-ketone; 3-[2-[1-(phenmethyl)-4-piperidyl] ethyl]-5,6,8-three hydrogen-7H-isoxazole [4,5-g]-quinoline-7-ketone; 1-benzyl-4-((5,6-dimethoxy-1-indone)-and the 2-yl) methyl piperidine, 1-benzyl-4-((5,6-dimethoxy-1-indone)-2-ylidenyl) methyl piperidine, 1-benzyl-4-((5-methoxyl group-1-indone)-2-yl) methyl piperidine, 1-benzyl-4-((5,6-diethoxy-1-indone)-and the 2-yl) methyl piperidine, 1-benzyl-4-((5,6-methylene-dioxy-1-indone)-and the 2-yl) methyl piperidine, 1-(-nitrobenzyl)-4-((5,6-dimethoxy-1-indone)-and the 2-yl) methyl piperidine, 1-cyclohexyl methyl-4-((5,6-dimethoxy-1-indone)-and the 2-yl) methyl piperidine, 1-(-luorobenzyl)-4-((5,6-dimethoxy-1-indone)-and the 2-yl) methyl piperidine, 1-benzyl-4-((5,6-dimethoxy-1-indone)-2-yl) propyl group piperidines and 1-benzyl-4-((5-isopropoxy-6-methoxyl group-1-indone)-2-yl) methyl piperidine.

Exemplary calcium-channel antagonists comprises diltiazem

, omega-conotoxin GVIA, methoxyverapamil, amlodipine, Felodipine, Sileping and mibefradil.

Exemplary GABA-A receptor modulators comprises chlorethiazol; IDDB; Gaboxadol (4,5,6, the 7-tetrahydrochysene isoxazole is [5,4-c] pyridine-3-alcohol also); Ganaxolone (3 Alpha-hydroxies-3 Beta-methyl-5 α-pregnant (steroid) alkane-20-ketone); Fengabine (2-[(butyl imino-)-(2-chloro-phenyl-) methyl]-the 4-chlorophenol); 2-(4-p-methoxy-phenyl)-2,5,6,7,8,9-six hydrogen-pyrazolo [4,3-c] cinnolines-3-ketone; 7-cyclobutyl-6-(2-methyl-2H-1,2,4-triazole-3-ylmethoxy)-3-phenyl-1,2,4-triazolo [4,3-b] pyridazine; (3-fluoro-4-aminomethyl phenyl) N-(the 1-[(2-aminomethyl phenyl) methyl]-benzimidazolyl-2 radicals-yl } methyl)-N-amyl group methane amide; And 3-(aminomethyl)-5-methylhexanoic acid.

Exemplary potassium channel openers comprises diazoxide, flupirtine, Pinacidil, lemakalim, rilmakalim, Se Luokalin, PCO-400 and SKP-450 (2-[2 " (1 ", 3 " dioxolone)-2-methyl]-4-(2 '-oxo-1 '-pyrrolidyl)-6-nitro-2H-1-chromene).

Exemplary AMPA/ kainate receptor antagonist comprises 6-cyano group-7-Xiao based quinoxaline-2,3-two-ketone (CNQX); 6-nitro-7-sulfamyl benzo [f] quinoxaline-2,3-diketone (NBQX); 6,7-dinitrobenzene quinoxaline-2,3-diketone (DNQX); 1-(4-aminophenyl)-4-methyl-7, between 8--ethylenedioxy-5H-2, the 3-benzodiazepine

Hydrochloride; With 2,3-dihydroxyl-6-nitro-7-sulfamyl benzo-[f] quinoxaline.

Exemplary sodium channel antagonist comprises Ajmaline, procainamide, Tamboar and Riluzole.

Exemplary matrix-inhibitors of metalloproteinase comprises 4-[4-(4-fluorophenoxy) phenylsulfonamido] tetrahydropyrans-4-formic acid oxyamide; 5-methyl-5-(4-(4 '-fluorophenoxy)-phenoxy group)-pyrimidine-2,4, the 6-triketone; 5-just-butyl-5-(4-(4 '-fluorophenoxy)-phenoxy group)-pyrimidine-2,4,6-triketone and prinomastat.

Poly-(ADP ribose) polysaccharase (PARP) is the ribozyme that enriches, and it is by dna single splitting of chain activation cause NAD synthetic poly-(ADP ribose).Under standard conditions, PARP is by the activation of the DNA repair enzyme in the nuclear and raise the base excision reparation that participation is caused by oxidative stress.Therefore, PARP works in necrocytosis and DNA reparation.PARP also participates in regulating the cytokine expression of transmitting inflammation.Under dna damage over-drastic situation (for example acute over-exposure is in pathologic damage), the PARP overactivity, cause being characterized as NAD depletion based on the energy decline of cell and cause ATP consumption, necrocytosis, tissue injury and organ damage/depletion.PARP is believed to be helpful in neurodegeneration, by reducing Reduced nicotinamide-adenine dinucleotide (NAD+), reduces the Triphosaden (ATP that causes necrocytosis that can be by the prevention of PARP inhibitor subsequently; Cosi and Marien, Ann.N.Y.Acad.Sci., 890:227,1999).The exemplary visible Southan and of PARP inhibitor Szabo, Current Medicinal Chemistry, 10:321,2003.

Exemplary P38MAP kinases and c-jun-N-hold kinase whose inhibitor to comprise Pyridinylimidazoles, for example PD 169316, isomerized PD 169316, SB 203580, SB 202190, SB 220026 and RWJ67657.Other are described in United States Patent (USP) 6,288,089, and are incorporated herein by reference.

In an exemplary embodiment, the combined therapy of treatment or prevention MS comprises that one or more increase sirtuin protein levels of treatment significant quantity and/or active sirtuin regulate compound and one or more Avonex

(interferon beta-1a), Tysabri

(natalizumab) or Fumaderm

(the oral fumaric acid of BG-12/).

In another embodiment, the combined therapy of treatment or the prevent diabetes neuropathy or the associated patient's condition comprises one or more increase sirtuin protein levels of treatment significant quantity and/or active sirtuin regulates compound and one or more tricyclics (TCAs) (comprise, for example, Mi Paming, amitriptyline, Desipramine and nortriptyline), serotonin reuptake inhibitor (SSRIs) (comprises, for example, fluoxetine, Paroxetine, Sertraline and Citalopram) and antiepileptic drug (AEDs) (comprise, for example, gabapentin, Carbamzepine and topimirate).

In another embodiment, the invention provides a kind of use and comprise the combined therapy of at least a sirtuin activating compounds and at least a HDAC I/II inhibitor or the method for prevention polyglutamic acid amides disease.The example of HDAC I/II inhibitor comprises hydroxamic acid, cyclic peptide, benzamides, short chain fatty acid and depudecin.

The example of hydroxamic acid and hydroxamic acid derivs, but be not limited to, the two hydroxamic acid (subericbishydroxamic acid) of Trichostatin A (TSA), N-Vorinostat (SAHA), oxamflatin, suberic acid (SBHA) ,-the two hydroxamic acid (CBHA) of carbonyl-styracin, valproic acid and Clopyroxinum.TSA separates (Tsuji etc. (1976) J.Antibiot (Tokyo) 29:1-6) and finds as antifungal antibiotic is the potent inhibitor (Yoshida etc. of Mammals HDAC.(1990)J.Biol.Chem.265：17174-17179)。The discovery that TSA tolerance clone has the HDAC of change proves that this enzyme is the important target spot of TSA.Other hdac inhibitors based on hydroxamic acid, SAHA, SBHA and CBHA are synthetic compounds, and it can suppress HDAC under micromole or lower concentration in external or body.Glick etc., (1999) Cancer Res.59:4392-4399.These hdac inhibitors based on hydroxamic acid all have basic constitutional features: polarity hydroxamic acid end group links to each other with another polarity site that is connected to end group hydrophobic part (for example, phenyl ring) by hydrophobic methylene radical spacer (for example, 6 carbon length).The compound with this essential characteristic of research and development also falls into the scope that can be used as the hydroxamic acid of hdac inhibitor.

Cyclic peptide as hdac inhibitor mainly is a cyclic tetrapeptide.The example of cyclic peptide includes, but not limited to trapoxin A, apicidin and carboxylic phenolic acid peptide.Trapoxin A comprises 2-amino-8-oxo-9, the cyclic peptide of 10-epoxy-caprinoyl (AOE) part.Kijima etc., (1993) J.Biol.Chem.268:22429-22435.Apicidin shows potent, wide spectrum antiprotozoal activity and suppress the active fungal metabolite of HDAC under nanomolar concentration.Darkin-Rattray etc., (1996) Proc.Natl.Acad.Sci.USA.93; 13143-13147.The phenol cyclic peptide that contracts separates and is presented under the micro-molar concentration from Chromobacterium violaceum (Chromobacterium violaceum) and suppresses the HDAC activity.

The example of benzamides includes but not limited to MS-27-275.Saito etc., (1990) Proc.Natl.Acad.Sci.USA.96:4592-4597.The example of short chain fatty acid includes but not limited to butyrates (for example, butyric acid, arginine butyrate and phenyl butyrate (PB)).Newmark etc., (1994) Cancer Lett.78:1-5; With Carducci etc., (1997) Anticancer Res.17:3972-3973.In addition, show that under micro-molar concentration the depudecin (Kwon et al. (1998) Proc.Natl.Acad.Sci.USA.95:3356-3361) that suppresses HDAC also falls in the scope of histone deacetylase inhibitors described herein.Blood coagulation disorder

In other respects, increasing sirtuin protein level and/or active sirtuin adjusting compound can be used for the treatment of or preclude blood coagulation disorder (or disorder of hemostasis).Exchange makes land used as this paper, and term " hemostasis ", " blood coagulation " and " blood coagulation " are meant hemorrhage control, comprise the physiological characteristics of vasoconstriction and hemopexis.Blood coagulation helps to keep Mammals round-robin integrity after damage, inflammation, disease, birth defects, dysfunction or other destruction.After solidifying beginning, blood coagulation by some plasminogen sequential activation to their enzyme form carry out (referring to, for example, Coleman, R.W.et al. (eds.) Hemostasis andThrombosis, second edition, (1987)).These plasma glycoproteins comprise factor XI, plasma thromboplastin antecedent I, factor XI, plasma thromboplastin antecedent, factors IX, factor X, factor VII and hemoglutinin, are the proenzymes of serine protease.Have only when the protein cofactor with for example Factor IX and factor V is combined into complex body on the film surface, the great majority of these zymoplasms are effective on the physiology scale.Other blood factors are regulated and the localization clot forms, or the dissolving clot.Activated protein c is the specific enzymes of deactivation procoagulant composition.Calcium particle participates in many component reaction.Inherent approach is followed in blood coagulation, and wherein all protein ingredients are present in the blood, or follows external approach, and wherein the epicyte protein tissue factor plays a key effect.Clot forms and takes place when Fibrinogen forms Fibrinogen by the zymoplasm cutting.Clot is made of activatory thrombocyte and Fibrinogen.

Further, clot forms hemorrhage under the situation not only be limited in damage (hemostasis), and can cause serious organ damage and death in Atheromatosis by important artery or venous occlusion.Therefore, thrombus is the clot formation at the when and where of mistake.It comprises the complicacy of cascade and the biochemical reaction between the vessel wall composition of circulation haemproteins (thrombin), hemocyte (particularly thrombocyte) and damage of regulation and control.

Correspondingly, in order to prevent or treat the blood clotting obstacle, for example limbs of myocardial infarction, apoplexy, peripheral arterial disease or pulmonary infarction forfeiture the invention provides purpose and is to suppress anti-freezing and the antithrombotic therapy that clot forms.

Exchange as this paper and to make land used, " hematostatic adjustings " and " hematostatic regulation and control " comprise that hemostasis induces (for example, stimulate or increase) and hemostasis inhibition (for example, minimizing or reduction).

On the one hand, the invention provides by increasing sirtuin protein level and/or active sirtuin adjusting compound minimizing or suppressing object hematostatic method.Composition disclosed herein and method are useful to treatment or prevention thrombotic diseases.As used herein, term " thrombosis obstacle " comprises and is characterized as excessive or unwanted condensing or any obstacle or the patient's condition of styptic activity or hypercoagulability state.The thrombosis obstacle comprises and comprises platelet adhesion reaction and thrombotic disease or obstacle, and can show as thrombosed increase tendency, for example, the thrombosis in the thrombus quantity of increase, early stage thrombosis, thrombotic familial tendency and non-common site.The example of thrombosis obstacle comprises, but be not limited to, thromboembolism, venous thrombosis, pulmonary infarction, apoplexy, myocardial infarction, miscarriage, lack relevant thrombophilia with Antithrombin III, the C hypoproteinosis, the S hypoproteinosis, to the proteic resistance of activatory C, dysfibrinogenemia, the solution fibrin disease, homocystinuria, gestation, inflammatory disease, myeloproliferative disorder, arteriosclerosis, stenocardia, for example, unstable angina, disseminated inravascular coagulation, thrombotic thrombocytopenic purpura, cancer metastasis, sickle cell disease, glomerulonephritis and drug-induced thrombopenia (comprise, for example, heparin-induced thrombopenia).In addition, increase sirtuin protein level and/or active sirtuin regulate compound and can prevent thrombosis incident or pre-the control in the property treated clot dissolution or operational example such as angioplasty or intra-operative or obturation more afterwards.

In another embodiment, the medicinal composition scheme can comprise and being used for the treatment of or the medicine or the compound of the preclude blood coagulation disorder or the secondary patient's condition relevant with these patient's condition.Therefore, the medicinal composition scheme can comprise that one or more increase the sirtuin protein level and/or active sirtuin regulates compound and one or more anti-freezings or antithrombotic reagent.For example, one or more sirtuin adjusting compounds can combine with one or more following medicines of significant quantity: the factor inhibitors of the low molecular weight heparin of oral warfarin, supressor X and the II of acetylsalicylic acid, heparin and the inhibition vitamin K dependence factor, thrombin inhibitors, thrombocyte GP IIbIIIa acceptor inhibitor, tissue factor (TF) inhibitor, human von willebrand disease factor inhibitor, one or more participation hemostasis (particularly in coagulation cascade).In addition, increasing sirtuin protein level and/or active sirtuin adjusting compound can make up with thrombolytic drug such as t-PA, streptokinase, reptilase, TNK-t-PA and staphylokinase.

Weight control

In yet another aspect, increasing sirtuin protein level and/or active sirtuin adjusting compound can be used for the treatment of or increase of object of prevention weight or obesity.For example, increasing sirtuin protein level and/or active sirtuin adjusting compound can be used for, for example, treatment or prevention genetic obesity, alimentary obesity disease, the relevant obesity of hormone, the obesity relevant with medication are used to reduce weight or the minimizing or the increase of object of prevention weight of object.Needing the object of this treatment can be fat, the object fat, overweight, that maybe may become overweight of may growing fat.Fat or the overweight object of may growing fat can be differentiated, for example, takes in or its different combination based on family history, genetics, diet, activity level, medicine.

In other embodiments, increase sirtuin protein level and/or active sirtuin adjusting compound and can suffer from various can pass through to promote object weight reduction treatment or the other diseases that prevents and the objects of the patient's condition.This disease comprises, for example, hypertension, hypertension, high blood cholesterol, dyslipidemia, diabetes B, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, stenocardia, congestive heart failure, apoplexy, gallbladdergallstonecholetithiasis, cholecystitis and chololithiasis, gout, osteoarthritis, obstructive sleep apnea nuclear breathing problem, the cancer of some type (uterine endometrium for example, mammary gland, prostate gland, and colon), pregnancy complications, the female reproduction health of difference (irregular menses for example, sterile, irregular ovulation), bladder control problem (for example pressure incontinence); Uric acid nephrolithiasis; Psychological disorders (for example the health of dysthymia disorders, eating disorder, distortion image and lack self-esteem).Stunkard AJ, Wadden TA. (editor) Obesity:theory

And therapy, second edition .New York:Raven Press, 1993.Finally, the patient who suffers from AIDS can be developed lipodystrophy or insulin resistance to the combination treatment of treatment AIDS.

In another embodiment, increase sirtuin protein level and/or active sirtuin and regulate compound and can be used to suppress lipogenesis or adipocyte differentiation, though be external or body in.Especially, adipocyte was divided into adipocyte before the high cyclical level of Regular Insulin and/or rhIGF-1 (IGF) 1 can be prevented from raising.This method can be used for the treatment of or obesity prevention.

In other embodiments, increase sirtuin protein level and/or active sirtuin regulate compound and can be used to reduce appetite and/or increase full sense, thereby cause the weight reduction or avoid weight to increase.The object that needs this treatment can be overweight, fat object or the object that may become overweight or fat.This method can comprise every day or, the next day or weekly, give the object doses, for example the form of pill.This dosage is " appetite reduction dosage ".

In other embodiments, reducing sirtuin protein level and/or active sirtuin adjusting compound can be used to stimulate appetite and/or the weight increase.This method can comprise and gives object, the object that for example needs, and the reduction sirtuin albumen of pharmacy effective dose such as the level of SIRT1 and/or SIRT3 and/or active sirtuin regulate compound.Needing the object of this treatment can be to suffer from emaciation maybe may develop cachectic object.The also medicine that can make up.This method may further include monitoring of diseases or sirtuin activatory state in object, for example, and in fatty tissue.

Lipopectic method can be used for externally in the irritation cell, sets up the cell model that weight increases, and it can be used for, and for example, identifies the other drug that prevention weight increases.

Also provide the method for regulating lipogenesis or adipocyte differentiation, no matter in external or the body.Especially, adipocyte was divided into adipocyte before the high cyclical level of Regular Insulin and/or rhIGF-1 (IGF) 1 can be prevented from raising.This method can be used for the treatment of or obesity prevention.This method can be used to regulate obesity.Stimulate adipogenic method to comprise and make cells contacting reduce sirtuin protein level and/or active sirtuin adjusting compound.

In another embodiment, the invention provides by reducing the method that sirtuin protein level and/or active sirtuin regulate compound minimizing object body fat or lipid metabolism.This method comprises that giving a certain amount of sirtuin of object regulates compound, for example, and to reduce the significant quantity of fat burning fat from the WAT cell movement to blood neutralization/minimizing BAT cell.

The method that promotes appetite and/or weight to increase can comprise, for example, identifies that formerly object need reduce fat or lipid metabolism, for example, by the weighing object, the BMI of determination object, or the sirtuin activity in the lipid content of evaluation object or the object cell.This method also can comprise monitoring target, and for example, sirtuin regulates during the compound administration and/or afterwards.Administration can comprise one or more dosage, for example, sends or continuously with the slowly-releasing ball.Monitoring can comprise assessment hormone or meta-bolites.Exemplary hormone comprises Leptin, adiponectin, phylaxin and Regular Insulin.Exemplary meta-bolites comprises triglyceride level, cholesterol and lipid acid.

In one embodiment, reduce sirtuin protein level and/or active sirtuin and regulate the amount that compound can be used for regulating subcutaneous lipids in (for example, increasing) tissue, for example, the surperficial related tissue of facial tissue or other necks, hand, leg or lip.Sirtuin regulates compound can be used to increase hardness, moisture maintenance or tissue support characteristic.For example, sirtuin regulates compound can topical application, for example, with the other drug associating, for example, is used for the treatment of surperficial related tissue.Sirtuin regulates compound also can subcutaneous injection, for example, and in the zone that needs subcutaneous lipids to change.

The method of regulating weight may further include the level of monitoring target weight and/or sirtuin adjusting, for example, and in fatty tissue.

In an exemplary embodiment, increase sirtuin protein level and/or active sirtuin and regulate the combined therapy administration that compound can be used as treatment or prevention weight or obesity.For example, one or more increase sirtuin protein levels and/or active sirtuin regulate compound can with one or more anti-obesity drug regimen administrations.Exemplary anti-obesity medicine comprises, for example, Phenylpropanolamine, racephedrine, false racephedrine, PHENTERMINE, cholecystokinin-A agonist, monoamine re-uptake inhibitor (for example sibutramine), sympathomimetic, serotonin energy medicine (for example dexfenfluramine or S-768), dopamine agonist (for example bromocriptine), melanophore-stimulation hormone receptor agonists or mimic, melanophore-stimulation hormone analogs, cannabinoid receptor antagonists, melanochrome is assembled the hormone agonist, OB albumen (Leptin), the Leptin analogue, the Leptin receptor stimulant, galanin antagonist or GI lipase inhibitor or depressant (for example xenical see orlistat).Other fenisorexs comprise for example Exendin and ciliary neurotrophic factor Axokine for example of Magainin agonist, dehydroepiandrosterone or its analogue, glucocorticoid receptor agonist and antagonist, orexin receptor antagonists, the conjugated protein antagonist of urocortisol, glucagon-like peptide 1 receptor stimulant.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can administration reduce drug-induced weight increase.For example, increase sirtuin protein level and/or active sirtuin regulate compound can with the drug regimen administration that can stimulate appetite or cause that weight increases, especially, the weight increase is because the factor except water retention.Can cause the example of the medicine that weight increases, for example comprise, treating diabetes, for example, sulfourea (for example Glipizide and Glyburide), thiazolidinediones (for example U-721017E and Rosiglitazone), meglitinides, nateglinide, repaglinide, sulfonylurea medicine and Regular Insulin; Thymoleptic, comprise, for example, tricyclics (for example amitriptyline and Mi Paming), irreversible oxidase inhibitor (MAOIs), selective serotonin reuptake inhibitor (SSRIs), Wellbutrin, Paroxetine and Zispin; Steroid, for example, prednisone; Hormonotherapy; Quilonum Retard; Valproic acid; Carbamzepine; Chlorpromazine; Tiotixene; Beta-Blocking agent (for example Proprasylyte); α-Zu Zhiji (for example clonidine, Prazosin and terazosin); And contraceptive bian, comprise oral contraceptive (birth control medicine) or other comprise oestrogenic hormon and/or Progesterone (Depo-Provera, Norplant, Ortho), the contraceptive bian of testosterone or megestrol.In another exemplary embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound can be used as the part of smoking cessation scheme and prevent the weight that weight increases or minimizing has increased.

Metabolic disturbance/diabetes

In yet another aspect, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for the treatment of or prevent metabolic disturbance, for example insulin resistance, pre-diabetes, type ii diabetes and/or its complication.The administration that increases sirtuin protein level and/or active sirtuin adjusting compound can increase insulin sensitivity and/or reduce the object insulin level.The object that the object that needs this treatment can be object with insulin resistance or other type ii diabetes symptom in early stage, suffer from type ii diabetes maybe may develop the object of any of these patient's condition.For example, object can be the object with insulin resistance, for example, have high Regular Insulin cyclical level and/or related conditions, for example hyperlipidaemia, lipodystrophy, hypercholesterolemia, glucose tolerance reduction, hyperglycemia glucose level, other performances of X syndrome, hypertension, atherosclerosis and lipodystrophy.

In an exemplary embodiment, increase sirtuin protein level and/or active sirtuin and regulate the combined therapy administration that compound can be used as treatment or prevention metabolic disturbance.For example, one or more increase the sirtuin protein level and/or active sirtuin adjusting compound can make up with one or more antidiabetic drugs.Exemplary antidiabetic medicine comprises, for example, aldose reductase inhibitor, glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein-tyrosine phosphatase 1B inhibitor, two peptide protease inhibitors, Regular Insulin (comprising that oral biology can utilize insulin preparation), insulin mimetic, N1,N1-Dimethylbiguanide, Acarbose, peroxisome Proliferator-activated receptor-γ (PPAR-γ) part is troglitazone for example, rosaglitazone, U-721017E or GW-1929, sulfonylurea, glypentide, Glyburide or P-607, wherein the volume production of first and second compounds is given birth to result of treatment.Other chaff urine medicines comprise glucosidase inhibitor, glucagon-like-peptide-1 (GLP-1), Regular Insulin, PPAR α/γ dual agonists, meglitinide and α P2 inhibitor.In an exemplary embodiment, antidiabetic medicine can be DPP IV (DI-IV or DPP-IV) inhibitor, for example, and from LAF237 (the NVP DPP728 of Novartis; 1-[[[2-[(5-cyanopyridine-2-yl) amino] ethyl] amino] ethanoyl]-2-cyano group-(S)-tetramethyleneimine) or from the MK-04301 (referring to for example e.g., Hughes etc., Biochemistry 38:11597-603 (1999)) of Merck.

Inflammatory disease

In other respects, increase sirtuin protein level and/or active sirtuin and regulate disease or the obstacle that compound can be used for the treatment of or prevention is relevant with inflammation.Increase sirtuin protein level and/or active sirtuin adjusting compound the back administration can or take place before inflammation begins to take place, when taking place.When preventative use, preferred compound provides prior to any inflammatory response or symptom.Compound administration can prevent or reduce inflammation to reply or symptom.

The exemplary inflammation patient's condition comprises, for example, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, degenerative joint disease, SpA, gouty arthropathy, systemic lupus erythematosus, juvenile arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, diabetes (for example, insulin-dependent diabetes mellitus or juvenile onset diabetes), menstrual cramps, cystic fibrosis, inflammatory bowel, irritable bowel syndrome, Crohn ' s disease, mucous colitis, ulcerative colitis, gastritis, esophagitis, pancreatitis, peritonitis, alzheimer's disease, shock, ankylosing spondylitis, gastritis, conjunctivitis, pancreatitis (acute or chronic), multiple organ damage syndrome (for example, septicemia or wound complication), myocardial infarction, atherosclerosis, apoplexy, reperfusion injury (for example, because cardiopulmonary bypass or kidney dialysis), acute glomerulonephritis, vasculitis, thermal damage (for example, sunburn), necrotizing enterocolitis, granulocyte shifts related syndromes and/or Sjogren ' s syndrome.The exemplary skin inflammation patient's condition comprises, for example, and eczema, atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriatic and have the tetter of acute inflammation composition.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for the treatment of or prevent transformation reactions and breathe the patient's condition, comprise asthma, bronchitis, pulmonary fibrosis, allergic rhinitis, oxygen intoxication, pulmonary emphysema, chronic bronchitis, adult respiratory distress syndrome and any chronic obstructive pulmonary disease (COPD).This compound can be used for the treatment of chronic hepatitis to be infected, and comprises hepatitis B and hepatitis C.

In addition, increase sirtuin protein level and/or active sirtuin regulate compound can be used for the treatment of autoimmune disease and/or with autoimmune disease related inflammation organ-tissues autoimmune disease (for example, Raynaud ' s syndrome) for example, scleroderma, myasthenia gravis, transplant rejection, endotoxin shock, Sepsis, psoriatic, eczema, dermatitis, the multiple sclerosis disease, autoimmune thyroiditis, uveitis, systemic lupus erythematosus, addison's disease, autoimmunity polyadenous body disease (being also referred to as autoimmune polyglandular syndrome) and Grave ' s disease.

In certain embodiments, increase sirtuin protein level and/or active sirtuin regulate compound can be separately or be used for the treatment of with other or the compound of preventing inflammation is used in combination.Exemplary anti-inflammatory medicaments comprises, for example, steroid (for example, hydrocortisone, corticoid, fluorine cortisone, prednisone, 6 Alpha-Methyl prednisones, triamcinolone, Betamethasone Valerate or dexamethasone), nonsteroidal anti-inflammatory drug (NSAIDS (for example, acetylsalicylic acid, Paracetamol, Tolmetin, Ibuprofen BP/EP, mefenamic acid, piroxicam, Maxicom, rofecoxib, celecoxib, R-ETODOLAC or nimesulide).In another embodiment, the other treatment medicine is microbiotic (for example, vancomycin, penicillin, amoxycilline Trihydrate bp, Ampicillin Trihydrate, cefotaxime, rocephin, Cefixime Micronized, rifampinmetronidazole, doxycycline or a Streptomycin sulphate).In another embodiment, the other treatment medicine is PDE4 inhibitor (for example, roflumilast or a rolipram).In another embodiment, the other treatment medicine is antihistaminic agent (for example, marezine, atarax, promethazine or a benadryl).In another embodiment, the other treatment medicine is antimalarial drug (for example, Artemisinin, Artemether, artsunate, chloroquini phosphas, Mefloquine Hydrochloride, Doxycycline Hyclate, Tirian, atovaquone or a Halfan).In one embodiment, the other treatment medicine is drotrecogin alfa.

The further example of antiphlogiston comprises, for example, Aceclofenac, Cuyantong, e-kharophen caproic acid, Paracetamol, phenosal, Acetanilide, acetylsalicylic acid, S-adenosylmethionine, Warner-Lambert), Modrasone, alfentanil, alphasone, alperidine, alminoprofen, aloxiprin, pacify your pain, aluminium two (acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, pyramidon, amixetrine, Salicylate ammonium, Ampiroxicam, Amtolmetin Guacil, anileridine, quinizine, antrafenine, Azapropazone, beclometasone, bindazac, Benorilate BENO, Benzpiperylone, benzydamine, the benzyl morphine, bermoprofen, Betamethasone Valerate, Betamethasone Valerate-17-valerate, Bezitramide, bisabolol (α-bisabolol), Bromfenac, asepsin, acetate 5 bromosalicylic acid ester, the 5-bromosaligenin, betadid, bucloxic acid, BCP, budesonide; bufexamac (bufexamac); bumadizon; buprenorphine; butacetin; butibufen; Butorphanol; carbamazepine; carbiphene; Ro 20-5720/000 baaprine; trichloro-butyl alcohol; chlorine prednisone; chlorthenoxazine; choline salicylate; Viophan; cinmetacine; Ciramadol; clidanac; Clobetasol; Clocortolone; clometacine; Clonitazene; Sch-10304; clopiran; Syntestan; clove; morphine monomethyl ether; Eucodin; codeine phosphate; codeine sulfate; Scheroson; cortivazol; cropropamide; Crotethamide; Cyc; deflazacort; dehydrotestosterone; desomorphine; desonide; desoximetasone; dexamethasone; Dexamethasone-21-isonicotinate; relane; d-moramide; Propoxyphene; deoxycorticosterone; Wy-16225; diampromide; Heroin (diamorphone); diclofenac; difenamizole; Z-876; diflorasone; diflucortolone; Diflonid; difluprednate; paracodin; acetyl dihydrocodeinone; Paramorphan; dihydroxyaluminum acetylsalicylate; lokarin; Dimepheptanol; Takaton; dioxaphetyl butyrate; Piperidyl Amidone; diprocetyl; Sulpyrine; ditazole;

The happiness health, nron, enfenamic acid, biosone, epirizole, eptazocine, etherylate, Ethoxybenzamide, Ethoheptazine, carmurit, Ethylmethylthiambutene, Ethylmorphine, R-ETODOLAC, etofenamate, etonitazene, Eugenol, felbinac, fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, Fentiazac, fepradinol, Feprazone, floctafenine, Fluazacort, the flucloronide, Flufenamic Acid, aniprime, remove the fluorine fluocinonide, Sch-14714, flunoxaprofen, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocortin butyl, fluocortolone, p-fluorophenyl ethyl sulfone, flurandrenolide, P-1742, flupirtine, fluprednidene, the fluorine Ultracortene-H, Fluproquazone, Cordran, U-27182, Fluticasone, fluderma, Fosfosal, gentisinic acid, R 1707, Glucametacin, spirosal, Guaiazulene, halcinonidedcorten, halogen Beta rope, Halometasone, Topicon, diacetylmorphine, dihydrocodeinone, Hydrocortamate, hydrocortisone, hydrocortisone acetate, the hydrocortisone succsinic acid, hydrocortisone half amber ester, hydrocortisone 21-lysine salt, the hydrocortisone cipionate, hydromorphone, bemidone, ibufenac, Ibuprofen BP/EP, ibuproxam, imidazole salicylate, indomethacin, Indoprofen, Isofezolac, isoflupredone, isoflupredone acetate, isoladol, isomethadone, isonixin, Yi Suoke acid (isoxepac), isoxicam, cetobemidone, Ketoprofen BP 93, ketorolac, right-lactophenin, lefetamine, levallorphan, Dromoran, Levophenacylmorphan, Lofentanil, lonazolac, lornoxicam, the loxoprofen, lysine acetylsalicylate, depersolon, meclofenamic acid, Zpoflogin, mefenamic acid, meloxicam, meperidine, the methyl prednisone, Meptid, mesalamine, Metazocine, methadone, methotrimeprazine, medrat, Methylprednisolone Acetate, Urbason Solubile, hydrogenated methyl sprinkles the Buddhist nun, U 67590A, Metiazic Acid, Metofoline, metopon, Reumatox, N-22, Mometasone, R-445, morphine, Srm-Rhotaard, morphine sulfate, Retarcyl, myrophine, Maxicom, nalbuphine, nalorphine, 1-Naphthyl Salicylate, naprosine, narceine, nefopam, gewalan, neopiran, niflumic acid, nimesulide, 5 '-nitro-2 '-the propoxy-Acetanilide, remove the first levorphanol, Normethadone, normorphine, Piperidyl Amidone, Olsalazine, opium, oxaceprol, oxametacin (oxametacine) Evil promazine, oxycodone, oxymorphone, crovaril, Papaveretum, dillar, Renytoline, Parsal, pentazocine Perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine hydrochloride, phenocoll, phenoperidine, Phenopyrazone, phenomorphan, Vesipyrin, Phenylbutazone, salol, fenyramidol, piketoprofen, piminodine, pipebuzone, Palerol, Pirazolac, Piritramide, piroxicam, pirprofen, Niflan, prednicarbate, dehydrohydro-cortisone, prednisone, W-4869, methylene prednisolone, proglumetacin, Proheptazine, promedol, propacetamol, ipropethidine, disopyramide, disopyramide, Propyphenazone, Soz 43-715, Pirocrid aerbron, ramifenazone, remifentanyl, rimazolium metilsulfate, ethrisin, salicin, salicylic amide, Salicylamide O-acetic Acid, Whitfield's ointment, Salicylsulfuric Acid, salsalate, Salverine, simetride, sufentanil, sulfasalazine, sulindac, superoxide-dismutase, sutoprofen, suxibuzone, Talniflumate, tenidap, tenoxicam, Terofenamate, Tetrrine, thiazolinobutazone (thiazolinobutazone), tiaprofenic acid, FK-1160, tilidine, tienoridine, the mercapto hydrocortisone, clotame, Tolmetin, tramadol, triamcinolone, Triamcinolone Acetonide, tropesin, diviminol, xenbucin, Ximoprofen, zaltoprofen and Zomepirac sodium salt.

In an exemplary embodiment, increasing sirtuin protein level and/or active sirtuin adjusting compound can treat or preventing inflammation with the administration of selective COX-2-2 inhibitor.Exemplary selective COX-2-2 inhibitor comprises; for example; deracoxib; parecoxib; celecoxib; valdecoxib; rofecoxib; L-791456; Luo Mei former times cloth (lumiracoxib); 2-(3; the 5-difluorophenyl)-3～[4-(methylsulfonyl) phenyl]-2-cyclopentenes-1-ketone; (S)-6; 8-dichloro 2-(trifluoromethyl)-2H-1-chromene-3-formic acid; 2-(3; the 4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl) phenyl]-3-(2H)-pyridazinone; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide; the tertiary butyl 1 benzyl-4-[(4-oxo-piperidine-1-yl } alkylsulfonyl] piperidines-4-formate, 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzsulfamide; and salt and prodrug.

Flush

On the other hand, increase sirtuin protein level and/or active sirtuin and regulate incidence or the severity that compound can be used to reduce flush and/or disease symptoms hot flush.For example, the inventive method comprises separately or is used in combination increase sirtuin protein level and/or active sirtuin adjusting compound with other drug, reduces the incidence or the severity of cancer patient flush and/or hot flush.In other embodiments, this method provides increases sirtuin protein level and/or active sirtuin adjusting compound minimizing menopause and the incidence of postmenopausal women's flush and/or hot flush or the application of severity.

In yet another aspect, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used to be reduced to the flush of other drug treatment side effect and/or the incidence or the severity of hot flush, for example, drug-induced flush.In certain embodiments, the method that treats and/or prevents drug-induced flush comprises that the patient who needs it is a kind of and comprises the preparation that at least a flush inducing compounds and at least a increase sirtuin protein level and/or active sirtuin are regulated compound.In other embodiments, the method of medicine inductive flush comprises that giving one or more compounds of inducing flush respectively regulates compound with one or more sirtuin, for example, wherein sirtuin adjusting compound is not formulated in the identical composition with the flush induced drug.When using the preparation that separates, sirtuin regulates compound can (1) administration in the administration of flush induced drug, (2) with the administration off and on of flush induced drug, (3) with respect to the administration of flush induced drug administration intersection, (4) prior to flush induced drug administration administration, (5) administration after the administration of flush induced drug is with (6) its different combination.Exemplary flush induced drug comprises, for example, and nicotinic acid, faloxifene, thymoleptic, antipsychotic drug, chemotherapeutic drug, calcium channel blocker and microbiotic.

In one embodiment, increase sirtuin protein level and/or active sirtuin and regulate the flush side effect that compound can be used to reduce vasodilator or antilipemic agent (comprising anticholesteremic and lipotropic drug).In an exemplary embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used to reduce the flush relevant with the nicotinic acid administration.

Nicotinic acid, 3-pyridine carboxylic acid or nicotinic acid are with for example trade(brand)name Nicolar , SloNiacin

, Nicobid With Time Release Niacin The antilipoid medicine of selling.The treatment that nicotinic acid is used for for example hyperlipidaemia, hypercholesterolemia and atherosclerotic dyslipidemia much year.People know that this compound shows following beneficial effect for a long time: reduce human body total cholesterol, low-density lipoprotein or " LDL cholesterol ", triglyceride level and lipophorin a (Lp (a)), increase high-density lipoprotein (HDL) or " the HDL cholesterol " of expectation simultaneously.

General dosage range is extremely about 3 grams of about 1 gram every day.Selected formulation is depended in nicotinic acid common every day of administration after meal 2 to 4 times.Nicotinic acid commerce can obtain its two kinds of formulations at present.A kind of formulation be administration every day 3 or 4 times immediately or the snap-out release sheet.Discharge (" IR ") niacin preparation immediately and after absorption, discharge all nicotinic acid usually in about 30 to 60 minutes.Another formulation is the slowly-releasing form that is suitable for administration every day 2 to 4 times.Opposite with the IR preparation, slowly-releasing (" SR ") niacin preparation design discharges a large amount of medicines in particular time interval, keeps nicotinic acid treatment level in 12 or 24 hours long-time for example after absorption in the blood flow to be absorbed into.

As using ground herein, term " nicotinic acid " is meant that comprising nicotinic acid or its organism metabolism except that nicotinic acid itself is nicotinic acid, therefore generation and the nicotinic acid compound of same function in fact.Generation comprises with the exemplary compound of nicotinic acid similar action, for example, Radecol ester (nicotinyl alcohol tartrate), six hydrochloric acid d-sorbitol esters (d-glucitol hexanicotinate), nicotinic acid aluminum salt, niceritrol and d, 1-α-Vitamine E Nicotinate.Each this compound is generically and collectively referred to as " nicotinic acid " at this paper.

In another embodiment, the invention provides the method for the hyperlipidaemia that treats and/or prevents flush side effect with minimizing.This method comprises the step that the increase sirtuin protein level and/or the active sirtuin of the nicotinic acid of the object treatment significant quantity that needs and the amount that enough reduces flush regulate compound.In an exemplary embodiment, nicotinic acid and/or sirtuin regulate compound can the administration at night.

In another representational embodiment, this method comprises the application that increases sirtuin protein level and/or the side effect of active sirtuin adjusting compound minimizing raloxifene flush.Raloxifene some position in vivo works as estrogen-like, but is not hormone.It helps to prevent to reach the women's in climacteric osteoporosis.Osteoporosis cause bone attenuation gradually, crisp, and more may fracture.Yi Weite (Evista) slows down the bone-loss that takes place climacteric, reduces because osteoporosis and the risk of spinal fracture.The common side effect of raloxifene is hot flush (perspiring and flush).This is to because the women who has suffered from hot flush climacteric is uncomfortable.

In another representational embodiment, this method comprises the application that increases sirtuin protein level and/or active sirtuin adjusting compound minimizing thymoleptic or the side effect of antipsychotic drug flush.For example, increasing sirtuin protein level and/or active sirtuin adjusting compound can use in conjunction with (difference or co-administered) serotonin reuptake inhibitor, 5HT2 receptor antagonist, anticonvulsive agent, NRI, alpha-2-adrenoceptor antagonists, NK-3 antagonist, nk 1 receptor antagonist, PDE4 inhibitor, neuropeptide Y 5 receptor antagonists, D4 receptor antagonist, 5HT1A receptor antagonist, 5HT1D receptor antagonist, CRF antagonist, oxidase inhibitor or sedative hypnotic.

In certain embodiments, increase sirtuin protein level and/or active sirtuin and regulate the part that compound can reduce the treatment of flush as five hydroxytryptamine reuptake inhibitor (SRI).In some preferred embodiment, SRI is optionally five hydroxytryptamine reuptake inhibitor (SSRI), for example fluoxetinoid (fluoxetine, norfluoxetine) or nefazodonoid (nefazodone, hydroxynefazodone, oxonefazodone).Other exemplary SSRI comprise duloxetine, Venlafaxine, Midalcipran, Citalopram, Myroxim, Paroxetine and Sertraline.Increase sirtuin protein level and/or active sirtuin and regulate the part that compound also can be used as the sedative hypnotic treatment, described sedative hypnotic for example is selected from benzodiazepine

Class (for example alprazolam, chlordiazepoxide

, chlordiazepoxide

, chlorine nitrogen

Salt, sentil, diazepam, halazepam, lorazepam, oxazepam and prazepam), zolpidem and barbiturates.In other embodiments, increase sirtuin protein level and/or active sirtuin and regulate the part that compound can be used as the treatment of 5-HT1A acceptor portion agonist, the 5-HT1A acceptor portion agonist for example is selected from buspirone, flesinoxan, gepirone hydrochloride and ipsapirone.Increase sirtuin protein level and/or active sirtuin and regulate the part that compound also can be used as the NRI treatment, NRI for example is selected from tertiary amine tricyclics and secondary amine tricyclics.Exemplary tertiary amine tricyclics comprises amitriptyline, chlorimipramine, P-3693A, Mi Paming and trimeproprimine.Exemplary secondary amine class tricyclics comprises Omnipress, Desipramine, maprotiline, nortriptyline and protriptyline.In certain embodiments, increase sirtuin protein level and/or active sirtuin and regulate the part that compound can be used as the oxidase inhibitor treatment, oxidase inhibitor for example is selected from Isocarboxazid, Phenelzine, Tranylcypromine, selegiline and Moclobemide.

In another representational embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used to reduce for example flush side effect of the chemotherapeutic drug of endoxan, tamoxifen.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used for for example flush side effect of the calcium channel blocker of amlodipine.

In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used to reduce antibiotic flush side effect.For example, increasing sirtuin protein level and/or active sirtuin adjusting compound can be used in combination with levofloxacin.Levofloxacin is used for the treatment of the infection in susceptible bacterial nasal sinus, skin, lung, ear, air flue, bone and joint.Levofloxacin also usually is used for the treatment of urinary system infection, comprises those infection to other antibiotics resistances, and prostatitis.Levofloxacin is effective in the infectious diarrhea that treatment intestinal bacteria, campylobacter jejuni and shiga bacillus cause.Levofloxacin also can be used for the treatment of different obstetrics to be infected, and comprises mazoitis.

Eye disease

One aspect of the present invention is by giving the sirtuin conditioning agent of being selected from of patient dosage compound disclosed herein or its pharmacy acceptable salt, prodrug or metabolic derivative, suppresses, reduces or other modes are treated VI method.

Aspect some, vision impairment is caused by optic nerve or central nervous system injury of the present invention.In special embodiment, optic nerve injury is that for example the high intraocular pressure that causes of glaucoma causes.In other special embodiments, optic nerve injury is that neural swelling causes, neural swelling is often replied relevant with for example infection in optic neuritis or immunity (for example autoimmunization).

Glaucoma describe one group with visual field defective, optic disk cup (the cupping of the optic disc) disease relevant with optic nerve injury.These are commonly called glaucoma optic nerve DPN.Most of glaucomas are common, but not always, raise relevant with intraocular pressure.The exemplary form of glaucoma comprises glaucoma and penetrating keratoplasty, acute angle-closure, the chronic angle-closure, chronic open-angle, angle recession, aphakic and the intraocular lens, drug induced, hyphema, intraocular tumor, the teenager, Lens-Particle, low pressure, virulent, neovascular, phacolytic, Phacomorphic, pigment, plateau iris, formerly send out geneogenous, the primary angle of release, peel off, secondary is geneogenous, Adult Suspect, one-sided, uveitic, ocular hypertension, eye tension force is low excessively, peripapillary scleral ectasia process in Posner-Schlossman syndrome (Posner-SchlossmanSyndrome) and ocular hypertension and the primary open angle glaucoma.

Intraocular pressure also can be implanted and raise by the various operation techniques of for example Phacoemulsification (that is cataract surgery) and for example intraocular lens's structure.In addition, especially in spinal surgery or longer time of any patient operation can cause the operation of the intraocular pressure that raises.

Optic neuritis (ON) is the optic nerve inflammation and causes the acute visual forfeiture.Itself and multiple sclerosis (MS) height correlation show ON at first as patient MS of 15-25%, and patient's ON diagnosis of 50-75% suffers from MS.ON also with infect (for example, virus infection, meningitis, syphilis), inflammation (for example, deriving from vaccine), infiltration is relevant with local asphyxia.

Another patient's condition that causes optic nerve injury is preocular ischemic optic neuropathy (AION).There is two types AION.Artery inflammatory AION results from giant cell arteritis (vasculitis) and cause acute visual forfeiture.Non-arteritis AION comprises except that resulting from all cases of the ischemic optic neuropathy the giant cell arteritis.Though as if combine inflammation and ischemic mechanism, the physiopathology of AION is unclear.

Other optic nerve injuries are relevant with demyelination (demyleination), inflammation, local asphyxia, toxin or optic nerve wound usually.The exemplary patient's condition of optic nerve injury comprises that demyelinating optic neuropathy (optic neuritis, retrobulbar optic neuritis), vagina nervi optici meningioma, adult's optic neuritis, children's optic neuritis, preocular ischemic optic neuropathy, rear portion ischemic optic neuropathy, compressibility optic neuropathy, papilloedema, pseudopapilloedema and toxic/nutritional optic neuropathy become.

The neuroscience patient's condition that other are relevant with visual loss, though directly not relevant with optic nerve injury, comprise amblyopia, Bells palsy, chronic progressive external ophthalmoplegia, multiple sclerosis, pseudotumor cerebri and trigeminal neuralgia.

Aspect some, vision impairment is caused by retina injury of the present invention.In special embodiment, retina injury is (for example, arteriosclerosis, the vasculitis) that is caused by the circulatory disorders that flows to eyes.In special embodiment, retina injury is broken by macula lutea and is caused (for example exudative or non-exudative macular degeneration).

Exemplary retinal diseases comprises exudative age-related macular degeneration, non-exudative age-related macular degeneration, retina electronics prosthesis and the age-related macular degeneration of RPE transplantability, acute multifocal placoid pigment epitheliopathy, acute retinal necrosis, vitelliform macular degeneration, branch retinal artery occlusion, branch retinal vein occlusion, cancer is correlated with and relevant autoimmunity retinopathy, central retinal artery occlusion, central retinal vein occlusion, central serous chorioretinopathy, eales disease, the macula lutea cephacoria, the sex change of grid sample, large aneurysm, diabetic macular edema, the Irvine-Gass macular edema, macular hole, SRNM, diffuse unilateral subacute neuroretinitis, unartificial lens CME, POHS, exudative detachment of retina, the postoperative detachment of retina, the proliferative detachment of retina, source, hole property detachment of retina, traction detachment of retina, retinitis pigmentosa, the CMV retinitis, retinal neuroblastoma, retinopathy of prematurity, birdshot sample retinopathy, background diabetic retinopathy, PDR becomes, hemoglobinopathy, the Purtscher retinopathy, the Valsalva retinopathy, juvenile retinoschisis, senile retinoschisis, terson's syndrome and white point syndrome.

Other exemplary diseases (for example comprise the eye infectation of bacteria, conjunctivitis, keratitis, tuberculosis, syphilis, gonorrhoea), the outside retinal necrosis of carrying out property or the relevant eye disease relevant of other HIV of virus infection (for example, eye hsv, varicella zoster virus, the cytomegalovirus retinitis, human immunodeficiency virus (HIV)) and HIV secondary with other immunodefiiciencies.In addition, eye disease comprises fungal infection (for example, the mould genus choroiditis of beads, histoplasmosis), protozoal infections (for example, toxoplasmosis) and for example ocular toxocariasis and sarcoid other diseases.

One aspect of the present invention is the sirtuin conditioning agent disclosed herein by the object therapeutic dose that needs this treatment, suppress, reduce or treat the VI method of the object of experience chemotherapeutic agent (for example, the medicine of the rising intraocular pressure of neurotoxic medicine, for example steroid) treatment.

The present invention is the sirtuin conditioning agent disclosed herein by the object therapeutic dose that needs this treatment on the other hand, suppresses, reduces or the treatment experience comprises for example VI method of the object of operation on spinal cord of the operation carried out in eye or other ventricumbent position.Operated eye comprises cataract, iridotomy and lens displacement technique.

Another aspect of the present invention is the sirtuin conditioning agent disclosed herein by the object therapeutic dose that needs this treatment, and treatment comprises and suppressing and prophylactic treatment, comprises the old eye disease of cataract, xeropthalmus, retina injury etc.

Cataractous formation is relevant with some biochemical variations of crystalline lens, and for example the sodium of lipid, amino acid and the protein oxidation of the antioxidants ascorbic acid of level decline and gsh, increase, increase and calcium, amino acid forfeiture and lens metabolism descend.The lens that lacks blood vessel is suspended in the eyes forward extracellular fluid.Nutrient substance, for example xitix, gsh, vitamin-E, selenium, Vitamin P complex and carotenoid are that to keep the lens transparency necessary.Low-level selenium causes causing the increase of the hydrogen peroxide of radical, and it is by selenium-dependency antioxidase glutathione peroxidase neutralization.Lens protectiveness glutathione peroxidase also depends on amino acids methionine, halfcystine, glycine and L-glutamic acid.

Cataract also can develop owing to the semi-lactosi that suitable metabolism is found in the milk-product that contain the disaccharide that lactose, monose semi-lactosi and glucose forms.If can find and correct metabolism early, cataract can be prevented, be postponed, be slowed down and even may be reversed.

Retina injury is especially owing to changing the reaction that free radical causes in (AMD) in glaucoma, diabetic retinopathy and the macular degeneration relevant with the age.Eyes are parts of central nervous system, have limited regenerative power.Retina is made up of numerous polyunsaturated fatty acid that contains maximum concentration (PFA) and easily oxidated neurocyte.Radical is produced by the plastosome in the ultraviolet ray that enters eyes and rod and the vertebra, and it produces conversion light is the energy that the vision impulsion needs.Free radical causes the peroxidation of PFA by hydroxyl or super-oxide group, and described hydroxyl or super-oxide group are bred other radical again.Radical causes the temporary transient or permanent damage of retinal tissue.

Glaucoma is regarded as causing the obstacle of the intraocular pressure (IOP) of rising usually, and it causes the optic nerve fiber permanent damage, but the glaucoma case of sixth can not develop elevated IOP.This disease is understood that it is a kind of vascular perfusion of minimizing and the increase of neurotoxic factor now.Nearest research has hinted as L-glutamic acid, nitrogen protoxide and peroxynitrite salt level in the eye of the retinal ganglial cells cause of death and has raise.Nerve protection medicine may be the future of glaucoma nursing.For example, the nitric oxide synthase inhibitors blocking-up forms peroxynitrite salt from nitrogen protoxide and super-oxide.In nearest research, the animal retinal ganglial cells loss of aminoguanidine, nitric oxide synthase inhibitors treatment reduces.It obtains conclusion and thinks that nitrogen protoxide causes cytotoxicity and causes neurotoxicity in central nervous system in many tissues in the eye.

When microvascular abnormality that the development of basic blood vessel mainly is made up of the feature and the inter-retinal hemorrhage of microaneurysm purpura, the diabetic retinopathy generation.The oxidative metabolism product is participated in the morbidity of diabetic retinopathy directly, and radical increases the generation of somatomedin, causes the proliferation activity that improves.The nitrogen protoxide that vascular endothelial cell generates also can cause the lax vasorelaxation that causes vessel segment of smooth muscle cell.Retinal ischemia and anoxic betide after artery basement membrane thickened, endothelium propagation and the perithelial cells loss.Oxygenation is inadequate to cause that capillary vessel is inaccessible or it is impaired not have perfusion, arteriovenous shunt, slow blood flow and RBC release oxygen ability.The lipid peroxidation of retinal tissue also can be owing to radical damage takes place.

Macula lutea is responsible for our acute central vision, is made up of photic sense cell (vertebra), and basic retinal pigment epithelium (RPE) and choroid nourishing also help to remove waste material.The vitamin A substrate of RPE and phytochrome nourishes vertebra and the digestion vertebra outer point of canopy (cones shed outer tips).RPE is exposed to high-caliber uv-radiation and suppresses the secretion factor that blood vessel takes place.Choroid comprises the intensive vasoganglion that nutrition is provided and removes waste material.

In AMD, canopy awl point (the shed cone tips) is become indigestible by RPE, and its cell is being collected too many undigested material after and dead.The collection of indigestion waste material is called druse, forms under RPE.The phototoxicity damage also causes the gathering of lipofuscin in the RPE cell.The druse gathering hinders oxygen and nutrient substance to be transported to retinal tissue in interior lipofuscin of cell and the Bruch ' s film, and finally causes RPE and sight sensor dysfunction.In exudative AMD, blood vessel by Bruch ' s film damaged from entochoroidea growth and can under RPE, grow, from choroidal detachment and liquid body exudate or hemorrhage.

Macular pigment, the amphiblestroid protection factor of a kind of prevention sun damage is assembled and to be formed by the trophicity carotenoid of deriving, for example xenthophylls, transport the fatty xanthein of carrier as other important nutrient and zeaxanthin.Antioxidant, for example vitamins C and E, β-Hu Luobusu and xenthophylls and zinc, selenium and copper all are found in the healthy macula lutea.Except nutrition is provided, these antioxidant protection avoid causing the radical damage of macular degeneration.

Another aspect of the present invention is the sirtuin conditioning agent disclosed herein by the object therapeutic dose that needs this treatment, prevention or treatment stress, chemical damage or radiation-induced ocular injury.The damage of the radiation of eyes or electromagnetism can comprise CRT ' s or be exposed to sunlight or damage that UV causes.

In one embodiment, the medicinal composition therapy can comprise the medicine or the compound of treatment or the prevention eye disease or the secondary patient's condition relevant with these patient's condition.Therefore, the medicinal composition therapy can comprise the medicine of one or more sirtuin activators and one or more treatment eye diseases.For example, one or more sirtuin activating compounds can with one or more following drug regimens of significant quantity: reduce the medicine of intraocular pressure, the medicine for the treatment of glaucomatous medicine, treatment optic neuritis, the amphiblestroid medicine of treatment CMV, the medicine of treatment multiple sclerosis and/or microbiotic etc.

In one embodiment, the sirtuin conditioning agent can be in conjunction with the therapy administration that reduces intraocular pressure.One group of therapy comprises the generation of blocking aqueous humor.For example, local beta-adrenaline antagonist (timolol and betaxolol) reduces the generation of aqueous humor.Local timolol causes in 30 minutes that IOP descends and reached the peak effect at 1-2 hour.Reasonable plan is 1 of 0.5% timolol, per 30 minutes, administration 2 times.The carbonic anhydrase inhibitor acetazolamide also reduces the generation of aqueous humor and should give in conjunction with local beta-agonists.After giving the predose of 500mg, gave 250mg in per 6 hours.Medicine can be oral like this, intramuscular or intravenously give.In addition, α 2-antagonist (for example, Aplonidine) works by reducing aqueous humor.Their effect is adding the topical administration beta blocker.They have got permission to be used to control the acute rising of pressure behind anterior chamber's laser operation, but have reported treatment acute angle closure glaucoma's validity.Reasonable plan be per 30 minutes 1, administration 2 times.

Second group of therapy that reduces intraocular pressure comprises minimizing vitreum volume.Hyperosmotic drugs can be used for the treatment of acute attack.These medicines are taken water out of eyeball by the blood height is oozed.50% cold soln of oral dosage 1mL/kg glycerine (mix make with lemon juice its better to eat) is often to use.Glycerine changes glucose in liver; If suffer from the people of diabetes after accepting glycerine, become hyperglycemia they can need additional Regular Insulin.Oral Isosorbide is a kind of metabolism inert alcohol, also can be as the permeant of suffering from patient acute angle closure glaucoma.Usually dosage is oral 100g (45% solution of 220cc).This inert alcohol should not obscured with the cardiac drug Dilatrate-SR based on nitrate that is used for stenocardia and congestive heart failure.Giving N.F,USP MANNITOL with the dosage vein of 1.0-1.5mg/kg also is that patient effective and pernicious and vomiting can tolerate well.These hyperosmotic drugs should carefully use in any patient that the congestive heart failure medical history arranged.

The 3rd group of therapy comprises that the promotion aqueous humor outflows from eye.Miotic helps to alleviate the trabecular network obstruction from iridocorneal angle tractive iris and by the periphery iris.2% (blue eyes)-4% (pinhole eyeball) pilocarpine can be administration in per 15 minutes in initial 1-2 hour.More frequent administration or more high dosage can bring out the general cholinergic crisis.Sometimes NSAIDS also is used to reduce inflammation.

The medicine of exemplary minimizing intraocular pressure comprises ALPHAGAN

P (Allergan) (brimonidine tartrate ophthalmic solution), AZOPT

(Alcon) (brinzolamide ophthalmic suspension), BETAGAN

(Allergan) (the Levobunolol Hydrochorid ophthalmic solution, USP), BETIMOL

(Vistakon) (timolol ophthalmic solution), BETOPTIC S

(Alcon) (betaxolol hydrochloride), brimonidine tartrate (Bausch ﹠amp; Lomb), carteolol hydrochloride (Bausch ﹠amp; Lomb), COSOPT

(Merck) (dorzolamide hydrochloride-timolol maleate ophthalmic solution), LUMIGAN (Allergan) (bimatoprost ophthalmic solution), OPTIPRANOLOL

(Bausch ﹠amp; Lomb) (metipranolol ophthalmic solution), TIMOLOL GFS (Falcon) (the timolol maleate eye is with becoming gelating soln), TIMOPTIC (Merck) (timolol maleate ophthalmic solution), TRAVATAN (Alcon) (travoprost ophthalmic solution), TRUSOPT

(Merck) (dorzolamide hydrochloride ophthalmic solution) and XALATAN

(Pharmacia ﹠amp; Upjohn) (latanoprost for eyes solution).

In one embodiment, the sirtuin conditioning agent can combined treatment and/or is prevented glaucomatous therapy administration.The example of a glaucoma medicine is DARANIDE

Tablet (Merck) (daranide).

In one embodiment, the sirtuin conditioning agent can combined treatment and/or the therapy administration of prevention optic neuritis.The example of optic neuritis medicine comprises DECADRON

Phosphoric acid salt injection (Merck) (dexamethasone sodium phosphate), DEPO-MEDROL

(Pharmacia ﹠amp; Upjohn) (medrat acetate), HYDROCORTONE

Tablet (Merck) (hydrocortisone), ORAPRED

(Biomarin) (prednisolone phosphate disodium oral solution) and PEDIAPRED (Celltech) (prednisolone phosphate sodium, USP).

In one embodiment, the sirtuin conditioning agent can combined treatment and/or the therapy administration of prevention CMV retinopathy.The medicine of treatment CMV retinopathy comprises CYTOVENE

(ganciclovir capsule) and VALCYTE

(Roche Laboratories) (valganciclovir hydrochloride tablet).

In one embodiment, the sirtuin conditioning agent can combined treatment and/or the therapy administration of prevention multiple sclerosis.The example of this class medicine comprises DANTRIUM

(Procter ﹠amp; GamblePharmaceuticals) (Dantrolene Sodium), NOVANTRONE (Serono) (mitoxantrone), AVONEX

(Biogen Idec) (interferon beta-1a), BETASERON

(Berlex) (interferon beta-1b), COPAXONE

(Teva Neuroscience) (glatiramer acetate injection) and REBIF (Pfizer) (interferon beta-1a).

In addition, have the macrolide of various active and/or mycophenolic acid can with sirtuin conditioning agent co-administered.Macrolide antibiotics comprises tacrolimus, ciclosporin, sirolimus, everolimus, ascosin, Abboticine, azithromycin, Clarith, clindamycin, lincomycin, his erythromycin, EN-141, Spiramycin Base, diacetyl mydecamycin, tylosin, Roxithromycin, ABT-773, Ketek, leucomycin and lincosamide.

Plastosome relative disease and obstacle

In certain embodiments, the invention provides treatment and can benefit from the disease of mitochondria activity increase or the method for obstacle.This method comprises the sirtuin activating compounds of the object treatment significant quantity that needs.The mitochondria activity that increases is meant that mitochondria activity increases, and keeps mitochondrial sum (for example, mitochondrial mass) simultaneously, increases mitochondria number thereby increases mitochondria activity (for example, plastosome is biological to be taken place by stimulating) or its combination.In certain embodiments, the disease that can benefit from mitochondria activity and increase comprises disease relevant with mitochondria dysfunction or obstacle with obstacle.

In certain embodiments, the treatment method that can benefit from disease that mitochondria activity increases or obstacle can comprise and identifies the object of suffering from mitochondria dysfunction.The handicapped method of diagnostics lines plastochondria may relate to molecular genetic, pathological and/or biochemical analysis, and these are summarized in Cohen and Gold, and ClevelandClinic Journal of Medicine is among the 68:625-642 (2001).The handicapped a kind of method of diagnostics lines plastochondria be Thor-Byrne-ier scale (referring to for example, Cohen and Gold, supra; Collin S.et al., Eur Neurol.36:260-267 (1996)).Other method of measuring mitochondria number and function comprises, for example, enzyme analyzes that (for example, the cyclophorase or the ATP biosynthesizing factor for example ETC enzyme or tricarboxylic acid cycle enzyme), mensuration or mitochondrial mass, plastosome volume and/or mitochondria number, Mitochondrial DNA quantize, monitoring intracellular Ca2+ stable state and/or to the cell response of this stable state perturbation, to the evaluation of pro-apoptotic irritant reaction, the mensuration that free radical generates.These class methods are known in the art and are described in, for example, and U.S. Patent Publication No.2002/0049176 and the reference of wherein quoting.

Plastosome is vital to the eukaryotic survival and the appropriate functional of nearly all type.In fact the plastosome in any cell type can suffer from the geneogenous or acquired defect that influences its function.Therefore, influence the significance sign of mitochondrial defects of respiratory chain function and symptom clinically and be heterogeneous with variable, this depends on the seriousness and the influenced cells physiological demand of the distribution of defective plastosome in cell and their defectives.Not meristem with high energy demand, for example, nervous tissue, skeletal muscle and cardiac muscle are responsive especially to mitochondrial respiratory chain dysfunction, but any organ systems all may be affected.

Disease relevant with mitochondria dysfunction and obstacle comprise that the active defective of mitochondrial respiratory chain causes the disease and the obstacle of this disease in the Mammals or the development of obstacle physiopathology.This comprises 1) the active congenital hereditary defective of the one or more parts of mitochondrial respiratory chain; With 2) the active acquired defect of the one or more parts of mitochondrial respiratory chain, wherein this defective is caused by following factor: a) oxidative damage in the aging course; B) intracellular Ca2+ of Sheng Gaoing; C) attacked cellular exposure in nitrogen protoxide; D) anoxic or local asphyxia; E) microtubule related defects in the plastosome axonal transport; Or f) expression of plastosome uncoupling protein.

Disease or obstacle that can benefit from mitochondria activity increases for example generally include, and the oxidative damage of free radical mediated causes the disease of tissue deterioration, cell to experience the disease of natural death of cerebral cells and the disease that cell can't experience natural death of cerebral cells inadequately.Exemplary disease or obstacle that can benefit from mitochondria activity increases comprise, for example, AD (alzheimer's disease), ADPD (alzheimer's disease and Parkinson's disease), AMDF (ataxia, myoclonus and deafness), autoimmune disease, cancer, CIPO (chronic intestinal pseudoobstruction companion's myopathy and ophthalmoplegia), congenital muscular dystrophy, CPEO (chronic progressive external ophthalmoplegia), DEAF (the maternal inheritance induced deafness or Aminoglycoside inductive deafness), DEMCHO (dementia and tarantism), diabetes (I type or II type), DIDMOAD (diabetes insipidus, diabetes, optic atrophy, deaf), DMDF (diabetes and deafness), dystonia, motion does not tolerate, ESOC (epilepsy, apoplexy, optic atrophy, descend with cognition), FBSN (the striatum necrosis of familial both sides), (morbific baby's myocardosis adds FICP, MELAS-dependency myocardosis), GER (gi tract backflow), HD (Huntington Chorea), KSS (Kearns-Sayre syndrome), " after a while-morbidity " myopathy, LDYT ( Leber ' s hereditary optic neuropathy and open The power obstacle), leigh's syndrome, LHON (leber hereditary optic neuropathy), LIMM (mortality baby's mitochondrial myopathy), MDM (myopathy and diabetes), MELAS (mitochondriopathy myopathy, lactic acidosis and the outbreak of apoplexy sample), MEPR (myoclonic epilepsy and consciousness are degenerated), MERME (the overlapping disease of MERRF/MELAS), MERRFS (myoclonic epilepsy and broken red muscle fiber), MHCM (maternal inheritance hypertrophic cardiomyopathy), MICM (maternal inheritance myocardosis), MILS (maternal inheritance subacute necrotizing encephalopathy), plastosome Encephalocardiomyopathy, mitochondrial encephalomyopathy, MM (mitochondrial myopathy), MMC (parent myopathy and myocardosis), MNGIE (myopathy and ophthalmoplegia externa, neuropathy, stomach and intestine, encephalopathic), many body system plastosome obstacle (myopathy, encephalopathic, insomnia, anakusis, peripheral neurophaty), NARP (neuromyasthenia, ataxia, and retinitis pigmentosa; Alternative phenotype (alternate phenotype) at this position is reported as Leigh disease), PD (Parkinson's disease), Pearson's syndrome, PEM (carrying out encephalopathy (HIE)), PEO (PEO), PME (PME), PMPS (Pearson's marrow-pancreas syndrome), psoriatic, RTT (Rett syndrome), schizophrenia, SIDS (sudden infant death syndrome (SIDS)), SNHL (sensorineural hearing loss), (the clinical manifestation scope is carried out sexual dysfunction and mortality myocardosis to truncal ataxia from spasm paraparesis to many body system in different familials performances, dysphonia, serious hearing loss, spirit is degenerated, blepharoptosis, ophthalmoplegia, far-end cyclone and diabetes), or Wolfram syndrome.

Disease or obstacle that other can benefit from mitochondria activity increases generally include, for example, Freed relies uncommon (family name) ataxia and other ataxia, amyotrophic lateral sclerosis (spinal cord) lateral sclerosis (ALS) and other motor neurone diseases, macular degeneration, epilepsy, alpers syndrome, multiple plastosome deletion syndrome, the MtDNA deletion syndrome, complex body I deficiency disease, complex body II (SDH) deficiency disease, complex body III deficiency disease, cytochrome C oxidase (COX, complex body IV) deficiency disease, complex body V deficiency disease, adenine nucleotide transposon (ANT) defective, pyruvic oxidase (PDH) defective, ethyl malonic acid uraturia companion lacticemia, 3-methylpentene diacid uraturia companion lacticemia, going down property of period of infection intractable epilepsy, going down property of period of infection Asperger syndrome, going down property of period of infection autism, attention-deficit hyperactivity disease (ADHD), going down property of period of infection cerebral paralysis, going down property of period of infection dislexia, matrilinear inheritance thrombopenia and leukemia syndrome, (the mitochondrial ataxia of MARIAHS syndrome, recurrent infection, aphasia, Hypouricemia/atelomyelia (hypomyelination), epileptic seizures and dicarboxylic acid uraturia), the ND6 myodystonia, period of infection is gradually moved back property in sexual cycle vomiting syndrome, 3-hydroxy-iso-butyric acid blood urine companion lacticemia, diabetes companion lacticemia, the reactive nervous syndrome (URNS) of uridine, DCM (dilated cardiomyopathy), spleen lymphoma and renal tubular acidosis/diabetes/ataxia syndrome.

In other embodiments, the invention provides treatment and suffer from the method for the object of plastosome obstacle, this obstacle results from, but be not limited to craniocerebral injury and cerebral edema after the wound, apoplexy (the inventive method is to prevention or prevent that reperfusion injury is useful), Lu Yi body dementia, hepatorenal syndrome, acute hepatic failure, NASH (non-alcoholic liver decline fat hepatitis), anticancer transfer/undifferentiated carcinoma treatment, the congestive heart failure of the special property sent out, atrial fibrillation (non-valve), Wolff-Parkinson-White syndrome, the special property sent out heart-block, the prevention of Acute Myocardial Infarction focus diffusion, the familial migraine, irritable bowel syndrome, non-q wave myocardial infarction Secondary cases prevention, premenstrual syndrome, the prevention of liver kidney renal failure syndrome, antiphospholipid antibody syndrome, eclampsia/preeclampsia, the ovum sterility, ischemic heart disease/stenocardia, with Shy-Drager and non-classified dysautonomia syndrome.

The method of the relevant plastosome obstacle of the treatment side effect relevant with the pharmacology medicine is provided in another embodiment.The pharmacy type relevant with the plastosome obstacle comprises reverse transcriptase inhibitors, proteinase inhibitor, DHOD inhibitor etc.The example of reverse transcriptase inhibitors comprises, for example, Zidovodine (AZT), stavudine (D4T), zalcitabine (ddC), Didanosine (DDI), Fluoroiodoarauracil (FIAU), Lamivudine(3TC), Abacavir etc.The example of proteinase inhibitor comprises, for example, and ritonavir, indinavir, Saquinavir, nelfinavir etc.The example of dhodh inhibitors (DHOD) comprises, for example, and leflunomide, brequinar etc.

Reverse transcriptase inhibitors not only suppresses ThermoScript II, also suppresses the required polysaccharase γ of mitochondrial function.Therefore the polysaccharase gamma activity suppresses (for example, using reverse transcriptase inhibitors) and causes mitochondria dysfunction and/or mitochondrial mass decline, and it shows as hyperlactacidemia in patient.Such patient's condition can be benefited from the increase of mitochondria number and/or the improvement of mitochondrial function, for example, and by giving sirtuin activating compounds.

The common sympton of mitochondrial disease comprises myocardosis, myasthenia and atrophy, hypoevolutism (comprise motion, language, cognition or carry out function), ataxia, epilepsy, renal tubular acidosis, peripheral neurophaty, optic neuropathy, autonomic neuropathy, neurogenic intestinal dysfunction, sensorineural hearing loss, neurogenic bladder dysfunction, DCM (dilated cardiomyopathy), migraine, liver failure, lacticemia and diabetes.

In certain embodiments, the invention provides treatment and can benefit from the disease of mitochondria activity increase or the method for obstacle, comprise one or more sirtuin activating compounds of object that need it and the combination of other treatment medicine, the other treatment medicine for example, medicine (the antioxidant for example that is used for the treatment of mitochondria dysfunction, VITAMIN or respiratory chain cofactor), be used to reduce medicine (for example, the anti-epileptic outbreak medicine of the symptom relevant with disease that comprises mitochondria dysfunction or obstacle, be used to alleviate the medicine of neuropathic pain, the medicine that is used for cardiac dysfunction), cardiovascular agent (as hereinafter further describing ground), chemotherapeutic drug (as hereinafter further describing ground) or anti-neurodegeneration medicine (as hereinafter further describing ground).In an exemplary embodiment, the invention provides treatment and can benefit from the disease that mitochondria activity increases or the method for obstacle, comprise combining of one or more sirtuin activating compounds of object of needing it and one or more following medicines: ubiquinone ₁₀, L-carnitine, VitB1, riboflavin, niacinamide, folic acid, vitamin-E, selenium, Thioctic Acid or prednisone.This paper also provides the composition that comprises this combination.

In exemplary embodiment, the invention provides by the sirtuin activating compounds treatment that gives object treatment significant quantity and can benefit from the disease of mitochondria activity increase or the method for obstacle.Exemplary disease or obstacle comprise, for example, neuromuscular disorder (for example, Friedreich ' s ataxia, muscular dystrophy, multiple sclerosis etc.), neural unstable obstacle (epilepsy obstacle for example, migraine etc.), hypoevolutism, the neurodegeneration obstacle (for example, alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis etc.), local asphyxia, renal tubular acidosis, age related neurodegeneration and cognitive decline, chemotherapy fatigue, age related or the menopause of chemotherapy inductive or menstrual cycle or ovulate irregular, mitochondrial myopathy, (for example, calcium gathers injury of mitochondria, excitotoxicity, nitrogen protoxide exposes, anoxic etc.) and the plastosome abnormality.

Family ataxia (FA) genetically deficient, modal hereditary ataxia is identified and called after " frataxin " recently.In FA, after one section normal development, develop into paralysis and dead coordination lack usually 30 and 40 years old between development.Most affected tissue is spinal cord, peripheral nerve, cardiac muscle and pancreas.The common lost-motion control of patient also is restricted in the wheelchair, and be subjected to the torment of in heart failure and diabetes usually.The hereditary basis of FA comprises that the GAA trinucleotide series connection in the coding frataxin gene intron zone repeats.These multiple exist and cause the genetic transcription and the expression that reduce.Frataxin is relevant with the regulation and control of plastosome iron level.When cell frataxin content was low, excessively iron was gathered in the plastosome, promotes oxidn damage and subsequently plastosome sex change and dysfunction.When the GAA of medium number repeated in the frataxin gene intron, ataxic serious clinical phenotypes can not develop.But with about 5% non-diabetic physiognomy ratio, the trinucleotide of these moderate-lengths is found among the patient who suffers from non insulin dependent diabetes of 25-30%.In certain embodiments, the sirtuin activating compounds can be used for the treatment of the patient who suffers from the obstacle relevant with frataxin disappearance or defective, and this obstacle comprises family ataxia, myocardial dysfunction, diabetes and as the diabetic complication of peripheral neurophaty.

Muscular dystrophy is meant the h disease that comprises that the neuromuscular 26S Proteasome Structure and Function is degenerated, and causes skeletal muscle atrophy and myocardial dysfunction usually.For Duchenne muscular dystrophy, differential protein sudden change or disappearance, dystrophin are all relevant with its nosetiology.Mouse with dystrophin gene of deactivation shows some characteristics of muscular dystrophy, and about 50% the active defective of mitochondrial respiratory chain is arranged.The final common pathway that neuromuscular is degenerated in most of cases is the mitochondrial function damage of calcium mediation.In certain embodiments, the sirtuin activating compounds can be used to reduce the rate of descent of muscle function ability and improve patient's muscle function state of suffering from muscular dystrophy.

Multiple sclerosis (MS) is the neuromuscular disease that deteriorates to feature with focus inflammation and cerebral white matter autoimmunity.Periodic worsen or the upper respiratory tract that outbreak is significantly bacteroidal and viral with no matter relevant with other infection, show that mitochondria dysfunction works in MS.The neurone mitochondrial respiratory chain that nitrogen protoxide (being generated by the stellate cell that relates to inflammation and other cells) causes suppresses to relate to the molecule mechanism as causing MS.In certain embodiments, no matter can be used to suffer from the multiple sclerosis patient be the treatment when showing effect of prevention and disease progression to the sirtuin activating compounds.

Epilepsy is present among the patient who suffers from mitochondrial cytopathies usually, comprises a series of outbreak severities and frequency, and for example, disappearance, enhancing, slow, myoclonus and epileptic state betide isolated epilepsy or one day many times.In certain embodiments, the sirtuin activating compounds can be used for the treatment of the patient who suffers from mitochondria dysfunction secondary epilepsy, comprises reducing epilepsy active frequency and severity.

The metabolism of suffering from recidivity migraine patient be studies show that the mitochondria activity defective is relevant with this obstacle usually, show as impaired oxidative phosphorylation and too much lactic acid generation.This defective is not necessarily because the Mitochondrial DNA hereditary defect.The migraine object is extremely sensitive to nitrogen protoxide, and nitrogen protoxide is the endogenous inhibitor of cytochrome c oxidase.In addition, suffer from mitochondrial cytopathies for example the patient of MELAS suffer from the recidivity migraine usually.In certain embodiments, the sirtuin activating compounds can be used for the treatment of suffers from the migrainous patient of recidivity, comprises ergot compound or the refractory headache of 5-hydroxytryptamine receptor antagonist.

Neural or neural mental retardation is typically found at the children that suffer from mitochondrial disease.The neural growth that connects and reinvent and need intensive biosynthesizing activity, synthetic particularly including neurone film and myelin, the two all needs pyrimidine nucleotide as cofactor.Uridine relates to the inactivation of sugar and to the transfer of glycolipid and glycoprotein.Cytidine nucleotide is derived from uridylate, is important to the synthetic of main membrane phospholipid composition of for example phosphatidylcholine, and phosphatidylcholine is accepted its choline part from cytidine diphosphocholine (cytidine diphosphocholine).Cause pyrimidine to synthesize the impaired patient's condition for mitochondria dysfunction (because acquisition or defective with good conditionsi of Mitochondrial DNA defective or any mitochondria dysfunction as exicitoxic or mediated by nitric oxide) or other, cell proliferation and axon elongation are impaired at the critical stage that neurone interconnects and grow in the loop, cause neural moral function for example language, motion, social activity, execution function and cognitive skill hypoevolutism or stop.With the autism is example, and the phosphate cpd Magnetic Resonance Spectrum measure to show and to exist the sphere of film and film precursor to owe synthetic (undersynthesis) in the brain, shows by uridine diphosphate (UDP)-sugar of reducing and is contained in the cytidine nucleoside derivates level of film in synthesizing.The disease that with the hypoevolutism is characteristics comprises the special Cotard of thunder, spread sexual development slow (or PDD-NOS " NOS spread sexual development slow " distinguishes itself and concrete for example autistic subclass), autism, Asperger ' s syndrome and just becoming the attention deficit/hyperactivity disorder (ADHD) that generally acknowledged neural circuit is carried out the slow or backwardness of functional development at all.In certain embodiments, the sirtuin activating compounds can be used for the treatment of suffers from neurodevelopment slow (for example, comprising motion, language, execution function and cognitive skill) or other neurosciencies of neural system and neural spirit growth and for example muscle and non-nervous tissue's body hypoevolutism of incretory gland or the patient who stops.

With old and feeble, alzheimer's disease (AD) is relevant with Parkinson's disease two the pathogenesis of significant serious neurodegenerative disease all comprise mitochondria dysfunction.Especially, complex body I defective not only often is found in the nigrostriatum neurone of degenerating in Parkinson's disease, also is found in the muscle and hematoblastic peripheral tissues and cell that resembles patient Parkinson.In alzheimer's disease, the mitochondrial respiratory chain activity usually is suppressed, especially complex body IV (cytochrome c oxidase).Also have, the mitochondrial respiratory function is suppressed fully owing to aging, further strengthens harmful sequela of the additional molecule damage that influences the respiratory chain function.Other factors except former hair line plastochondria dysfunction become neurodegenerative basis in AD, PD and the associated disorders.Excitatory stimulation and nitrogen protoxide all relate to this two kinds of diseases, and aggravation mitochondrial respiratory chain defective and its deleterious effect are in the extended factor of the background of respiratory chain dysfunction.Huntington Chorea is also included within the mitochondria dysfunction of being attacked in the brain zone, with excitatory stimulation and the mutual synergy that causes the mitochondria dysfunction of neuronal degeneration.In certain embodiments, the sirtuin activating compounds is useful to treatment with slowing down the relevant neurodegenerative disease progress of age that comprises AD and PD.

One of main hereditary defect of patient of suffering from amyotrophic lateral sclerosis (ALS or Lou Gehrig ' s disease) is the sudden change or the shortage of copper-Cu/Zn SOD (SOD1) (a kind of antioxidant enzyme).Plastosome had not only produced but also had been the main target spot of reactive oxygen species.Electronics is the most significant physiology of free radical source in the Mammals system to the invalid transfer of oxygen in the plastosome.The shortage of antioxidant or antioxidant enzymes can cause or aggravate the plastosome sex change.Similar symptom and pathology among mutant SOD1 transgenic mice development and the people ALS.Advancing of disease has confirmed to relate to mitochondrial oxidation destruction in these animals, next is that motor neuron deterioration and clinical symptom take place.Patient's ALS skeletal muscle has low plastosome complex body I activity.In certain embodiments, the sirtuin activating compounds can be used for the treatment of the progress that ALS reversed or delayed clinical symptom.

By the terminal electron acceptor cell that reoxidizes at complex body IV forfeiture cytochrome c, anoxic causes the active direct inhibition of mitochondrial respiratory chain, and indirectly, particularly in neural system, forms by excitotoxicity and nitrogen protoxide after the secondary anoxic.In the patient's condition, organize relative oxygen level low such as cerebral anoxia, stenocardia or sicklemia crisis.In these situations, the compound protection that increases mitochondria activity is subjected to the invasion and attack tissue to avoid the anoxybiotic deleterious effect, weakens the delayed cell death of secondary, and quickens to recover from hypoxic organizational stress and damage.In certain embodiments, the sirtuin activating compounds can be used to prevent cerebral ischemia or the post-traumatic delayed cell death of anoxic (betiding the apoptosis in about 2 to 5 days zone such as hippocampus or cortex after the cerebral ischemia attack).

No matter basic respiratory chain dysfunction is inborn or local asphyxia or such as the cell toxicity medicament inductive of cis-platinum, often observes the oxypathy that renal insufficiency causes in suffering from the patient of mitochondrial disease.Renal tubular acidosis often need give the pH value that exogenous sodium bicarbonate is kept blood and tissue.In certain embodiments, the sirtuin activating compounds can be used for the treatment of renal tubular acidosis and the other forms of renal tubal dysfunction that the mitochondrial respiratory chain defective causes.

In normal aging course, exist carrying out property of mitochondrial respiration-chain function to go down.Beginning in about 40 years old, the rising of human mitochondrial DNA defective aggregate index, mitochondrial respiratory chain active nucleus-adjusting element descends simultaneously.Many mitochondrial DNA damages especially have selective advantage in the postmitotic cells in the plastosome turnover.The mechanism that proposes is that the plastosome of respiratory chain defective causes still less oxidative damage (mitochondrial respiratory is the main source of interior free yl) than the plastosome of complete function respiratory chain to it.Therefore, the plastosome of normal function is accumulated oxidative damage to membrane lipid quickly than defective plastosome, and is therefore degraded by lysosome " mark ".Because the transformation period of intracellular plastochondria is approximately 10 days, selective advantage can cause functional plastosome to replace the plastosome that those respiratory activities reduce fast, especially in slow noble cells.In case net result is reduction the gene of the mitochondrial protein of plastosome oxidative damage is undergone mutation, this defective plastosome can spread all over cell fast, reduces or eliminates or its respiration capability.The organism level that accumulates in of this cell causes aging or degenerative disease.This with muscle in the carrying out property mosaicism of cell of the active defective of electron transport be consistent, in the cell of normal activity, almost lack the active cell of cytochrome c oxidase (COX) and consistent with taking a walk at random from the COX-negative cells high rate of old object biopsy.Thereby; organism can be in the face of such situation in old and feeble or various mitochondrial diseases; promptly the time in the face of the decline of carrying out property of irresistible mitochondrial respiration-chain function; irreplaceable postmitotic cells (for example, neurone, bone and cardiac muscle) must be protected and its function keep significant degree.Handicapped plastosome neurone becomes more responsive to the damage of for example excitability damage gradually.Plastosome depletion causes great majority to follow old and feeble degenerative disease (especially neurodegeneration).Congenital mitochondrial disease generally includes the neurodegeneration of early stage generation, and it is similar to the disease that takes place in having people's aging course of NM from birth on basic mechanism.In certain embodiments, the sirtuin activating compounds can be used for the treatment of or weaken cognitive decline and other old and feeble sex change consequences.

Be subjected to oxidative stress or for example in the cell of the cancer chemotherapy medicine of cis-platinum because the bigger vulnerability of Mitochondrial DNA and littler effective reparation, mitochondrial DNA damage than the nuclear dna damage more extensive also continue longer.Though Mitochondrial DNA is more more responsive to damage than nuclear DNA, in some cases, its mutagenesis to chemical carcinogen tolerates relatively.This is because plastosome is the genome by destroying its defective to the mitochondrial DNA damage of some type but not attempts repairing them.This causes after the cytotoxicity chemotherapy whole mitochondria dysfunction in for some time.Usually do not tolerate with weak " chemotherapy fatigue ", long-term weak and motion such as the clinical application of the chemotherapeutics of cis-platinum, mitomycin and ring phosphinylidyne ammonia, these in addition can recover the back at the blood of this class medicine and gastrointestinal toxicity and continue.In certain embodiments, the sirtuin activating compounds can be used for the treatment and the prevention of the cancer chemotherapy side effect relevant with mitochondria dysfunction.

Because be transmitted to those that are present in ovocyte when the plastosome of fetus all comes leisure conceived, the key function of ovary is to keep the genomic integrity of plastosome in the ovocyte.Mitochondrial DNA deletion can be detected about the age of menopause, and also relevant with abnormal menstrual cycle.Because cell can not directly detect and the Mitochondrial DNA defective is reacted, and can only detect the cytoplasmic secondary effect of influence, for example breathe the synthetic defective of impaired, redox state or pyrimidine, the product of this mitochondrial function is selected as ovocyte and the signal of follicle atresia participates in, when Mitochondrial Genome Overview tolerance range and functional activity can not guarantee, finally can cause menopause.This is similar to the apoptosis in the cell of dna damage, the active procedure of its experience cell suicide when the genome tolerance range can not be finished by repair process.The women who suffers from the gonadal mitochondrial cytopathies of influence can experience amenorrhoea early usually or show the primary circulation unusually.The cytotoxicity cancer chemotherapy is induced amenorrhoea early usually, with the corresponding osteoporotic risk that increases.The amenorrhoea of chemotherapy inductive is normally because primary ovarian failure.The incidence of chemotherapy inductive amenorrhoea increases as the function of the menopause female age of accepting chemotherapy, and points to and relate to plastosome.Mitochondrial respiratory or the ovulation of protein synthesis inhibitor inhibitory hormone inductive, and the generation of the ovary steroid hormone of inhibition response pituitary gonadotropic hormone.Suffer from the syndromic women of Down ' s and experience menopause prematurely usually, also early send out Alzheimer sample dementia easily.In Down ' s syndrome patient and tardy alzheimer's disease, as one man find the low activity of Terminal oxidase.Mitochondrial function is suitably supported or mitochondria dysfunction is compensatory thereby protection is avoided age relevant or menopause of chemotherapy inductive or menstrual cycle or ovulates irregular is useful.In certain embodiments, the sirtuin activating compounds is useful to treatment and prevention amenorrhoea, irregular ovulation, menopause or menopause secondary consequence.

In certain embodiments, sirtuin adjusting compound is useful to the treatment mitochondrial myopathy.The scope of mitochondrial myopathy from the gentleness of extraocular muscle, slowly carrying out property is unable to serious, fatal infantile myopathy and many body system brain myopathy.Some symptoms have determined that some is overlapping between them.The symptom of determining that influences muscle comprises PEO, Kearns-Sayre syndrome (ophthalmoplegia, pigmentary retinopathy changes, cardiac conduction defective, cerebellar ataxia and sensorineural hearing loss), MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis and the outbreak of apoplexy sample), MERFF syndrome (myoclonic epilepsy and ragged red fibers), the umbilical cord distribution is unable and infantile myopathy (optimum or serious with fatal).Because plastosome is excessively assembled, adopt the muscle biopsy sample of Gomori ' s three look dyeings of improvement to show ragged red fibers.Can be detected in the transhipment of substrate and the biochemical defect of utilization, tricarboxylic acid cycle, oxidative phosphorylation or respiratory chain.A large amount of mitochondrial DNA point mutations and disappearance are described, are passed in mode parent, non-Mendelian.The nuclear encoded mitochondrial enzyme is undergone mutation.

In certain embodiments, the sirtuin activating compounds can be used for the treatment of the patient who suffers from mitochondrial toxicity damage, and the toxic damages that the calcium that for example results from is accumulated, excitotoxicity, nitrogen protoxide expose, drug-induced toxic damages or anoxic.

The basic mechanism of cell injury especially in excitable tissue, relates to owing to handle the too much calcium that the mechanism defective enters cell by the seepage or the intracellular Ca2+ of plasma membrane.Plastosome is the main site of calcium accumulative, is used to preferentially that energy from respiratory chain absorbs calcium but not to be used for ATP synthetic, and it causes the depleted spiral of plastosome to descend, because take in the ability that mitochondrial calcium causes reducing energy conduction.

Excitatory amino acid overstimulation neurone is the common mechanism that central nervous system cell is dead or damage.The activation of glutamate receptor, the activation of nmda receptor hypotype especially by name, part raises by intracellular Ca2+ in the excitatory stimulation and causes mitochondria dysfunction.On the contrary, mitochondrial respiratory and oxidative phosphorylation lack makes cell to the excitatory stimulation sensitivity, cause contact to normal cell may be harmless excitatory neurotransmitter or necrocytosis or damage during toxin.

Nitrogen protoxide (about 1 micromole) suppress Terminal oxidase (complex body IV) and thereby suppress mitochondrial respiratory, in addition, prolong the activity that contact nitrogen protoxide (NO) irreversibly reduces complex body I.Thereby the NO of physiology or pathology concentration suppresses the biosynthesizing of pyrimidine.Nitrogen protoxide relates to the multiple neurodegenerative disease that comprises inflammation of the central nervous system and autoimmune disease, and with neuronal excitability and anoxic after damage between be situated between relevant.

Oxygen is the respiratory chain terminal electron acceptor.Oxygen lack infringement electric transmission chain activity, it is synthetic and to reduce ATP synthetic to cause reducing pyrimidine by oxidative phosphorylation.Under real oxygen free condition, if uridine and pyruvic acid (or a kind of oxidation NADH is to optimize the similar active drug that glycolysis-ATP generates) are provided, human cell multiplication also keeps viability.

In certain embodiments, the sirtuin activating compounds can be used for the treatment of and unusual relevant disease or the obstacle of plastosome.

The transcribing of Mitochondrial DNA of coding respiratory chain component needs nuclear factor.In neuron axon, plastosome must shuttle in nucleus to keep the respiratory chain activity.If aixs cylinder transportation is because anoxic or owing to such as the medicine of the taxol that influences microtubule stability and impaired, then incur loss away from nuclear mitochondrial Terminal oxidase.Correspondingly, use the treatment of sirtuin activating compounds can be used for promoting that nuclear-plastosome interacts.

Owing to overflow from mitochondrial respiratory chain, particularly when damaging electronics in the defective of one or more respiratory chain components when metabolic intermediate is delivered to molecular oxygen in an orderly manner, plastosome is the main source of free radical and reactive oxygen species.In order to reduce oxidative damage, cell can compensate by expressing plastosome uncoupling protein (UCP), has identified several albumen wherein.Reply oxidative damage, inflammatory cytokine or too much the lipid load for example transcribe UCP-2 when fatty liver and fatty hepatitis.Through discharge crossing over the proton gradient of mitochondrial inner membrane, UCP reduces and overflows reactive oxygen species from plastosome, in fact consumes the energy that produced by metabolism and reduces the exchange of oxidative damage and cell is coerced energy become easily injured as a kind of.

Muscle performance

In other embodiments, the invention provides the method that improves muscle performance by the sirtuin activating compounds for the treatment of significant quantity.For example, the sirtuin activating compounds can be used to improve physical endurance (for example, carrying out the ability of health tasks such as for example motion, manual work, sports), suppresses or delay physical fatigue, improves blood oxygen level, improves the healthy individual vigor, improves work capacity and tolerance, minimizing muscle fatigue, reduces pressure, improve heart and cardiovascular function, raising sexuality, increases muscle ATP level and/or reduce lactic acid in the blood.In certain embodiments, this method comprises the sirtuin activating compounds that gives a certain amount of increase mitochondria activity, increases plastosome biosynthesizing and/or increase mitochondrial mass.

Exercise performance is meant the ability that sportsmen's muscle is carried out when participating in sports activites.The increase of the increase by muscular contraction force of enhanced exercise performance, strength, speed and tolerance, Muscle contraction amplitude, the shortening of muscle response time is measured when stimulating and shrink.The sportsmen is meant the people who participates in any tangential movement and attempt to obtain strength, speed and the raising of tolerance level in its performance, for example, and body building person, cyclist, long-distance runner, dash man etc.The sportsmen understands train hard, promptly carries out fierce sports or match on every Wendesdays more than the sky.The sportsmen attempts to improve general health and fitness enthusiasts happy, that improve energy level, and they moved about 1-2 hour for about weekly three times at every turn.The exercise performance that improves is by the ability that overcomes muscle fatigue, the ability that maintains vigour for a long time and more effective exercise performance.

In the stage of sportsmen's muscle performance, create the condition that allows in long-time match of higher tolerance level or training and make us expecting.But the rapid and fierce anoxic of skeletal muscle is used through regular meeting and is caused the exercise performance that damages, and with strength and the forfeiture of work output and muscle fatigue, pain and the handicapped generation of increase.Even have realized that now single force exhausts moving period, or for this reason for example muscle injury, tolerance or power exhaust any acute injury of motion to body, or choose date for operation and have the metabolic characteristics that influence the upset of muscle performance in short-term and long-term stage.Muscle metabolism/enzymic activity and genetic expression all are affected.For example, the source depletion of skeletal muscle nitrogen metabolism obstacle and metabolisable energy betides widely in the muscle activity.After deamination improved serum ammonia and the selective oxidation as the muscle fuel source, amino acid comprised branched-chain amino acid, discharges from muscle, and this has strengthened metabolic acidosis.In addition, flesh contraction movement catalytic efficiency and nitrogen enzyme activity change and energy metabolism meeting descend to some extent.And then the protein metabolism effect starts from the position that the protein synthesis rate descends and the degraded of non-contractile protein increases.These metabolic processes are also with the further free radical generation of muscle injury cell.

In rapid and secular motion, need the reverse of the metabolic and the tired factor of non-metabolic from fatigue recovery.The factor of known participant's muscle fatigue, for example lactic acid salt, ammonia, hydrogen ion etc. provide fatigue/recovery process imperfect and not satisfied explanation, also have other unknown factors to participate in (Baker etc. probably, J.Appl.Physiol.74:2294-2300,1993; Bazzarre etc., J Am.Coll.Nutr.11:505-511,1992; Dohm etc., Fed.Proc.44:348-352,1985; Edwards In:Biochemistry of Exercise, Proceedings of the Fifth International Symposium on the Biochemistry of Exercise (Poormans compiles for Kutrgen, Vogel), 1983; MacDougall etc., Acta Physiol.Scand.146:403-404,1992; Walser etc., Kidney Int.32:123-128,1987).The effect of nutritional additive and Chinese medicine additive raising muscle performance has also been analyzed in many researchs.

The muscle performance in the endurance exercise, free radical and oxidative stress index are affected at pathophysiological state.Mass data now shows, and oxidative stress causes in the pathophysiological state muscle consumption or atrophy, and (summary is seen Clarkson, P.M.Antioxidants and physical performance.Crit.Rev.FoodSci.Nutr.35:31-41; 1995; Powers, S.K.; Lennon, S.L.Analysis of cellular responsesto free radicals:Focus on exercise and skeletal muscle.Proc.Nutr.Soc.58:1025-1033; 1999).For example, the muscular disorders for muscular endurance and function are all compensated has related to the effect of nitrogen protoxide (NO).In muscular dystrophy, especially owing to form those of potein deficiency of malnutrition gene-glycoprotein complex body (DGC), with the enzyme of synthetic NO, (NOS) is relevant for nitric oxide synthetase.Relevant with the DGC defective underfedly studies show that recently, a mechanism of cell injury be with cell in NOS change and the relevant functional local asphyxia of destruction of the normal provide protection of NO.This provide protection is to shrink in the associability vasoconstriction to induce ischemic prevention in the increase.Rando (Microsc ResTech 55 (4): 223-35,2001) is verified, and oxidative damage is prior to pathological change, and the muscle cell of DGC defective has the susceptibility that the oxidation challenge is increased.Because the excessive lipid peroxidation of free radical also has been proved to be the factor (Russo etc., Med Hypotheses.39 (2): 147-51,1992) in the myopathy of McArdle ' s disease for example.And the amyotrophy that mitochondria dysfunction is relevant with the age (skeletal muscle reduce disease) is relevant to be well-known, though study insufficiently, radical damage has been proved to be acting factor, and (summary is seen Navarro, A.:Lopez-Cepero, J.M.; Sanchez del Pino, M.L.Front.Biosci.6:D26-44; 2001).Other symptoms comprise that acute skeletal muscle reduces disease, for example myatrophy and/or the emaciation relevant with burn, lie up, limb brake or great chest, abdomen and/or bone surgery.Expect that method of the present invention also can effectively treat the relevant pathology patient's condition of muscle.

In certain embodiments, the invention provides the method that the new dietary composition that comprises the sirtuin conditioning agent, its preparation method and use said composition are improved exercise performance.Correspondingly, for providing, those people of the motion of the popularity definition that participates in comprising the work that the motion that needs endurance and needs repeat muscular exertion have therapeutic composition, the food and drink that improve physical endurance and/or inhibition physical fatigue effect.This dietary composition can add and comprise ionogen, caffeine, VITAMIN, carbohydrate etc.

Other application

Increase that sirtuin protein level and/or active sirtuin regulate that compound can be used for the treatment of or prophylaxis of viral infections (for example influenza, bleb or parillomarvirus infections) or as anti-mycotic agent.In certain embodiments, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used as the part administration for the treatment of with the medicine medicinal composition of other treatment virus disease, the medicine of other treatment virus disease comprises, for example acyclovir, ganciclovir and Zidovodine.In another embodiment, increase sirtuin protein level and/or active sirtuin adjusting compound and can be used as the part administration for the treatment of with other antifungal drug medicinal composition, antifungal drug comprises, for example, local anti-mycotic agent for example fluconazole (Fluconazole), itraconazole (R-51211), KETOKONAZOL (nizoral) and miconazole (miconazole nitrate I.V.) of ciclopirox, clotrimazole, econazole, miconazole, nystatin, oxiconazole, Triaconazole and tolnaftate or general anti-mycotic agent for example.

Treatable as described herein object comprises eukaryote, Mammals for example, for example, people, sheep, ox, horse, pig, dog, cat, inhuman primate, mouse and rat.Treatable cell comprises eukaryotic cell, for example, comes from above-mentioned object, or vegetable cell, yeast cell and prokaryotic cell prokaryocyte, for example, and bacterial cell.For example, regulate compound and can give the ability that domestic animal is improved their agriculture conditions of tolerance longer time.

Increase sirtuin protein level and/or active Sirtuin adjusting compound and also can be used for the tolerance that plant increases life-span, stress tolerance and pair cell apoptosis.In one embodiment, compound is used for plant, for example, on the basis of one-period, or is used for fungi.In another embodiment, plant gene is modified produced compound.In another embodiment, before plucking and transporting, use compound treatment plant and fruit to improve its tolerance to damaging in transit.Plant seed also can contact with compound described herein, for example, is used to preserve them.

In other embodiments, increase sirtuin protein level and/or active Sirtuin and regulate the life-span that compound can be used to regulate yeast cell.The situation that expectation prolongs the yeast cell life-span comprises any use zymic process, for example, makes beer, sour milk and baked goods, for example, and bread.Zymic with prolongs life uses and causes using yeast still less or make yeast have activity in over a long time.Being used for the proteinic yeast of recombinant production or other mammalian cells also can handle as described herein.

Increase sirtuin protein level and/or active Sirtuin adjusting compound and also can be used for the tolerance that insect increases life-span, stress tolerance and pair cell apoptosis.In this embodiment, compound can be used for useful insect, and for example, honeybee and other relate to the insect of plant pollination.In a specific embodiment, compound can be used for relating to the honeybee that honey is produced.Usually, method described herein can be applied to any organism with commercial significance, for example, and eukaryote.For example, they can be used for fish (water industry) and bird (for example, chicken and poultry).

More the increase sirtuin protein level of high dosage and/or active Sirtuin regulate compound and also can be used as the adjusting of intervention silencer and the sterilant that the growth period apoptosis is regulated.In this embodiment, compound can be used for plant, and uses methods known in the art to guarantee that compound is effectively biological to insect larvae, and invalid to plant.

At least consider the contact (Longo and Finch, Science, 2002) between breeding and life-span, increase sirtuin protein level and/or active Sirtuin adjusting compound and can be used to influence for example breeding of insect, animal and microorganism of organism.

4. measure

The additive method of this paper expection comprises the compound of evaluation adjusting sirtuin or the screening method of medicine.Medicine can be a nucleic acid, and is for example fit.Mensuration can be carried out in based on cell or acellular form.For example, mensuration can be included in sirtuin can be made sirtuin and testing drug cultivation (or contact) and monitoring or be determined at the testing drug existence sirtuin when not existing with respect to testing drug under the condition of the medicament adjusting of known adjusting sirtuin adjusting level.The adjusting level of sirtuin can be measured by the ability of measuring its deacetylated substrate.Exemplary substrate is can be from BIOMOL (Plymouth Meeting, PA) acetylated peptide of Huo Deing.Preferred substrate comprises the p53 peptide, for example comprises those of acetylize K382.Particularly preferred substrate is Fluor de Lys-SIRT1 (BIOMOL), that is, and and acetylated peptide Arg-His-Lys-Lys.Other substrates are the peptides that derive from human histone H3 and H4 or acetylated amino acids.Substrate can be a fluorescence.Sirtuin can be SIRT1, Sir2, SIRT3 or its part.For example, reorganization SIRT1 can obtain from BIOMOL.Reaction can be carried out about 30 minutes and stop, and for example, used niacinamide to stop.HDAC fluorescence activity mensuration/drug discovery test kit (AK-500, BIOMOL Research Laboratories) can be used to measure the acetylize level.Similar mensuration is described in Bitterman etc., (2002) J.Biol.Chem.277:45099.Sirtuin regulates level and can compare with the sirtuin adjusting level in the presence of one or more (individually or simultaneously) compound that can be used as the positive or negative contrast described herein in the mensuration.Used sirtuin can be sirtuin albumen or its part of total length in the mensuration.Because as if this paper shown activating compounds and interacted with the N end of SIRT1 that used protein comprises the N end parts of sirtuin in the mensuration, for example, the about 1-176 of SIRT1 or 1-255 amino acid; The about 1-174 of Sir2 or 1-252 amino acid.

In one embodiment, shaker test comprises that (i) is fit under the condition of the deacetylated substrate of sirtuin sirtuin be contacted with the acetylize substrate with testing drug when testing drug does not exist; (ii) measure substrate acetylize level; the lower testing drug that shows did not stimulate deacetylated by sirtuin when wherein substrate acetylize level did not exist with respect to testing drug when testing drug exists, and substrate acetylize level when when testing drug exists, not existing with respect to testing drug the higher testing drug that shows suppress the deacetylated of sirtuin.

Identify that regulating the method that for example stimulates or suppress the medicine of sirtuin in the body can comprise that (i) is fit to make under the condition of the deacetylated substrate of sirtuin the cells contacting testing drug and can enters the substrate of cell when I class and II class HDACs exist when testing drug does not exist; (ii) measure substrate acetylize level; the lower testing drug that shows did not stimulate deacetylated by sirtin when wherein substrate acetylize level did not exist with respect to testing drug when testing drug exists, and substrate acetylize level when when testing drug exists, not existing with respect to testing drug the higher testing drug that shows suppress the deacetylated of sirtuin.Preferred substrate is an acetylated peptide, and also preferably it is a fluorescence, as further described herein.This method may further include dissolved cell and measures substrate acetylize level.Can add concentration range in cell is the about 10mM of about 1 μ M-, preferred about 10 μ M-1mM, even 100 μ M-1mM more preferably from about, for example, the substrate of about 200 μ M.Preferred substrate is an acetylize Methionin, for example, ε-acetyl-l-lysine (Fluor de Lys, FdL) or Fluor deLys-SIRT1.Preferred I class and II class HDACs inhibitor are Trichostatin A (TSA), and it can be at about 0.01-100 μ M, and preferably about 0.1-10 μ M for example uses under the concentration of 1 μ M.Use test compound culturing cell and substrate can carry out about 10 minutes to 5 hours, preferably about 1-3 hour.Because TSA suppresses all I class and II class HDACs, and some substrate, for example, Fluor de Lys is the substrate of SIRT2 difference, or even the worse substrate of SIRT3-7, and this mensuration can be used to identify the interior conditioning agent of body of SIRT1.

5. pharmaceutical composition

Sirtuin described herein regulates compound and can use one or more physiologically acceptable carriers or vehicle to prepare in the mode of routine.For example, sirtuin regulates compound and its physiologically acceptable salt and solvate and can prepare and be used for by for example following manner administration: injection (for example, SubQ, IM, IP), suck or be blown into (by mouth or nose) or mouth, cheek, hypogloeeis, through skin, nose, non-enteron aisle or rectal administration.In one embodiment, the sirtuin compound can be in the site that target cell exists, that is, and and specific tissue, organ or fluid (for example, blood, cerebrospinal fluid etc.) site-specific delivery of drugs.

Sirtuin regulates compound can comprise whole body and part or site-specific delivery of drugs with many kinds of mode of administration preparations.Usually visible Remington ' the s Pharmaceutical Sciences of technology and preparation, Meade PublishingCo., Easton, PA.For parenterai administration, preferred injection comprises intramuscular, intravenously, intraperitoneal and subcutaneous.For injection, compound can be formulated in the liquor, compatible buffer reagent, for example Hank ' s solution or Ringer ' s solution on the preferred physiology.In addition, compound can be with the solid form preparation and is redissolved at once before use or suspendible.Also comprise lyophilized form.

For oral administration, pharmaceutical composition for example can adopt, the form of tablet, lozenge or capsule is by ordinary method and pharmaceutically acceptable vehicle tackiness agent (for example, pregelatinized corn starch, polyvinylpyrrolidone or Vltra tears) for example; Weighting agent (for example, lactose, Microcrystalline Cellulose or secondary calcium phosphate); Lubricant (for example Magnesium Stearate, talcum powder or silicon-dioxide); Disintegrating agent (for example, yam starch or primojel); Or wetting agent (for example sodium lauryl sulphate) preparation.Tablet can be with method dressing well known in the art.The liquid preparation of oral administration for example can adopt, the form of solution, syrup or suspension, or they can be used as water or other suitable vehicle dissolved drying products before use.This liquid preparation can be by conventional method and pharmaceutically acceptable additive suspension agent (for example sorbitol syrups, derivatived cellulose or hydrogenation edible-fat) for example; Emulsifying agent (for example Yelkin TTS or gum arabic); Non-water vehicle (for example ationd oil, grease, ethanol or fractionated vegetable oil); And sanitas (for example right-methyl hydroxybenzoate or propyl ester or Sorbic Acid) prepares.If suitable, preparation also can contain buffering salt, seasonings, tinting material and sweeting agent.Can suitably prepare the oral preparations that the controlled release of active ingredient thing is provided.

For inhalation (for example lung is sent), sirtuin regulates the form that compound can aerosol spray, use suitable propelling agent, for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas are sent from pressure packing or atomizer easily.In the aerocolloidal situation of pressure, can determine dose unit by the valve that the amount of sending metering is provided.Can prepare capsule that contains the described compound and the powdered mixture of the powder matrix that suits such as lactose or starch and the cartridge case that for example is used for for example gelatin of sucker or insufflator.

Sirtuin regulates compound and can be mixed with by injection, for example injects the injection formulations of the parenterai administration of (bolus injection) or continuous infusion in a large number.Available additional preservatives is formulated in injection formulations for example in ampoule or the multi-dose container and is prepared into unit dosage.Composition can adopt this type of form of oil or the vectorial suspension of water, solution or emulsion, and can contain formula agent, for example suspension agent, stablizer and/or dispersion agent.Alternatively, before can being to use, activeconstituents uses suitable vehicle, for example the powder type of aseptic aqueous solution.

Sirtuin regulates compound also can be mixed with rectal compositions, for example contains the suppository or the retention enema of suppository base commonly used such as theobroma oil or other glyceryl ester.

Except that previous formulations, sirtuin regulates compound also can be mixed with storage storehouse (depot) preparation.Can give this prolonged action preparation by (for example subcutaneous or intramuscular) implantation or by intramuscularly.Therefore, for example, available suitable polymer or hydrophobic material (for example emulsion in acceptable oil) or ion exchange resin, or slightly soluble derivative, for example slightly soluble salt preparation sirtuin regulates compound.Controlled release preparation also comprises patch.

In certain embodiments, compound described herein can prepare that (summary is seen Begley, Pharmacology ﹠amp for delivery to central nervous system (CNS); Therapeutics 104:29-45 (2004)).The ordinary method that medicine is delivered to CNS comprises: Neurological Surgery strategy (for example, intracerebral injection or Intraventricular infusion); Attempt to open up a kind of molecule manipulation (for example, comprise and self can not pass the drug regimen of BBB) of medicine of BBB endogenous transporting pathway to the generation of the mosaic fusion rotein of the transit peptides of endotheliocyte surface molecular affinity; Design increases the fat-soluble pharmacology strategy of medicine (for example, water soluble drug and lipid or cholesterol carrier combines); With of short duration the breaking of oozing disruptive BBB integrity by height (by to carotid artery infusion mannitol solution or for example use of the biologic activity medicine of angiotensin peptide).

Obtaining the dynamic (dynamical) a kind of possibility of slowly-releasing is that active compound embedding or capsule are encapsulated in the nano particle.Nano particle can be used as powder, adds the powdered mixture or the suspension administration of vehicle.The colloidal suspension of nano particle can the administration easily by the intubate of minor diameter.

Nano particle is that diameter is about the particle of 5nm to about 1000nm.Hereinafter the term of Shi Yonging " nano particle " is meant that active compound is scattered in the particle that forms in the polymeric matrix, be also referred to as " nanometer ball ", also be meant the nano particle of forming by the nuclear that contains the active compound that wraps up by polymeric film, be also referred to as " nanocapsule ".In certain embodiments, nano particle preferably has about 50nm to 500nm, and particularly about 100nm is to the diameter of 200nm.

Nano particle can be by the in-situ polymerization or the use ready-formed polymer manufacture of dispersed monomer.Because the polymkeric substance of in-situ preparing usually can not biological degradation and/or is comprised the serious byproduct of toxicology, preferably by the nano particle of prefabricated polymer manufacture.The nano particle of prefabricated polymer manufacture can pass through different technologies, for example, by emulsion evaporation, solvent exchange, saltout, mechanical mill, microprecipitation and spread by emulsification prepares.

By above-described method, nano particle can use dissimilar polymkeric substance to make.For being used for method of the present invention, preferably by the nano particle of biocompatible polymer preparation.Term " biocompatibility " is meant that material is to the not serious effect of biological environment after introducing biological environment.From biocompatible polymer, particularly preferably be also biodegradable polymkeric substance.Term " biodegradable " be meant after introducing biological environment material by enzyme or chemical degradation for can eliminate subsequently than small molecules.Example is that for example poly-(lactic acid) (PLA) from the polyester of hydroxycarboxylic acid, gather (oxyacetic acid) (PGA), polycaprolactone (PCL), the multipolymer of lactic acid and oxyacetic acid (PLGA), the multipolymer of lactic acid and caprolactone, poly-epsilon-caprolactone, polyhydroxybutyrate and poe, urethane, polyanhydride, polyacetal, poly-dihydropyrane (polydihydropyrans), polybutylcyanoacrylate, natural polymer for example alginate comprises dextran and cellulosic polysaccharide with other, collagen protein and albumin.

Suitable surface-modifying agent can be preferably selected from known organic and inorganic drug vehicle.This vehicle comprises various polymkeric substance, low-molecular-weight oligomer, natural product and tensio-active agent.Preferred surface-modifying agent comprises nonionic and ionogenic surfactant.The representative example of surface-modifying agent comprises gelatin, casein, Yelkin TTS (phosphatide), gum arabic, cholesterol, tragakanta, stearic acid, Zephiran chloride, calcium stearate, Zerol, cetostearyl alcohol, cetomacrogol (cetomacrogol), emulsifying wax, lose sorbitol ester, Voranol EP 2001, for example, polyglycol ether (macrogol ethers) is Cetomacrogol 1000 (cetomacrogol 1000) for example, castor oil derivatives, the polyoxyethylene sorbitan fatty acid ester, for example, commercial obtainable TweensTM, polyoxyethylene glycol, polyoxyethylene stearic acid ester, colloidal silica, phosphoric acid salt, sodium lauryl sulphate, calcium carboxymethylcellulose, Xylo-Mucine, sodium carboxymethylcellulose pyce, Natvosol, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, neusilin, trolamine, polyvinyl alcohol and polyvinylpyrrolidone (PVP).These surface-modifying agents of great majority are known drug vehicle and are described in detail in American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press is among the 1986 Handbook of Pharmaceutical Excipients that co-publicate.

Further describing of nano particle of preparation for example can be seen, United States Patent (USP) 6,264,922, and its content is incorporated herein by reference.

Liposome is the further drug delivery system that is easy to inject.Correspondingly, in the method for the invention, the form administration that active compound also can the liposome delivery system.Liposome is well known to those skilled in the art.Liposome can be by many kinds of phosphatide, and for example the stearylamide of cholesterol, phosphatldylcholine is made.The inventive method available liposome comprises all types of liposomes, includes but not limited to little unilamellar vesicle, big unilamellar vesicle and multilamellar vesicle.

Liposome is used for many therapeutic purpose, especially, is used to transport medicine to target cell.Advantageously, liposome-pharmaceutical preparation provides and improves the possibility that medicine is sent character, and it comprises, for example, and control drug release.Liposome usually needs long cycling time and arrives target region, cell or site.This was necessary when especially, target region, cell or site were not positioned near the administration part.For example, during the administration of liposome general, need with hydroaropic substance dressing liposome, for example, as the hydrophilic polymer chains dressing prolongation liposome blood circulation time of polyoxyethylene glycol (PEG).This surface modification liposome is commonly referred to " long circulation " or " stefic stabilization " liposome.

A kind of surface modification to liposome is that the attachment molecules amount is generally the polyglycol chain of about 1000 dalton (Da) to about 5000Da, and the lipid of about 5 molar percentages (%) composition liposome (referring to, for example, Stealth Liposomes, CRC Press, Lasic, D. and Martin, F. compiles, Boca Raton, Fla., (1995)), and the reference of wherein quoting.Compare with the non-surface modification liposome that is easy to from blood, to eliminate fast and in liver and spleen, accumulate, the pharmacokinetics that this liposome shows has the advantages that the dose dependency reduces after liver and spleen are by mononuclear phagocyte system (MPS) picked-up liposome, and the significant prolongation blood circulation time.

In certain embodiments, isolate complex body increase complex body circulating half-life or isolation and increase the tolerance of nucleic acid the degraded of for example nuclease degradation.

Term used herein " isolation " is meant that with relevant for example " isolated " " isolation group " reduces complex body described herein and serum complement or be present in the non-special interactional ability of other materials in the serum in external or body.Isolating group can reduce the interaction of complex bodys and these materials or combine by one or more mechanism, comprise, for example, non-specific space or non-specific interaction of electrons.This interactional example comprise non-specific electrostatic interaction, coulombic interaction, Van der Waals interact, sterically hindered etc.For as isolating the group that group works, do not find out that it may reduce serum complement or other matter interactions, association or bonded mechanism.Can be by measuring complex body whether in conjunction with the serum material or be attached to which kind of degree and determine whether a group can be used as the isolation group.

Should be noted that " isolation group " can be polyfunctional.For example, an isolation group also can play for example effect of the target factor.Isolate group and can be meant that also with regard to its mechanism of isolating complex body be polyfunctional.Do not want to be subjected to the mechanism or the theoretical restriction that have proposed, this multi-functional examples of groups of isolating is responsive intracellular membrane destructiveness synthetic polymer, for example PPAA or PEAA of pH value.Some poly-(alkyl acrylic) has been proved destruction cell inner membrance and kept okioplast surface film complete (Stayton etc., (2000) J.Controll.Release 65:203-220; Murthy etc., (1999) J.Controll.Release 61:137-143; WO 99/34831), thus cell biological availability and the effect of playing the target factor increased.But PPAA reduces the serum complement of its participation and combining of complex body, therefore plays the effect of isolating group.

The another kind of mode of preparation, the especially solution of the sirtuin conditioning agent of preparation example such as trans-resveratrol or derivatives thereof is by using cyclodextrin.Cyclodextrin be meant α-, β-or γ-Huan Hujing.Cyclodextrin is described in detail in the United States Patent (USP) 4,727,064 of Pitha etc., and it is incorporated herein by reference.Cyclodextrin is the ring oligomer of glucose; These compounds and any molecule can enter the compound formation clathrate complex of cyclodextrin molecular lipotropy cavity.

The cyclodextrin of the present composition can be α-, β-or γ-Huan Hujing.Alpha-cylodextrin comprises six Glucopyranose subunits; Beta-cyclodextrin comprises seven Glucopyranose subunits; γ-Huan Hujing comprises eight Glucopyranose subunits.Molecule be considered to α-, β-or γ-Huan Hujing in form the truncated cone of nuclear opening respectively with 4.7-5.3 dust, 6.0-6.5 dust and 7.5-8.3 dust.Composition of the present invention can comprise two or more α-, β-or the mixture of γ-Huan Hujing.But, composition of the present invention only comprise usually α-, β-or γ-Huan Hujing in a kind of.

The preferred cyclodextrin of great majority in the present composition is amorphous cyclodextrin compound.Amorphous cyclodextrin is meant the noncrystal mixture of cyclodextrin, wherein mixture by α-, β-or γ-Huan Hujing preparation.Generally speaking, amorphous cyclodextrin is to prepare by the non-selective alkylation that needs the cyclodextrin material.The suitable alkylating agent that is used for this purpose includes but not limited to propylene oxide, Racemic glycidol, iodoacetarnide, chloracetate and 2-diethylamino diethylaluminum monochloride.React and obtain containing multiple mixture of ingredients, thereby prevent cyclodextrin crystallization.Various alkanisation cyclodextrin can be produced, and depend on the alkylating agent of cyclodextrin initiator and use and certainly different.What be fit to the present composition in amorphous cyclodextrin is hydroxypropyl, hydroxyethyl, glucosyl group, malt-base and trisaccharide maltose radical derivative, carboxamide methyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and the diethylamino group-beta-cyclodextrin of beta-cyclodextrin.

The dissolved trans-resveratrol example is provided in Marier etc. in the presence of cyclodextrin, among the J.Pharmacol.Exp.Therap.302:369-373 (2002), its content is incorporated herein by reference, and wherein uses the resveratrol solution of 0.9% the prepared in saline 6mg/mL contain 20% hydroxypropyl-beta-cyclodextrin.

As mentioned above, the composition of material of the present invention comprises the amorphous cyclodextrin of preferred replacement and the aqueous formulation of one or more sirtuin conditioning agents.The relative quantity of Sirtuin conditioning agent and cyclodextrin is different to the effect of compound with cyclodextrin because of the relative quantity of every kind of sirtuin conditioning agent.Generally speaking, the ratio of the weight of sirtuin conditioning agent compound and cyclodextrin compound weight is in the scope of 1: 1 and 1: 100.Be selected from the compound of sirtuin conditioning agent and cyclodextrin 1: 5 to 1: 50 scope, more preferably to be considered to increase sirtuin conditioning agent recycle degree be the most effective for the weight of 1: 10 to 1: 20 scope and weight ratio.

Importantly, if non-enteron aisle comprises the aqueous solution of sirtuin conditioning agent and cyclodextrin, particularly by intravenous route, then cyclodextrin is substantially free of pyrogenic contaminants.Multi-form cyclodextrin, for example amorphous cyclodextrin can be from many Sigma-Aldrich that comprise, and (retailer place USA) buys Inc. for St.Louis, Mo..The method for preparing hydroxypropyl-beta-cyclodextrin is disclosed in the United States Patent (USP) 4,727,064 of Pitha etc., and it is incorporated herein by reference.

Other of cyclodextrin solubilising application of compound are described visible US 2005/0026849, and its content is incorporated herein by reference.

Disintegration or dissolve dosage form are useful to rapid absorption, particularly cheek and the hypogloeeis absorption of pharmaceutically active substances fast.Fast the fusion formulation is useful to the patient who swallows such as the common solid dosage difficulty of lozenge and tablet as old and children's patient.In addition, fuse formulation fast and avoided the shortcoming relevant with for example chewable dosage forms, wherein active substance time length in disease population plays an important role in the degree of the amount of determining odor mask and the grittiness that patient may not accept active substance.

In order to overcome this problem, manufacturers has developed many quick fusion solid dosage oral preparations.They can be from comprising Cima Labs, Fuisz Technologies Ltd., Prographarm, R.P.Scherer, Yamanouchi-Shaklee, and McNeil-PPC, manufacturers's place's acquisition of Inc.Dissimilar quick dissolved solids oral dosage forms is sold by all these manufacturerss.Referring to patent and the publication of Cima Labs, for example United States Patent (USP) 5,607, and 697,5,503,846,5,223,264,5,401,513,5,219,574 and 5,178,878, WO 98/46215, WO 98/14179; Fuisz Technologies patent is the part of BioVail now, and for example United States Patent (USP) 5,871,781,5,869,098,5,866,163,5,851,553,5,622,719,5,567,439 and 5,587,172; The United States Patent (USP) 5,464,632 of Prographann; The patent of R.P.Scherer is United States Patent (USP) 4,642,903,5,188,825,5,631,023 and 5,827,541 for example; The Yamanouchi-Shaklee patent is United States Patent (USP) 5,576,014 and 5,446,464 for example; The Janssen patent is United States Patent (USP) 5,807,576,5,635,210,5,595,761,5,587,180 and 5,776,491 for example; The United States Patent (USP) 5,639,475 and 5,709,886 of Eurand America Inc.; The United States Patent (USP) 5,807,578 and 5,807,577 of L.A.B.Pharmaceutical Research; The patent of Schering Corporation is the U.S. 5,112,616 and 5,073,374 for example; The United States Patent (USP) 4,616,047 of Laboratoire L. LaFon; The United States Patent (USP) 5,501,861 of Takeda Chemicals Inc.Ltd.; United States Patent (USP) 6,316,029 with Elan.

At one fast in the example of fusion tablet preparation, the particle of the quick fusion sheet by spraying drying or the preparation of presuppression process is with mixed with excipients and use conventional tablet manufacturing machine to be pressed into sheet.Particle can with many kinds of carrier combinations that comprise low density, high-ductility sugar, inductile sugar, polyvalent alcohol combination, directly be pressed into the dissolving that performance improves and the tablet of disintegration properties then.

The hardness of tablet of the present invention is generally about 2 to about 6Strong-Cobb unit (scu).Tablet quick disintegration or dissolving when chewing in this durometer level.In addition, tablet disintegration fast in water.On average, the tablets of common 1.1 to 1.5 grams when not stirring disintegration in 1-3 minute.This quick disintegration is beneficial to the release of active substance.

The particle that is used to prepare tablet can be, for example, and the mixture of low density alkaline earth salt or carbohydrate.For example, the mixture of alkaline earth salt comprises the combination of lime carbonate and magnesium hydroxide.Similarly, the fusion tablet can the method according to this invention prepare fast, the inventive method is used in combination: A) spray-dired additional light calcium carbonate/maltodextrin, B) magnesium hydroxide and C) comprise instant Sorbitol Powder, the eutectic polyvalent alcohol of Xylitol and mannitol makes up.These material mixing are made very easy dissolving and promote the quickly disintegrated low density tablet of fast activeconstituents.In addition, presuppression can be incorporated in the identical tablet with spray-dired particle.

For quick fusion tablet formulation, be used for sirtuin conditioning agent of the present invention and can be for example solid, particulate, particle, crystal, oil or solution form.Being used for sirtuin conditioning agent of the present invention can be spray dried prod or the adsorptive than the grit form that has been pre-pressed into reduction medicine taste.Be used for active constituents of medicine of the present invention can with the carrier spraying drying that prevents that when chewing activeconstituents from extracting easily from tablet.

Except directly joining in the tablet of the present invention, in being incorporated into preparation before, medicine self can be processed by the density that the presuppression method obtains to increase.

Being used for presuppression method of the present invention can be used to send poorly soluble pharmaceutical material and improve the release of this pharmaceutical material at regular dosage form.This allow to use sends the medicine of suitable biological utilisation level than low dosage level, and thereby reduces the toxic level of present marketed drugs and new chemical entities.Poorly soluble pharmaceutical material can use with the form of the nano particle of nanometer size.

Except activeconstituents and particle, fuse tablet fast and can use conventional carrier or vehicle and definite already pharmaceutical technology to prepare by low density alkaline earth salt and/or water-soluble carbohydrate preparation.Conventional carrier or vehicle comprise, but be not limited to, thinner, wedding agent, tackiness agent are (for example, derivatived cellulose and acrylic acid derivative), the various materials of lubricant (for example, Magnesium Stearate or calcium, vegetables oil, polyoxyethylene glycol, talcum powder, sodium lauryl sulphate, polyoxyl 40 stearate), disintegrating agent, tinting material, seasonings, sanitas, sweeting agent and for example buffer reagent and sorbent material.

The other description of fusion tablet preparation can be seen for example United States Patent (USP) 5,939,091 fast, and its content is incorporated herein by reference.

Pharmaceutical composition (comprising cosmetic formulations) can comprise about 0.00001-100% weight for example one or more sirtuin described herein of 0.001-10% or 0.1-5% weight regulate compounds.

In one embodiment, described sirtuin herein being regulated compound mixes and contains the topical formulations that is fit to the topical carrier of topical usually and contains any this material known in the art.Can select topical carrier so that the composition that needs form to be provided, for example ointment, lotion, creme, microemulsion, gelifying agent, oil, solution etc., and can contain the material in natural existence or synthetic source.Preferred selected carrier does not have a negative impact to active medicine or other composition of topical formulations.The example that is used for suitable topical carrier herein comprises water, pure and mild other nonpoisonous organic solvent, glycerine, mineral oil, polysiloxane, Vaseline, lanolin, lipid acid, vegetables oil, p-Hydroxybenzoate, wax etc.

Preparation can be colorless and odorless ointment, lotion, creme, microemulsion and gelifying agent.

The sirtuin compound can mix in the ointment, the semi-solid preparation that it is a matrix with vaseline or other vaseline derivative generally normally.One skilled in the art will recognize that stand-by concrete ointment base, is to provide optimal drug to send and preferably can provide the matrix of other characteristic that needs and for example property of softening etc.The same with other carrier or vehicle, ointment base should be inertia, stable, non-irritating and nonsensitized.As setting forth among the Remington ' s that partly quotes at preamble, ointment base can be divided into four classes: oleaginous base; Emulsifiable base; Emulsifying base and water-soluble base.The oiliness ointment base comprises for example vegetables oil, the fat that obtains and the semi-solid hydrocarbon that obtains from vaseline from animal.But the emulsification ointment base that is called the ointment base of absorption again contains hardly or is not moisture, comprises for example hydroxystearin sulfate, lanolin anhydrous bp93 and hydrophilic petrolatum.The emulsification ointment base is water-in-oil (W/O) emulsion or oil-in-water (O/W) emulsion, for example comprises hexadecanol, Zerol, lanolin and stearic acid.Exemplary water-soluble ointment base is prepared by various molecular weight polyethylene glycol (PEGs); Further information is reference Remington ' s as above again.

Situin regulates compound and can mix in the lotion, and lotion normally is applied to the preparation that skin surface does not have friction, is that solids comprising active medicine are present in typical liquid or the semi-liquid preparations in water or the pure matrix.Lotion is the solid suspension normally, can contain the oil-in-water liq oily emulsion.Lotion is the preparation of preferably treating the bodice bulk area, because be easy to apply the more fluid composition.Insoluble substance in the usually necessary finely divided lotion.Lotion is included as suspension agent and the location that produces better dispersion and the compound that keeps active medicine and skin contact, for example methylcellulose gum, Xylo-Mucine etc. usually.The exemplary lotion preparation of uniting use with the inventive method comprises the mixture of propylene glycol and hydrophilic petrolatum, for example can be from Beiersdorf, and (Norwalk, Conn) trade mark of Huo Deing is Aquaphor to Inc. ^PTMThose.

Sirtuin regulates compound and can mix in the creme, and creme is oil-in-water or water in oil viscous liquid or semi-solid emulsion normally.The washing of cream base used water, and contain oil phase, emulsifying agent and water.Oil phase is made up of vaseline and Fatty Alcohol(C12-C14 and C12-C18) such as hexadecanol or stearyl alcohol usually; Although optional, the water volume surpasses oil phase usually, and contains wetting Agent for Printing Inks usually.Emulsifying agent in the creme as setting forth among the same Remington ' s, normally non-ionic type, anionic, cationic or zwitterionics.

Sirtuin regulates compound and can mix in the microemulsion, microemulsion normally two kinds of immiscible fluids is clarified dispersion as thermodynamically stable, the isotropy of oil and water, it is by surfactant molecule interfacial film stable (Encyclopedia of Plmrmaceutical) Technology (New York:Marcel Dekker, 1992) the 9th volume).For the preparation of microemulsion, tensio-active agent (emulsifying agent), cosurfactant (co-emulsifier), oil phase and water are essential.Suitable tensio-active agent comprises any tensio-active agent that can be used for preparing emulsion, for example is generally used for preparing the emulsifying agent of creme.Cosurfactant (or " co-emulsifier ") is selected from Polyglycerine derivative, glycerol derivative and Fatty Alcohol(C12-C14 and C12-C18) usually.Although optional, preferred solvent/co-emulsifier combination is selected from usually: Zerol and polyoxyethylene stearic acid ester; Polyoxyethylene glycol and palmityl glycol stearate (ethylene glycol palmitostearate); And tricaprylin and tricaprin and oleoyl polyethylene glycol glycerol ester (macrogolglyceride).Water not only comprises water but also comprises buffer reagent, glucose, propylene glycol, polyoxyethylene glycol usually; preferred low molecular poly (for example PEG 300 and PEG 400); and/or glycerine etc., and oil phase comprises the mixture of for example fatty acid ester, modified vegetable oil, silicone oil, glycerine one, two and three esters, one and the diester (for example oleoyl polyethylene glycol glycerol ester) etc. of PEG usually.

Sirtuin regulates compound and can mix in the gel preparation, its suspension of normally being made up of little inorganic particulate (two-phase system) or be evenly distributed on the semisolid systems that the big organic molecule (single-phase gels) in the whole carrier liq is formed basically.Can be by for example making active medicine, carrier liq and suitable jelling agent, for example tragacanth (2-5%), sodiun alginate (2-10%), gelatin (2-15%), methylcellulose gum (3-5%), Xylo-Mucine (2-5%), carbomer (0.3-5%) or polyvinyl alcohol (10-20%) mix, and mix until producing the semi-solid product of characteristic and prepare single-phase gels.Other suitable jelling agent comprises methyl hydroxylated cellulose, polyoxyethylene-polyoxypropylene, Natvosol and gelatin.Although gelifying agent generally uses aqueous carrier liquid, pure and mild oil also can be used as carrier liq.

Various additive well known by persons skilled in the art can be contained in preparation such as the topical formulations.The example of additive includes but not limited to solubility promoter, dermal osmosis accelerator, opalizer, sanitas (for example, antioxidant), jelling agent, buffer reagent, tensio-active agent (particularly nonionic and amphoterics), emulsifying agent, tenderizer, thickening material, stablizer, wetting agent, tinting material, perfume compound etc.It is particularly preferred comprising solubility promoter and/or dermal osmosis accelerator and emulsifying agent, tenderizer and sanitas.Best topical formulations comprises approximately: 2 weight %-60 weight %, solubility promoter and/or the dermal osmosis accelerator of preferred 2 weight %-50 weight %; 2 weight %-50 weight %, the emulsifying agent of preferred 2 weight %-20 weight %; 2 weight %-20 weight % tenderizers; With the sanitas of 0.01-0.2 weight % and the active medicine and the carrier (for example, water) of composition preparation remainder.

Dermal osmosis accelerator is used to make the intact skin of the active medicine of treatment level by the fair-sized area.Suitable promotor is well known in the art, for example comprises: low-level chain triacontanol, for example methyl alcohol, ethanol and 2-propyl alcohol; Alkyl methyl sulfoxide, for example methyl-sulphoxide (DMSO), Decylmethyl Sulphoxide (C ₁₀MSO) and tetradecyl methyl sulfoxide; Pyrrolidone, for example 2-Pyrrolidone, N-N-methyl-2-2-pyrrolidone N-and N-(hydroxyethyl) pyrrolidone; Urea; N, the N-diethyl--toluamide; C ₂-C ₆Alkanediol; Other solvent, for example dimethyl formamide (DMF), N,N-dimethylacetamide (DMA) and tetrahydrofurfuryl alcohol; With 1-substituted azetidine heptan-2-ketone, particularly 1-just-dodecane basic ring nitrogen heterocyclic heptan-2-ketone (bay nitrogen

Ketone; With Azone ^RTMTrade mark can be from Whitby Research Incorporated, Richmond, Va obtains).

The example of solubilizing agent includes, but are not limited to following: wetting ability ether, for example (ethoxydiglycol is as Transcutol for diethylene glycol monoethyl ether ^RTMCommerce can obtain) and the diethylene glycol monoethyl ether oleic acid ester (as Softcutol ^RTMCommerce can obtain); Polyethylene castor oil derivative, for example polyoxy 35 Viscotrol C, polyoxy 40 hydrogenation castor oils etc.; Polyoxyethylene glycol, particularly low molecular poly, for example PEG300 and PEG 400 and polyethyleneglycol derivative, for example PEG one 8 caprylic/capric glyceryl ester are (as Labrasol ^RTMCommerce can obtain); Alkyl methyl sulfoxide, for example DMSO; Pyrrolidone, for example 2-Pyrrolidone and N-N-methyl-2-2-pyrrolidone N-; And DMA.Multiple solubilizing agent also can be used as absorption enhancer.Single solubilizing agent can mix preparation, or the mixture of solubilizing agent can mix wherein.

Examples of suitable emulsifiers includes but not limited to those emulsifying agents and the assistant for emulsifying agent that relevant microemulsion formulation is set forth with assistant for emulsifying agent.Tenderizer comprises for example propylene glycol, glycerine, Isopropyl myristate, polypropylene glycol-2 (PPG-2) myristyl ether propionic ester etc.

Other active medicines also can be included in the preparation, commonly used sun-proof medicine in other antiphlogistons, anodyne, antimicrobial drug, antifungal drug, microbiotic, VITAMIN, antioxidant and the sun-screening agent for example, (for example include but not limited to anthranilic acid, benzophenone (particularly benzophenone-3), camphor derivatives, laurate, octyl methoxycinnamate), DBM (for example, butyl methoxyl group DBM), Para-Aminobenzoic (PABA) and its derivative, and salicylate (for example, octyl salicylate).

In some topical formulations, active medicine exists with the scope of the amount that accounts for the about 0.25wt.%-75wt.% of preparation, preferably account for the scope of the amount of the about 0.25wt.%-30wt.% of preparation, more preferably account for the scope of the amount of the about 0.5wt.%-15wt.% of preparation, most preferably account for the scope of the amount of the about 1.0wt.%-10wt.% of preparation.

The topical skin treating composition can be packaged in the use that suitable container adapts to its viscosity and human consumer's expection.For example, lotion or creme can be packaged in the bottle or the aerosol device of ball medicator or propellant actuated or the container of the pump that is suitable for finger manipulation is housed.When composition was creme, it only need be stored in indeformable bottle or the squeeze receptacle, for example in pipe or the bottle with cover.Composition also can be contained in as United States Patent (USP) 5,063, in 507 those capsules of describing.The encloses container of acceptable composition on the makeup that contain this paper definition correspondingly, also is provided.

In an alternative embodiment, be provided for the pharmaceutical preparation of oral or parenterai administration, preparation can comprise the aforesaid microemulsion of regulating compound that contains in this case, but can comprise the selectable pharmaceutically acceptable carrier that particularly is suitable for oral or non-enteron aisle drug administration, vehicle, additive etc.Alternatively, containing the microemulsion of regulating compound can need not to adjust substantially as above-mentioned oral or parenterai administration.

Phospholipid complex, for example trans-resveratrol-phospholipid complex and its preparation are described in the U.S. Patent Application Publication 2004/116386.Use method and its preparation of polyvalent alcohol/polymer microcapsule stabilizing active ingredient to be described among the US20040108608.In aqueous solution, use the method for amphipathic nature block polymer dissolving lipophilic compound to be described among the WO04/035013.

The eye patient's condition can be passed through, and for example, whole body, part, intraocular injection sirtuin regulate compound, or treats or prevent by insert discharging lasting releasing device that sirtuin regulates compound.Increase or minimizing sirtuin protein level and/or active sirtuin regulate compound and can send with carrier by pharmaceutically acceptable eye, keeping compound to contact the sufficiently long time with the eye surface like this makes compound permeate cornea and intraocular part zone, for example anterior chamber, back room, vitreum, aqueous humor, vitreum, cornea, iris/ciliary muscle, lens, choroid/retina and sclera.Pharmaceutically acceptable with carrier can be, for example, and ointment, vegetables oil or capsule encapsulation material.Alternatively, The compounds of this invention can be injected directly into vitreum and aqueous humor.In further selection scheme, compound can general give, and for example by venoclysis or injection, treats eyes.

Sirtuin described herein regulates compound and can be stored in the oxygen-free environment according to art processes.For example, trans-resveratrol or its analogue can be prepared in the air seal capsule of oral administration, Pfizer for example, the Capsugel that Inc produces.

According to the method that gives the object graft, can give to adopt sirtuin to regulate the cell of compound treatment in the body of for example earlier external back, it can be followed and give for example immune suppressant drug, for example cyclosporin A.For the general principle of pharmaceutical preparation, the reader can be with reference to Cell Therapy:Stem Cell Transplantation, Gene Therapy, and Cellular Immunotherapy, G.Morstyn and W.Sheridan compile, Cambridge University Press, 1996; With Hematopoietic Stem Cell Therapy, E.D.Ball, J.Lister and P.Law, Churchill Livingstone, 2000.

The toxicity of sirtuin adjusting compound and result of treatment can be operated by the standard pharmaceutical in cell cultures or the experimental animal and be measured.LD ₅₀Be 50% the lethal dosage of colony.ED ₅₀Be 50% the effective dosage of mass treatment.The dosage of toxicity and result of treatment is than (LD ₅₀/ ED ₅₀) be therapeutic index.The sirtuin adjusting compound that shows big therapeutic index is preferred.Though can use the sirtuin of performance toxic side effect to regulate compound, the care should be used to design minimizes targeting compounds to the not latent lesion of the cell of infection in the drug delivery system of being attacked tissue site, thereby reduces side effect.

Can be used to determine a series of dosage from the data that cell cultures is measured and zooscopy obtains in the human body use.The dosage of this compound can be positioned at a series of circulation compositions that comprise almost non-toxic or nontoxic ED50.Dosage can change in this scope, and this depends on the formulation of use and used route of administration.For any compound, the treatment effective dose can measure initial estimation by cell cultures.Dosage can be determined the IC that comprises that obtains to measure with animal model in cell cultures ₅₀The circulating plasma concentration range of (for example, test compounds obtains the maximum concentration that suppresses of symptom half).This information can be used for determining more accurately the useful dosage of human body.Concentration in the blood plasma can be passed through, for example, and high-performance liquid chromatogram determination.

6. test kit

This paper also provides test kit, for example is used for the treatment of the test kit of purpose or is used to regulate cell survival or regulates apoptotic test kit.One or more sirtuin that test kit for example can comprise with preliminary assay dosage regulate compounds.Test kit can randomly comprise device and the operation instruction that cell is contacted with compound.Device comprises that syringe, support and other regulate the device that compound is introduced (for example, the blood vessel of object) in the subject or is applied to subject's skin with sirtuin.

The test kit of another type of the present invention's expection is to identify that sirtuin regulates the test kit of compound.This test kit is included in (1) sirtuin in the isolating container or contains material and (2) sirtuin adjusting of the present invention compound of sirtuin.This test kit can be used for, and for example, the type of being at war with is measured the sirtuin that other compounds (being provided by the user usually) are provided and regulated active.In certain embodiments, these test kits further comprise the mensuration active reagent of sirtuin (for example, having the peptide of suitable indicator, for example those disclosed among the embodiment).

In another embodiment, the invention provides the composition of material, be included in the isolating formulation, but be mutually related sirtuin conditioning agent of the present invention and another kind of medicine [used identical medicine in combined therapy and composition].Term used herein " interrelated " is meant that isolating formulation is packaging together or interconnects in other mode, makes and easily find out that isolating formulation expection is sold and administration as the part of identical therapy.Medicine and sirtuin conditioning agent preferably are packaged together in Blister Package (blister pack) or other multicells packing, or in container that can isolating by the user (for example, by tearing two delineation lines between container) connect, sealing respectively (for example metallic foil bag etc.).

In another embodiment, the invention provides test kit, be included in the isolating container: a) sirtin conditioning agent of the present invention; And b) those medicines of other parts descriptions of another kind of for example specification sheets.

Unless otherwise indicated, the enforcement of present method can be used cytobiology, cell cultures, molecular biology, genetically modified organism, microbiology, recombinant DNA and the immunologic routine techniques in art technology.This technology is explained in the literature fully.Referring to, for example, Molecular Cloning ALaboratory Manual, the 2nd edition, Sambrook, Fritsch and Maniatis compile (Cold Spring HarborLaboratory Press:1989); DNA Cloning, I and II volume (D.N.Glover compiles, 1985); Oligonucleotide Synthesis (M.J.Gait compiles, 1984); Mullis etc., United States Patent (USP): 4,683,195; Nucleic Acid Hybridization (B.D.Hames and S.J.Higgins compile, 1984); Transcription AndTranslation (B.D.Hames and S.J.Higgins compile, 1984); Culture Of Animal Cells (R.I.Freshney, Alan R.Liss, Inc., 1987); Immobilized Cells And Enzymes (IRLPress, 1986); B.Perbal, A Practical Guide To Molecular Cloning (1984); The treatise, and Methods In Enzymology (Academic Press, Inc., N.Y.); Gene Transfer Vectors ForMammalian Cells (J.H.Miller and M.P.Calos compile, and 1987, Cold Spring HarborLaboratory); Methods In Enzymology, 154 and 155 volumes volumes such as () Wu, ImmunochemicalMethods In Cell And Molecular Biology (Mayer and Walker compile, Academic Press, London, 1987); Handbook Of Experimental Immunology, I-IV volume (D.M.Weir and C.C.Blackwell compile, 1986); Manipulating the Mouse Embryo, (Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y., 1986).

Embodiment

Now described the present invention prevailingly, be easier to understand by make the present invention with reference to following embodiment, described embodiment only is used to illustrate some aspect of the present invention and embodiment, does not limit the present invention in any way.

Synthetic and the sign of embodiment 1 Sirtuin conditioning agent

General line:

Route 1:

Route 2:

Route 3:

Route 4:

Test portion:

The used abbreviation of experimental section:

HATU=O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate

The NMM=4-methylmorpholine

DIEA=N, the N-diisopropylethylamine

DMF=N, dinethylformamide

CH ₂Cl ₂=methylene dichloride

The EtOAc=ethyl acetate

MeOH=methyl alcohol

Na ₂SO ₄=sodium sulfate

The PPA=polyphosphoric acid

Et ₃The N=triethylamine

The rt=room temperature

The preparation of 3-(thiazole is [5,4-c] pyridine-2-yl also) aniline:

Diisopropylaminoethyl formyl dithionic acid 4-aminopyridine-3-base ester (4-aminopyridin-3-yldiisopropylcarbamodithioate) is according to Smith et al, Sulfur Lett.1994 vol 17, p.197 and E.Ma, Molecules 2003, vol 8, p.678-686 the step preparation described in.

220mg diisopropylaminoethyl formyl dithionic acid 4-aminopyridine-3-base ester (0.81mmol) and triethylamine (0.175mL, 1.5 equivalents) are dissolved in the 6mL methylene dichloride together, are cooled to 10 ℃ (ice baths).(150mg, 1 equivalent 0.81mmol) are dissolved in the 3mL methylene dichloride, add to then in refrigerative diisopropylaminoethyl formyl dithionic acid 4-aminopyridine-3-base ester solution with the 3-nitrobenzoyl chloride.Mixture is warming up to room temperature, stirs 45 minutes.Reaction mixture dilutes with the 5mL methylene dichloride, the salt water washing.With organic layer drying (Na ₂SO ₄), concentrate and obtain 280mg midbody acid amide compound (thick yield 83%).

Midbody acid amide (280mg) is suspended among the 5mL 4N aq HCl, under refluxing, stirred 30 minutes.Reaction mixture is cooled to room temperature, with 3N NaOH neutralization, uses dichloromethane extraction.With organic layer drying (Na ₂SO ₄), concentrating under reduced pressure obtains also [5,4-c] pyridine (thick yield 95%) of 200mg compound (3-nitrophenyl) thiazole.

Also [5,4-c] pyridines (1.2mmol) and 30mLMeOH and 6mL water are mixed together with 310mg 2-(3-nitrophenyl) thiazole.(6 equivalents, 7.24mmol 400mg), stir reaction mixture 3 hours under refluxing to add the sodium sulfhydrate hydrate.Reaction mixture is cooled to room temperature, concentrates.The water layer dichloromethane extraction.Organic layer merges after drying (Na ₂SO ₄), concentrate and obtain 230mg compound 3-(thiazole is [5,4-c] pyridine-2-yl also) aniline (thick yield 84%) (MS, M ⁺+ H=228).

The preparation of compound 115:

With typical way, with 40mg 3-(thiazole is [5,4-c] pyridine-2-yl also) aniline (0.176mmol) and 1 equivalent 3,4, the 5-trimethoxy-benzoyl chloride is suspended in the 1mL pyridine together.Reaction mixture heated 10 minutes in 160 degree with the Biotage microwave reactor then.Then it is cooled to room temperature, concentrating under reduced pressure.The gained resistates uses 9: 1 CH ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=422).

Compound 113 and 114 preparation:

With suitable acyl chlorides is raw material, adopts the same steps as of preparation compound 115.

The preparation of compound 99:

With typical way, (25mg, 0.11mmol) with 18mg isocyanic acid 3,4-(methylene-dioxy) phenylester is suspended in the 1mL pyridine with 3-(thiazole is [5,4-c] pyridine-2-yl also) aniline.Reaction mixture heated 10 minutes in 140 degree with the Biotage microwave reactor then.Then it is cooled to room temperature, concentrates.The gained resistates uses 9: 1 CH ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=391).

The preparation of 3-amino-5-(thiazole is [5,4-c] pyridine-2-yl also) methyl benzoate:

(1.25g 5.58mmol) is suspended in 25mL CH with 5-nitro-m-phthalic acid mono-methyl ₂Cl ₂In, the adding oxalyl chloride (0.49mL, 5.58mmol).After adding 3 DMF, reaction mixture at room temperature stirs until all gas generation end and all solids and all dissolves.Then with the solution of acid chloride of this prepared fresh in 0 ℃ be added dropwise to diisopropylaminoethyl formyl dithionic acid 4-aminopyridine-3-base ester (1.5g, 5.58mmol) and triethylamine (0.77mL, 50mLCH 5.58mmol) ₂Cl ₂In the solution.The gained reaction mixture is warming up to room temperature, stirs 1 hour.Use 25mL salt solution termination reaction then, be divided into two-layer.With organic layer drying (Na ₂SO ₄), concentrate.The gained resistates is suspended among the 25mL 2N HCl, under refluxing, stirred 30 minutes.Then it is cooled to room temperature, solid collected by filtration, dry 1.0g 3-nitro-5-(thiazole is [5,4-c] pyridine-2-yl also) methyl benzoate that gets.This material is mixed with 20mL methyl alcohol, 3mL water and 1g sodium sulfhydrate hydrate then, under refluxing, stirred 2 hours.With the cooling of gained reaction mixture, concentrate.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate 150mg 3-amino-5-(thiazole is [5,4-c] pyridine-2-yl also) methyl benzoate (MS, M ⁺+ H=286).

The preparation of compound 133:

(150mg, 0.526mmol) with 3,4, (121mg 0.526mmol) mixes in the 1mL pyridine 5-trimethoxy-benzoyl chloride with 3-amino-5-(thiazole is [5,4-c] pyridine-2-yl also) methyl benzoate.Reaction mixture was heated 10 minutes in 160 degree with the Biotage microwave reactor.Then it is cooled to room temperature, concentrates.With 9: 1 CH of gained resistates use ₂Cl ₂: the MeOH mixture by chromatogram purification, obtains 90mg 3-(thiazole is [5,4-c] pyridine-2-yl also)-5-(3,4,5-trimethoxy benzamido) methyl benzoate (yield 36%) (MS, M ⁺+ H=480).

The preparation of compound 134:

(80mg 0.167mmol) is dissolved in 5mL THF and contains in the 2mL water of 30mg sodium hydroxide with 3-(thiazole is [5,4-c] pyridine-2-yl also)-5-(3,4,5-trimethoxy benzamido) methyl benzoate.Reaction mixture was at room temperature stirred 1 hour.Then it is acidified to pH4 with 6N HCl, concentrates.Solid collected by filtration, dry 60mg 3-(thiazole is [5,4-c] pyridine-2-yl also)-5-(3,4,5-trimethoxy benzamido) phenylformic acid (yield 78%) (MS, the M that get ⁺+ H=466).

The preparation of compound 135:

With 3-(thiazole is [5,4-c] pyridine-2-yl also)-(50mg 0.108mmol) is suspended among the anhydrous THF of 2mL with 1 equivalent NMM 5-(3,4,5-trimethoxy benzamido) phenylformic acid, is cooled to 0 ℃.Add isobutyl chlorocarbonate (1 equivalent), reaction mixture was stirred 45 minutes.Add NaBH then ₄The 0.5mL aqueous solution of (1 equivalent).Reaction mixture was stirred 30 minutes, be warming up to room temperature then, concentrate.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate thick product.With its CH with 9: 1 ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=452).

3-(oxazole is [5,4-b] pyridine-2-yl also) preparation of aniline:

(3.20g 0.025mol) is suspended in the 15mL pyridine, and (4.64g is in 15mL pyridine suspension 0.026mol) slowly to add to the 3-nitrobenzoyl chloride in ice bath with 2-chloro-pyridine-3-amine.Reaction mixture slowly is heated to room temperature, and stirring is spent the night.Next day, reaction mixture cools off with ice bath, slowly adds the 30mL Glacial acetic acid.The gained mixture washes (3 * 20mL) with water with 200mL EtOAc dilution.Then with organic layer drying (Na ₂SO ₄), concentrate.The gained resistates mixes with 10mL PPA, stirs 6 hours at 160 degree.Then with in the careful impouring 150mL of the reaction mixture water.Transfer pH to about 5 with solid NaOH, solid collected by filtration, drying.This material is mixed with 50mL MeOH, filter.Concentrated filtrate obtains 2.1g 2-, and (3-nitrophenyl) oxazole is [5,4-b] pyridine (yield 35%) (MS, M also ⁺+ H=242).

With 2-(3-nitrophenyl) oxazole also [5,4-b] pyridine (600mg, 2.49mmol) and 837mg sodium sulfhydrate hydrate (14.9mmol) mix with 25mL MeOH and 4mL water together.Reaction mixture stirred 3 hours under refluxing.Then it is cooled to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain also [5,4-b] pyridine-2-yl of 520mg 3-(oxazole) aniline (quantitatively thick yield) (MS, M ⁺+ H=212).

The preparation of compound 112:

With 3-(oxazole [5,4-b] pyridine-2-yl also) aniline and 3, the 4-dimethoxy-benzoyl chloride reacts under foregoing microwave reaction condition.Thick product uses 9: 1 CH ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=376).

Compound 74 and 111 preparation:

Use 3 respectively, 4-dimethoxy benzene sulfonyl chloride and 3-dimethylamino Benzoyl chloride hydrochloride are according to the step preparation of preparation compound 112.Final product uses 9: 1 CH ₂Cl ₂: the MeOH mixture, pass through chromatogram purification.

3-nitro-5-(oxazole is [4,5-b] pyridine-2-yl also) phenylformic acid and 3-nitro-5-(oxazole [4,5-b] pyridine-2-yl also) preparation of methyl benzoate:

(1.00g 9.16mmol) is dissolved among the 20mL DMF with 2.06g 5-nitro m-phthalic acid mono-methyl (9.16mmol), 5.2g HATU (13.7mmol) and 3.2mLDIEA (18.3mmol) with 2-amino-3-pyridone.Reaction mixture at room temperature stirred 18 hours.Then it is diluted with 200mL EtOAc, wash (3 * 25mL) with water.With organic layer drying (Na ₂SO ₄), concentrate.The gained resistates is mixed with 10mL PPA, under 160 degree, stirred 6 hours.With in the careful impouring 200mL of the reaction mixture water, transfer pH to 5 then with solid NaOH.By solid collected by filtration, drying obtains the product as 1: 1 mixture of methyl esters and acid.With mixture by being suspended in 150mL CH ₂Cl ₂Separate, filter then.Filtrate is methyl esters (MS, M ⁺+ H=300), solid is the acid of expectation, i.e. 3-nitro-5-(oxazole is [4,5-b] pyridine-2-yl also) phenylformic acid (MS, M ⁺+ H=286).

3-amino-N-(2-(dimethylamino) ethyl)-5-(oxazole is [4,5-b] pyridine-2-yl also) preparation of benzamide:

With 3-nitro-5-(oxazole [4,5-b] pyridine-2-yl also) (250mg, 0.877mmol) with 1 equivalent N, N-dimethyl-ethylenediamine, 500mg HATU (1.5 equivalent) and 0.3mL DIEA (2 equivalent) are dissolved among the 5mL DMF phenylformic acid together.Reaction mixture at room temperature stirred 18 hours.Then it is diluted with 50mLEtOAc, wash with water.With organic layer drying (Na ₂SO ₄), concentrate and obtain the nitro amide intermediate.It is dissolved in 50mL MeOH and the 5mL water with 200mg sodium sulfhydrate hydrate (4 equivalent).Reaction mixture stirred 1 hour under refluxing.Then it is concentrated into dried, with 1: 1 CH of 50mL ₂Cl ₂/ MeOH mixes, and filters.Filtrate concentrated obtains basically also [4,5-b] pyridine-2-yl of the 3-amino-N-of quantitative yield (2-(dimethylamino) ethyl)-5-(oxazole) benzamide (MS, M ⁺+ H=326).

The preparation of compound 153:

With 3-amino-N-(2-(dimethylamino) ethyl)-5-(oxazole [4,5-b] pyridine-2-yl also) benzamide and 3, the 4-dimethoxy-benzoyl chloride reacts under foregoing identical microwave condition.With 9: 1 CH of crude product use ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=490).

Compound 154 and 155 preparation:

Use suitable acyl chlorides, adopt the used same steps as of preparation compound 153.

4-(3-amino-5-(oxazole is [4,5-b] pyridine-2-yl also) benzoyl) preparation of piperazine-1-t-butyl formate:

With 3-nitro-5-(oxazole [4,5-b] pyridine-2-yl also) (250mg 0.877mmol) is dissolved among the 5mL DMF with 1 equivalent Boc-piperazine (163mg), 500mg HATU (1.5 equivalent) and 0.3mL DIEA (2 equivalent) phenylformic acid.Reaction mixture at room temperature stirred 18 hours.Then it is diluted with 50mLEtOAc, wash with water.With organic layer drying (Na ₂SO ₄), concentrate and obtain the nitro amide intermediate.It is dissolved in 50mL MeOH and the 5mL water with 200mg sodium sulfhydrate hydrate (4 equivalent).Reaction mixture stirred 1 hour under refluxing.Reaction mixture is concentrated water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain 300mg 4-(3-amino-5-(oxazole is [4,5-b] pyridine-2-yl also) benzoyl) piperazine-1-t-butyl formate.(MS，M ⁺+H＝424)。

The preparation of compound 107:

With 4-(3-amino-5-(oxazole is [4,5-b] pyridine-2-yl also) benzoyl) (100mg, 0.236mmol) and 47mg3,4-dimethoxy-benzoyl chloride (1 equivalent) is dissolved in the 1mL pyridine piperazine-1-t-butyl formate together.Reaction mixture heated 10 minutes in the Biotage microwave reactor.Then it is cooled to room temperature, concentrates.With 9: 1 CH of reaction product use ₂Cl ₂: the MeOH mixture by chromatogram purification, obtains the diamide derivatives of 120mg BOC protection.With its CH with 2mL 25%TFA ₂Cl ₂Solution-treated, room temperature was placed 1 hour.Then it is concentrated, obtains 3,4-dimethoxy-N-(3-(oxazole is [4,5-b] pyridine-2-yl also)-5-(piperazine-1-formyl radical) phenyl with the ether development) tfa salt (MS, the M of benzamide ⁺+ H=488).

Compound 138 and 139 preparation:

Use suitable acyl chlorides, adopt the used same steps as of preparation compound 107.

The preparation of compound 136:

With 3-nitro-5-(oxazole [4,5-b] pyridine-2-yl also) methyl benzoate (2.70g) and 3g sodium sulfhydrate hydrate (6 equivalent) mix with 100mL MeOH and 20mL water.Reaction mixture stirred 1 hour under refluxing.Then it is cooled to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the 600mg intermediate amine.The part of this intermediate amine (50mg) and 1 equivalent 3, the 4-dimethoxy-benzoyl chloride reacts under foregoing identical microwave reaction condition.With 9: 1 CH of crude product use ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=434).

The preparation of compound 137:

3-(3,4-dimethoxy benzamido)-5-(oxazole is [4,5-b] pyridine-2-yl also) methyl benzoate (20mg) is dissolved in 2mL THF and contains in the 1mL water of 2 equivalent NaOH.Reaction mixture at room temperature stirred 1 minute.Then it is acidified to pH5 with 6N HCl, concentrates.Filter the solid of collecting gained, drying obtains acid (MS, M ⁺+ H=420).

Compound 79,80 and 81 preparation:

Under foregoing identical microwave reaction condition, use suitable acyl chlorides to react 3-(2-methylthiazol-4-yl) aniline (Aldrich).Final product uses 9: 1 CH ₂Cl ₂: the MeOH mixture, pass through chromatogram purification.

The preparation of 2-amino-3-hydroxyl-6-picoline:

(Aldrich, 0.045mol) (6 equivalents 0.27mol) are dissolved in 250mL MeOH and 20mL H together with the 15g sodium sulfhydrate with 7.00g 3-hydroxyl-6-methyl-2-nitropyridine ₂Among the O.Reaction mixture stirred 5 hours under refluxing.Reaction mixture is cooled to room temperature,, is concentrated into dried with the dilution of 300mL dehydrated alcohol.The gained resistates is dissolved in 300mL CH ₂Cl ₂In 10mL MeOH.With mixture supersound process 10 minutes, placed room temperature 3 hours.By removing by filter the gained salt that be settled out this moment.Filtrate concentrating obtained thick amine.It is passed through short silicagel column (plug), with 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃The N wash-out carries out purifying.Obtain the amine (yield 89%) of 5.0g expectation altogether.

The also preparation of [4,5-b] pyridine of 5-methyl-2-(3-nitro-phenyl)-oxazoles:

With 1.2g 2-amino-3-hydroxyl-6-picoline (9.68mmol) and 1.60g 3-nitrobenzoic acid (1 equivalent), 4.4g HATU (Novabiochem, 1.2 equivalent, 11.6mmol) and 2.5mL DIEA (1.5 equivalents 14.5mmol) are dissolved among the 20mLDMF together.Reaction mixture at room temperature stirred 18 hours.Then it is diluted with 250mL EtOAc, wash (4 * 15mL) with water.With organic layer drying (Na ₂SO ₄), concentrate and obtain thick product.Chromatogram purification (pentane is to the 80%EtOAc/ pentane for Isco, gradient elution) obtains the amide intermediate (yield 42%) of 1.10g expectation.

(1.10g 4.00mmol) mixes with 7mL PPA, stirs 5 hours in 150 ℃ with this amide intermediate.Reaction mixture is cooled to about 80 ℃, with the dilution of 200mL water.This mixture is cooled off in ice bath, slowly transfer pH to 5 with solid NaOH.Filter to collect the gained solid, drying obtains the product of 600mg expectation, i.e. 5-methyl-2-(3-nitro-phenyl)-oxazoles [4,5-b] pyridine (2 step total recovery 24%) also.LC/MS shows purity＞95%.

The also preparation of [4,5-b] pyridine of 5-brooethyl-2-(3-nitro-phenyl)-oxazoles:

With typical way, with 400mg 5-methyl-2-(3-nitro-phenyl)-oxazoles also [4,5-b] pyridines (1.57mmol) be suspended in 50mL CCl with 280mg (1.57mmol) NBS and 20mg benzoyl peroxide ₄In.Reaction mixture stirred 4 hours under refluxing.LC/MS shows that about 50% is converted into the bromide of expectation.After refluxing again 2 hours, do not observe variation again.Add 1 equivalent NBS again, and refluxed again 4 hours.LC/MS shows that conversion fully.Reaction mixture is concentrated, and the gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH) obtain basically also [4,5-b] pyridine of the 5-brooethyl-2-of quantitative yield (3-nitro-phenyl)-oxazoles.

4-[2-(3-nitro-phenyl)-oxazoles are [4,5-b] pyridine-5-ylmethyl also]-preparation of piperazine-1-t-butyl formate:

With 5-brooethyl-2-(3-nitro-phenyl)-oxazoles also [4,5-b] pyridine (250mg, 0.75mmol) and Et ₃(0.200mL 1.5mmol) is dissolved in 5mL CH with 140mg Boc-piperazine to N together ₃Among the CN.Reaction mixture at room temperature stirred 18 hours.Then it is concentrated gained resistates and 25mL CH ₂Cl ₂Mix, use the salt water washing.With organic layer drying (Na ₂SO ₄), concentrate and to obtain basically also [4,5-b] pyridine-5-ylmethyl of the 4-[2-of quantitative yield (3-nitro-phenyl)-oxazoles]-piperazine-1-t-butyl formate.

4-[2-(3-amino-phenyl)-oxazoles are [4,5-b] pyridine-5-ylmethyl also]-preparation of piperazine-1-t-butyl formate:

With 4-[2-(3-nitro-phenyl)-oxazoles [4,5-b] pyridine-5-ylmethyl also]-(330mg 0.75mmol) is dissolved in 6mLMeOH and the 2mL water with 210mg sodium sulfhydrate hydrate (3.75mmol) piperazine-1-t-butyl formate.Reaction mixture stirred 4 hours under refluxing.As if based on LC/MS, reaction fully.Reaction mixture is cooled to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and to obtain basically also [4,5-b] pyridine-5-ylmethyl of the 4-[2-of quantitative yield (3-amino-phenyl)-oxazoles]-piperazine-1-t-butyl formate.

The preparation of compound 166:

With 4-[2-(3-amino-phenyl)-oxazole [4,5-b] pyridine-5-ylmethyl also]-(83mg, 0.2mmol) (44mg 0.2mmol) is dissolved in the 1mL pyridine piperazine-1-t-butyl formate together with 1 equivalent 3-dimethylamino Benzoyl chloride hydrochloride.Reaction mixture heated 10 minutes with Biotage microwave reactor (160 ℃).Then it is cooled to room temperature, concentrates.The gained resistates is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%EtN ₃) obtain 25mg 4-{2-[3-(3-dimethylamino-benzamido)-phenyl]-oxazoles [4,5-b] pyridine-5-ylmethyl also-piperazine-1-t-butyl formate (yield 23%).

With 4-{2-[3-(3-dimethylamino-benzamido)-phenyl]-oxazoles [4,5-b] pyridine-5-ylmethyl also }-(25mg 0.045mmol) is dissolved in the CH of 1mL 25%TFA to piperazine-1-t-butyl formate ₂Cl ₂In the solution, placed room temperature 1 hour.Then it is concentrated, and with gained resistates Et ₂O development obtains the 3-dimethylamino-N-[3-of quantitative yield (5-piperazine-1-ylmethyl-oxazoles are [4,5-b] pyridine-2-yl also)-phenyl basically]-tfa salt of benzamide.

The preparation of compound 514:

Except using 2-quinoxalinyl chlorine (2-quinoxaloyl chloride), prepare according to essentially identical step with preparation compound 166 detailed descriptions as acyl chlorides.

(1.00g 9.16mmol) is dissolved among the 20mL DMF with 2.06g 5-nitro m-phthalic acid mono-methyl (9.16mmol), 5.2g HATU (13.7mmol) and 3.2mLDIEA (18.3mmol) with 2-amino-3-pyridone.Reaction mixture at room temperature stirred 18 hours.Then it is diluted with 200mL EtOAc, wash (3 * 25mL) with water.With organic layer drying (Na ₂SO ₄), concentrate.The gained resistates is mixed with 10mL PPA, stirred 6 hours at 160 degree.With in the careful impouring 200mL of the reaction mixture water, transfer pH to 5 then with solid NaOH.Solid collected by filtration, drying obtain the product as 1: 1 mixture of methyl esters and acid.With this mixture by being suspended in 150mL CH ₂Cl ₂In separate, filter then.Filtrate is methyl esters (MS, M ⁺+ H=300), solid is the acid of expectation, i.e. 3-nitro-5-(oxazole is [4,5-b] pyridine-2-yl also) phenylformic acid (MS, M ⁺+ H=286).

The preparation of compound 164:

With 4-(3-amino-5-(oxazole is [4,5-b] pyridine-2-yl also) benzoyl) (100mg, 0.236mmol) with 47mg 3,4-dimethoxy-benzoyl chloride (1 equivalent) is dissolved in the 1mL pyridine piperazine-1-t-butyl formate together.Reaction mixture heated 10 minutes in the Biotage microwave reactor.Then it is cooled to room temperature, concentrates.With the CH of gained resistates with 9: 1 ₂Cl ₂: the MeOH mixture by chromatogram purification, obtains the diamide derivatives of 120mg BOC protection.With its CH with 2mL 25%TFA ₂Cl ₂Solution-treated placed room temperature 1 hour then.Then it is concentrated, grinds with ether and obtain 3,4-dimethoxy-N-(3-(oxazole is [4,5-b] pyridine-2-yl also)-5-(piperazine-1-formyl radical) phenyl) tfa salt (MS, the M of benzamide ⁺+ H=488).

The preparation of (3-nitro-5-oxazole is [4,5-b] pyridine-2-base-phenyl also)-methyl alcohol:

With typical way, with 3-nitro-5-(oxazole [4,5-b] pyridine-2-yl also) (770mg, 2.70mmol) (0.3mL 2.70mmol) is suspended among the anhydrous THF of 50mL phenylformic acid together, cools off with ice bath with NMM.(0.35mL, 2.70mmol), reaction mixture stirred 1 hour in 0 ℃ to add isobutyl chlorocarbonate.Add NaBH in 0 ℃ then ₄(reaction mixture stirred 45 minutes down in this uniform temp for 102mg, 6mL aqueous solution 2.70mmol).Then it is concentrated, the gained resistates is diluted with 10mL water.Water layer CH ₂Cl ₂Extraction.With organic layer drying (Na ₂SO ₄), concentrate and obtain 500mg (3-nitro-5-oxazole is [4,5-b] pyridine-2-base-phenyl also)-methyl alcohol (yield 68%, LC/MS detects purity＞95%).

The preparation of 4-(3-amino-5-(oxazole is [4,5-b] pyridine-2-base-phenyl also)-piperazine-1-t-butyl formate:

With typical way, with 250mg 3-nitro-5-(oxazole [4,5-b] pyridine-2-base-phenyl also)-methyl alcohol (0.923mmol) and 1 equivalent Et ₃N (130 μ L) is dissolved in 25mL CH together ₂Cl ₂In.Add methylsulfonyl chloride (1 equivalent, 70 μ L), reaction mixture is heated to room temperature, stirred 15 minutes.Then it is used the salt solution quenching, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain methanesulfonates (mesylate) intermediate.With this material and 130 μ L Et ₃N and 172mg Boc-piperazine (0.923mmol) are together with 4mL CH ₃CN mixes, and at room temperature stirs 1 day.Reaction mixture is concentrated, and the gained resistates passes through CH ₂Cl ₂And water sepn.With organic layer drying (Na ₂SO ₄), concentrate and obtain the 4-of quantitative yield (3-nitro-5-oxazole is [4,5-b] pyridine-2-base-benzyl also)-piperazine-1-t-butyl formate basically.This material is mixed with 6mL MeOH and 1mL water with 200mg sodium sulfhydrate hydrate.The gained reaction mixture stirred 1 hour under refluxing.Then it is cooled to room temperature, concentrates.The gained resistates with the dilution of 2mL water, is used CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain 280mg 4-(3-amino-5-oxazole is [4,5-b] pyridine-2-base-benzyl also)-piperazine-1-t-butyl formate.

The preparation of compound 159:

With 4-(3-amino-5-oxazole is [4,5-b] pyridine-2-base-benzyl also)-piperazine-1-t-butyl formate (0.2mmol) and 1 equivalent (40mg) 3, the 4-dimethoxy-benzoyl chloride mixes with the 1mL pyridine.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%EtN ₃).Then the product of purifying is used the CH of 2mL 25%TFA ₂Cl ₂Solution-treated 2 hours.Then it is concentrated gained resistates Et ₂O grinds, and obtains expecting tfa salt (MS, the M of product ⁺+ H=474).

The preparation of compound 160 and compound 161:

Use suitable acyl chlorides, adopt preparation compound 159 used same steps as to prepare.

Compound 3-dimethylamino methyl-5-oxazole is the preparation of [4,5-b] pyridine-2-base-aniline also:

With typical way, with 250mg (3-nitro-5-oxazole is [4,5-b] pyridine-2-base-phenyl also)-methyl alcohol (0.923mmol) and 1 equivalent Et ₃N (130 μ L) is dissolved in 25mL CH together ₂Cl ₂In.Add methylsulfonyl chloride (1 equivalent, 70 μ L), reaction mixture is heated to room temperature, stirred 15 minutes.Then it is used the salt solution quenching, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the methanesulfonates intermediate.This material is dissolved in 5mL CH with the THF solution of 2mL 2N-dimethylamine ₃Among the CN.Reaction mixture stirred under room temperature 2 hours.Then it is concentrated, the gained resistates is passed through CH ₂Cl ₂And water sepn.Separate organic layer, dry (Na ₂SO ₄), concentrate and obtain thick nitro-derivative.This material is mixed with 6mL MeOH and 1mL water with 200mg sodium sulfhydrate hydrate, under refluxing, stirred 1 hour.Reaction mixture is cooled to room temperature,, is concentrated into dried with the anhydrous EtOH dilution of 100mL.With gained resistates and 9: 1 CH of 10mL ₂Cl ₂/ MeOH mixes, and filters.Filtrate concentrating obtained also [4,5-b] pyridine-2-base-aniline of 220mg 3-dimethylamino methyl-5-oxazole.

The preparation of compound 156:

With 3-dimethylamino methyl-5-oxazole also [4,5-b] pyridine-2-base-aniline (0.2mmol) and 40mg 3,4-dimethoxy-benzoyl chloride (0.2mmol) mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained resistates is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain the product (MS, the M that expect ⁺+ H=433).

The preparation of compound 157 and compound 158:

Use suitable acyl chlorides, adopt preparation compound 156 used same steps as to prepare.

The preparation of (3-nitro-5-thiazole is [5,4-c] pyridine-2-base-phenyl also)-methyl alcohol:

With 3-nitro-5-thiazole also [5,4-c] pyridine-2-base-phenylformic acid (880mg, 2.92mmol) and NMM (0.32mL 2.92mmol) is suspended among the anhydrous THF of 50mL together.Reaction mixture is cooled off with ice bath, and the adding isobutyl chlorocarbonate (0.38mL, 2.92mmol).Reaction mixture stirred 40 minutes in 0 ℃.Add NaBH then ₄(110mg, 5mL aqueous solution 2.70mmol).Reaction mixture is warming up to room temperature then in 0 ℃ of stirring 30 minutes.It is concentrated, use CH then ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain crude product.By chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH) obtain 150mg (3-nitro-5-thiazole is [5,4-c] pyridine-2-base-phenyl also)-methyl alcohol.

3-dimethylamino methyl-5-thiazole is the preparation of [5,4-c] pyridine-2-base-aniline also:

(120mg is 0.418mmol) with refrigerative Et in ice bath with (3-nitro-5-thiazole is [5,4-c] pyridine-2-base-phenyl also)-methyl alcohol ₃N (87 μ L, 1.5 equivalents) is suspended in 20mL CH together ₂Cl ₂In.(32 μ L 0.418mmol), slowly are warming up to room temperature with reaction mixture to add methylsulfonyl chloride.Reaction mixture CH ₂Cl ₂With the salt water sepn.Separate organic layer, dry (Na ₂SO ₄), concentrate and obtain thick methanesulfonates intermediate.This material is dissolved in 2mL CH with the THF solution of 2mL 2N-dimethylamine ₃Among the CN.The gained reaction mixture was stirred under room temperature 2 hours.Then it is concentrated.The gained resistates is mixed with the water that 6mL MeOH and 2mL contain 200mg sodium sulfhydrate hydrate.Reaction mixture was stirred 3 hours under refluxing.Then it is cooled to room temperature,, is concentrated into dried with the anhydrous EtOH dilution of 100mL.With gained resistates and 10mL9: 1 CH ₂Cl ₂/ MeOH mixes, and filters.Filtrate is concentrated 3-dimethylamino methyl-5-thiazole [5, the 4-c] pyridine-2-base-aniline also obtain quantitative yield basically.

The preparation of compound 174:

With 3-dimethylamino methyl-5-thiazole also [5,4-c] pyridine-2-base-aniline (0.2mmol) and 47mg 3,4,5-trimethoxy-benzoyl chloride (0.2mmol) mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained resistates is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain product (MS, the M that 30mg expects ⁺+ H=479).

3-(oxazole is [4,5-b] pyridine-2-yl also) benzoic preparation:

(1g 9.16mmol) is dissolved among the 25mL DMF with m-phthalic acid mono-methyl (9.16mmol), 5.2g HATU (1.5 equivalent) and 3.2mL DIEA with 2-amino-3-pyridone.Reaction mixture stirred under room temperature 18 hours.Then it is diluted with the 150mL ethyl acetate, wash (5 * 20mL) with water.With organic layer drying (Na ₂SO ₄), concentrate and obtain the 3.2g midbody acid amide.This material is mixed with 10mL PPA, stirred 4 hours in 160 degree.Then it is cooled to room temperature, in the careful impouring 150mL water.Transfer pH to 5 with solid NaOH.Filter to collect the gained precipitation, drying obtains the acid of 380mg expectation, i.e. 3-(oxazole [4,5-b] pyridine-2-yl also) phenylformic acid.

The preparation of compound 102:

In order to form acid amides, with 3-(oxazole [4,5-b] pyridine-2-yl also) (30mg, 0.125mmol) with 3,4,5-trimethoxy-aniline (23mg, 1 equivalent) and 71mg HATU (1.5 equivalent) are dissolved among the 2mL DMF phenylformic acid together.After adding 45 microlitre DIEA (2 equivalent), reaction mixture was stirred under room temperature 18 hours.Then it is diluted with ethyl acetate, wash with water, concentrate.Products therefrom is used 9: 1 CH ₂Cl ₂: the MeOH mixture by chromatogram purification, obtains also [4,5-b] pyridine-2-yl of 3-(oxazole)-N-(3,4, the 5-trimethoxyphenyl) benzamide.(MS，M ⁺+H＝406)。

The preparation of compound 100, compound 101 and compound 103:

Use suitable amine, adopt preparation compound 102 used same steps as to prepare.

The 5-oxazole is the preparation of [4,5-b] pyridine-2-base-pyridin-3-yl amine also:

With typical method, 790mg 2-amino-3-pyridone (7.24mmol) and 1.00g 5-amino-nicotinic acid (7.24mmol) are mixed with 10mL PPA, stirred 6 hours in 200 ℃.Reaction mixture is cooled to about 100 ℃, in the careful impouring 100mL water.Transfer pH to 6, solid collected by filtration with solid NaOH.Get also [4,5-b] pyridine-2-base-pyridin-3-yl amine of 180mg 5-oxazole after the high vacuum dry altogether.

The preparation of compound 73:

With the 5-oxazole also [4,5-b] pyridine-2-base-pyridin-3-yl amine (25mg, 0.118mmol) with 24mg 2,4-dimethoxy-benzoyl chloride (0.118mmol) mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH) obtain 11mg product (MS, M ⁺+ H=377).

Compound 66,67 and 68 preparation:

Use suitable acyl chlorides, adopt and the 73 described substantially the same step preparations of preparation compound.

The preparation of 2-imidazo [2,1-b] thiazole-6-base-aniline:

With typical method, (300mg 1.23mmol) mixes with the 15mL methylethylketone, stirs 18 hours under refluxing with 123mg thiazolamine (1.23mmol) and 2-bromo-2 '-nitro-acetophenone.Then it is cooled to room temperature, filters.Concentrated filtrate.The gained solid is mixed with 20mL EtOH, add 5 dense HBr.Reaction mixture stirred 6 hours under refluxing.This moment, all materials all dissolved, and LC/MS detects and shows nitro intermediate (MS, the M that generates expectation ⁺+ H=246).Reaction mixture is concentrated, with the rare NaHCO of 20mL ₃Aqueous solution.Filter and collect the gained solid, drying obtains the 300mg nitro intermediate.This material is mixed with 15mL MeOH and 3mL water with 6 Equivalent Hydrogen sodium sulphite hydrates.Reaction mixture stirred 8 hours under refluxing.Then it is cooled to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain 260mg 2-imidazo [2,1-b] thiazole-6-base-aniline.

The preparation of compound 203:

(64mg, 0.30mmol) with 60mg 3,4-dimethoxy-benzoyl chloride (0.30mmol) mixes with the 1mL pyridine together with 2-imidazo [2,1-b] thiazole-6-base-aniline.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Reaction mixture is cooled to room temperature, concentrates.The gained resistates is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH) obtain the product (MS, the M that expect ⁺+ H=380).

The preparation of compound 204:

Use suitable acyl chlorides, adopt preparation compound 203 used same steps as to prepare.

Compound 707,739 and 740 preparation:

Except use 2-amino-4-methylthiazol when synthesis step begins, in last acid amides formation step, use outside the suitable acyl chlorides, adopt preparation compound 203 used same steps as to prepare.

The preparation of 6-(2-nitro-phenyl)-2-imidazo [2,1-b] thiazole-3-ethyl formate:

With typical method, (Combi-Blocks, 0.0123mol) (3.0g 0.0123mol) mixes with the 25mL methylethylketone together with 2-bromo-2 '-nitro-acetophenone with 2.1g thiazolamine-4-ethyl formate.Reaction mixture was stirred 18 hours under refluxing.Then it is cooled to room temperature, removes by filter some solids.Filtrate concentrating obtained 3.10g 6-(2-nitro-phenyl)-2-imidazo [2,1-b] thiazole-3-ethyl formate (MS, M ⁺+ H=318).

The preparation of [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl alcohol:

(14.50g 0.0458mol) mixes with the 100mL water that contains 7.3gNaOH (4 equivalent) with 100mLTHF with 6-(2-nitro-phenyl)-2-imidazo [2,1-b] thiazole-3-ethyl formate.Reaction mixture at room temperature stirred 18 hours.Then it is concentrated.With water layer CH ₂Cl ₂Washing is once used 6N HCl acidifying then.Solid collected by filtration, drying obtain 7.4g acid intermediate.(7.4g, 0.0256mol) (2.8mL 0.0256mol) mixes with the anhydrous THF of 200mL together, is cooled to 0 ℃ with NMM with this material.(3.35mL, 0.0256mol), reaction mixture stirred in ice bath 3 hours to add isobutyl chlorocarbonate.Add NaBH ₄(0.97g, 30mL aqueous solution 0.0256mol).Reaction mixture stirred 45 minutes in 0 ℃.Then it is warming up to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain crude product.Obtain 5.20g[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl by chromatogram purification (Isco uses pentane/EtOAc mixture)]-methyl alcohol (yield 74%).

4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazole-3-ylmethyl]-preparation of piperazine-1-t-butyl formate:

(1.0g is 3.64mol) with 1 equivalent Et with [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl alcohol ₃N (0.51mL) is dissolved in 100mL CH together ₂Cl ₂In.(1 equivalent 0.28mL), is heated to room temperature with reaction mixture, stirs 15 minutes to add methylsulfonyl chloride.Then it is used the salt solution quenching, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the methanesulfonates intermediate.With this material and 0.51mLEt ₃N and 680mg Boc-piperazine (3.64mmol) are together with 4mL CH ₃CN mixes, and at room temperature stirs 1 day.Reaction mixture is concentrated, and the gained resistates passes through CH ₂Cl ₂And water sepn.With organic layer drying (Na ₂SO ₄), concentrate and obtain the product of quantitative yield basically.This material is mixed with 6mL MeOH and 1mL water with 200mg sodium sulfhydrate hydrate.The gained reaction mixture was stirred 24 hours under refluxing.Then it is cooled to room temperature, concentrates.The gained resistates with the dilution of 2mL water, is used CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain 0.90g 4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazole-3-ylmethyl]-piperazine-1-t-butyl formate.

The preparation of compound 207:

With 4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazole-3-ylmethyl]-piperazine-1-t-butyl formate (0.3mmol) and 1 equivalent (60mg) 3, the 4-dimethoxy-benzoyl chloride mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N).Then the product of purifying is used the CH of 2mL 25%TFA ₂Cl ₂Solution-treated 2 hours.Then it is concentrated gained resistates Et ₂O grinds tfa salt (MS, the M of the product that obtains expecting ⁺+ H=478).

Compound 208,326,327,328,329,330,337,338,440,441,442,443,444,445,446,447,448,510,511,512,543,544,708,709,710,733,735,736,737,738,743 and 744 preparation:

Use suitable acyl chlorides or SULPHURYL CHLORIDE, adopt preparation compound 207 used same steps as to prepare.Compound 623,624,625,644,645,692,695,697 and 698 is to use suitable acyl chlorides, prepares according to preparation compound 207 used steps.Acyl chlorides is commercially available or is prepared by carboxylic acid as follows: with the N of carboxylic acid (1.0mmol), thionyl chloride (2.0mmol) and catalytic amount, dinethylformamide (DMF) (2) refluxed 1 hour in toluene (2mL).Reactant is cooled to room temperature, the acyl chlorides that vacuum concentration obtains expecting.

The preparation of 2-(3-dimethylamino methyl-imidazo [2,1-b] thiazole-6-yl)-aniline:

(435mg is 1.58mmol) with 1 equivalent Et with [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl alcohol ₃N (0.330mL) is dissolved in 25mL CH together ₂Cl ₂In.(1 equivalent 0.12mL), is warming up to room temperature with reaction mixture, stirs 15 minutes to add methylsulfonyl chloride.Then it is used the salt solution quenching, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the methanesulfonates intermediate.The THF solution of this material with 4mL 2N-dimethylamine is mixed with 4mL THF, at room temperature stirred 3 hours.Reaction mixture is concentrated, and the gained resistates passes through CH ₂Cl ₂And water sepn.With organic layer drying (Na ₂SO ₄), concentrate and obtain the product of quantitative yield basically.This material is mixed with 6mL MeOH and 1mL water with 200mg sodium sulfhydrate hydrate.The gained reaction mixture stirred 6 hours under refluxing.Then it is cooled to room temperature,, concentrates with the anhydrous EtOH dilution of 100mL.With gained resistates and 20mL 9: 1CH ₂Cl ₂/ MeOH mixes, and filters.Filtrate concentrating obtained 2-(3-dimethylamino methyl-imidazo [2,1-b] thiazole-6-yl)-aniline.

The preparation of compound 205:

With 2-(3-dimethylamino methyl-imidazo [2,1-b] thiazole-6-yl)-aniline (0.3mmol) and 1 equivalent (60mg) 3, the 4-dimethoxy-benzoyl chloride mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain the product expected, be faint yellow solid (MS, M ⁺+ H=437.

The preparation of compound 206:

Use suitable acyl chlorides, adopt preparation compound 205 used same steps as to prepare.

The preparation of 2-(3-morpholine-4-base-imidazo [2,1-b] thiazole-6-yl)-aniline:

(435mg is 1.58mmol) with 1 equivalent Et with [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl alcohol ₃N (0.330mL) is dissolved in 25mL CH together ₂Cl ₂In.(1 equivalent 0.12mL), is heated to room temperature with reaction mixture, stirs 15 minutes to add methylsulfonyl chloride.To use the salt solution quenching then, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the methanesulfonates intermediate.With this material and 0.33mL Et ₃N and 0.14mL morpholine are together with 6mL CH ₃CN mixes.Reaction mixture at room temperature stirred 18 hours.Concentrate it next day, and the gained resistates passes through CH ₂Cl ₂And water sepn.With organic layer drying (Na ₂SO ₄), concentrate and obtain the product of quantitative yield basically.This material is mixed with 6mLMeOH and 1mL water with 200mg sodium sulfhydrate hydrate.The gained reaction mixture was stirred 6 hours under refluxing.Then it is cooled to room temperature,, concentrates with the anhydrous EtOH dilution of 100mL.With gained resistates and 20mL 9: 1CH ₂Cl ₂/ MeOH mixes, and filters.Filtrate concentrating obtained 2-(3-morpholine-4-base-imidazo [2,1-b] thiazole-6-yl)-aniline.

The preparation of compound 209:

With 2-(3-morpholine-4-base-imidazo [2,1-b] thiazole-6-yl)-aniline (0.3mmol) and 1 equivalent (60mg) 3, the 4-dimethoxy-benzoyl chloride mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain the product expected, be faint yellow solid (MS, M ⁺+ H=479).

The preparation of compound 210:

Use suitable acyl chlorides, adopt preparation compound 209 used same steps as to prepare.

The preparation of 6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-2-ethyl formate:

With typical method, (Astatech 5.81mmol) mixes with 50mL acetone ketone with 1.42g2-bromo-2 '-nitro-acetophenone, stirs 18 hours under refluxing with 1.0g thiazolamine-5-ethyl formate.Then with its filtration.Filtrate concentrating obtained midbody acid amide (MS, M ⁺+ H=336).This material is mixed with 20mL EtOH with 6 dense HBr, under refluxing, stirred 4 hours.Reaction mixture is cooled to room temperature, concentrates.With the rare NaHCO of gained resistates ₃Aqueous solution dilution.Solid collected by filtration, drying obtain 6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-2-ethyl formate (MS, M ⁺+ H=318).

The preparation of [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazol-2-yl]-methyl alcohol:

(660mg 2.08mmol) is dissolved among the 12mL THF, adds the 10mL aqueous solution of NaOH (4 equivalent) with 6-(2-nitro-phenyl)-2-imidazo [2,1-b] thiazole-2-ethyl formate.Reaction mixture stirred 12 hours at 50 ℃.Then it is cooled to room temperature, concentrates.Water layer is acidified to pH5 with 6N HCl.Solid collected by filtration, drying obtain the acid of quantitative yield basically.(0.23mL 2.08mmol) mixes with the anhydrous THF of 20mL together, cools off in ice bath with NMM with this material (2.08mmol).(0.27mL 2.08mmol), stirs reaction mixture 30 minutes in 0 ℃ to add isobutyl chlorocarbonate.Add NaBH ₄(80mg, 5mL aqueous solution 2.08mmol).Reaction mixture concentrates then in 0 ℃ of stirring 30 minutes.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate.(Isco uses CH by chromatogram purification ₂Cl ₂Mixture gradient elution with MeOH) obtain 190mg[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazol-2-yl]-methyl alcohol.

The preparation of 2-(2-dimethylamino methyl-imidazo [2,1-b] thiazole-6-yl)-aniline:

Except using [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazol-2-yl]-methyl alcohol is as outside the starting raw material, employing used substantially the same step in the process of preparation 2-(3-dimethylamino methyl-imidazo [2,1-b] thiazole-6-yl)-aniline prepares.

The preparation of compound 178:

With 2-(2-dimethylamino methyl-imidazo [2,1-b] thiazole-6-yl)-aniline (0.3mmol) and 1 equivalent (60mg) 3, the 4-dimethoxy-benzoyl chloride mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained resistates is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain the product expected, be faint yellow solid (MS, M ⁺+ H=437).

The preparation of compound 179:

Use suitable acyl chlorides, adopt preparation compound 178 used same steps as to prepare.

4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazol-2-yl methyl]-preparation of piperazine-1-t-butyl formate:

Except using [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazol-2-yl]-methyl alcohol is as outside the starting raw material, adopt and preparation 4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazole-3-ylmethyl]-process of piperazine-1-t-butyl formate in the substantially the same step preparation of used step.

The preparation of compound 270:

With 4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazol-2-yl methyl]-piperazine-1-t-butyl formate (0.2mmol) and 1 equivalent (40mg) 3, the 4-dimethoxy-benzoyl chloride mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is passed through chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N).The product of purifying is used the CH of 2mL 25%TFA ₂Cl ₂Solution-treated 2 hours.Then it is concentrated gained resistates Et ₂O grinds tfa salt (MS, the M of the product that obtains expecting ⁺+ H=478).

The preparation of compound 271 and compound 513:

Use suitable acyl chlorides, adopt preparation compound 270 used same steps as to prepare.

The preparation of 3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ethyl formate:

Prepare 4-(2-nitro-phenyl)-thiazol-2-yl amine as follows: with 2-bromo-2 '-(1.75g, 7.2mmol) (1.09g 14.4mmol) mixes with the anhydrous EtOH of 50mL nitro-acetophenone together, stirs 2 hours under refluxing with thiocarbamide.Reaction mixture is cooled to room temperature, concentrating under reduced pressure.The gained resistates is used CH with the alkalization of the 20mL 1N NaOH aqueous solution ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the 4-of quantitative yield (2-nitro-phenyl)-thiazol-2-yl amine basically.

(1.60g 7.2mmol) mixes with the 50mL methylethylketone with 0.90mL ethyl bromide acetone (7.2mmol), stirs 24 hours under refluxing with 4-(2-nitro-phenyl)-thiazol-2-yl amine.(0.90mL, 7.2mmol), reaction mixture stirred 8 hours under refluxing again to add normal ethyl bromide acetone again.Reaction mixture is cooled to room temperature, concentrating under reduced pressure.The gained resistates is by chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 5%MeOH) obtain 1.2g 3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ethyl formate (yield 52%).

The preparation of [3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-yl]-methyl alcohol:

(1.2g 3.78mmol) mixes with the water that 50mLTHF and 50mL contain 600mg NaOH (4 equivalent) with 3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ethyl formate.Reaction mixture stirred 8 hours for 50 ℃.Then it is cooled to room temperature, concentrating under reduced pressure.Water layer is acidified to pH6 with 6N HCl.Filter and collect the gained solid, drying obtains the acid of 465mg intermediate.(465mg, 1.61mmol) (0.18mL 1.61mmol) mixes with the anhydrous THF of 50mL together with NMM with this intermediate acid.Reaction mixture cools off in ice bath, and the adding isobutyl chlorocarbonate (0.21mL, 1.61mmol).Place 0 ℃ after 30 minutes, add NaBH ₄The 2mL aqueous solution (240mg).The gained reaction mixture in 0 ℃ of stirring 30 minutes, is concentrated then.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain thick alcohol.By chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 5%MeOH) obtain 200mg[3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-yl]-methyl alcohol (yield 45%).

4-[3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ylmethyl]-preparation of piperazine-1-t-butyl formate:

With [3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-yl]-methyl alcohol (200mg, 0.727mmol) and Et ₃N (0.10mL, 0.727mmol) same together 50mLCH ₂Cl ₂Mix, in ice bath, cool off.(56 μ L 0.727mmol), are warming up to room temperature with reaction mixture, stir 30 minutes to add methylsulfonyl chloride.With reaction mixture salt solution quenching, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the methanesulfonates intermediate of quantitative yield basically.With this material and triethylamine (0.10mL, 0.727mmol) and the Boc-piperazine be dissolved in together in the 10mL acetonitrile.This reaction mixture was at room temperature stirred 18 hours.Then it is concentrated.The gained resistates is by water and CH ₂Cl ₂Separate.Separate organic layer, dry (Na ₂SO ₄), concentrate and obtain the 4-[3-of quantitative yield (2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ylmethyl basically]-piperazine-1-t-butyl formate.

4-[3-(2-amino-phenyl)-imidazo [2,1-b] thiazole-6-ylmethyl]-preparation of piperazine-1-t-butyl formate:

With 4-[3-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ylmethyl]-(320mg 0.73mmol) mixes with 20mL MeOH and the 5mL water that contains sodium sulfhydrate hydrate (244mg, 6 equivalents) piperazine-1-t-butyl formate.Reaction mixture stirred 4 hours under refluxing.Then it is cooled to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain 280mg 4-[3-(2-amino-phenyl)-imidazo [2,1-b] thiazole-6-ylmethyl]-piperazine-1-t-butyl formate (yield 92%).

The preparation of compound 560:

With 4-[3-(2-amino-phenyl)-imidazo [2,1-b] thiazole-6-ylmethyl]-(45mg 0.1mmol) mixes with the 1mL pyridine with 1 equivalent (40mg) 2-quinoxalinyl chlorine piperazine-1-t-butyl formate.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is by chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N).Then the product of purifying is used the CH of 2mL 25%TFA ₂Cl ₂Solution-treated 2 hours.Then it is concentrated gained resistates Et ₂O grinds tfa salt (MS, the M of the product that obtains expecting ⁺+ H=470).

The preparation of compound 559:

Use suitable acyl chlorides, adopt preparation compound 560 used same steps as to prepare.

The preparation of 1: 1 mixture of 6-(2-chloro-pyridin-3-yl)-imidazo [2,1-b] thiazole-3-ethyl formate and 6-(2-bromo-pyridin-3-yl)-imidazo [2,1-b] thiazole-3-ethyl formate:

1: 1 mixture for preparing 2-bromo-1-(2-chloro-pyridin-3-yl)-ethyl ketone and 2-bromo-1-(2-bromo-pyridin-3-yl)-ethyl ketone according to the step described in the WO2005/061476.This mixture (5.6g, about 0.0240mol) is mixed with the 150mL methylethylketone with 2-amino-thiazolyl--4-ethyl formate (4.6g), under refluxing, stirred 18 hours.Reaction mixture is concentrated.Gained resistates and 150mL CH ₂Cl ₂Mix, filter.Filtering solid is unreacted 2-amino-thiazolyl--4-ethyl formate.Filtrate concentrating obtained 1: 1 mixture (3.0g altogether) of pure basically 6-(2-chloro-pyridin-3-yl)-imidazo [2,1-b] thiazole-3-ethyl formate and 6-(2-bromo-pyridin-3-yl)-imidazo [2,1-b] thiazole-3-ethyl formate.

The preparation of 1: 1 mixture of 6-(2-chloro-pyridin-3-yl)-3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole and 6-(2-bromo-pyridin-3-yl)-3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole:

With 6-(2-chloro-pyridin-3-yl)-imidazo [2,1-b] 1: 1 mixture (3.0g) of thiazole-3-ethyl formate and 6-(2-bromo-pyridin-3-yl)-imidazo [2,1-b] thiazole-3-ethyl formate mixes with 100mL THF with the 25mL water that contains 3gNaOH.Reaction mixture stirred 3 hours in 50 ℃.Then it is cooled to room temperature, concentrates.Water layer is acidified to pH5 with 6N HCl, and the gained mixture is filtered.Collect solid and obtain the acid of 2.14g intermediate.

This acid mixture of 1: 1 (2.14g) is mixed with the anhydrous THF of 250mL with NMM (0.85mL), in ice bath, cool off.Add isobutyl chlorocarbonate (1.0mL), reaction mixture is warming up to room temperature, stirred 3 hours.Reaction mixture is cooled off in ice bath, add NaBH ₄The 20mL aqueous solution (0.29g).Reaction mixture was stirred 30 minutes, be warming up to room temperature then.It is concentrated, use CH subsequently ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the 1.5g intermediate ethanol.

With this 1: 1 intermediate ethanol mixture (1.5g) and Et ₃N (0.80mL) is dissolved in 100mLCH together ₂Cl ₂In, in ice bath, cool off.Add methylsulfonyl chloride (0.44mL), reaction mixture is warming up to room temperature.With reaction mixture salt solution quenching, be divided into two-layer.With organic layer drying (Na ₂SO ₄), concentrate and obtain the intermediate methanesulfonates.With this material and 0.8mL Et ₃N and 0.5mL morpholine together immediately with 30mLCH ₃CN mixes.Reaction mixture stirred 3 hours in 50 ℃.The concentrating under reduced pressure reaction mixture, the gained resistates passes through CH ₂Cl ₂And water sepn.Separate organic layer, dry (Na ₂SO ₄), concentrate and obtain crude product.By chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain 1: 1 mixture of 720mg 6-(2-chloro-pyridin-3-yl)-3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole and 6-(2-bromo-pyridin-3-yl)-3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole.

The preparation of (4-methoxyl group-benzyl)-[3-(3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-pyridine-2-yl]-amine:

With 6-(2-chloro-pyridin-3-yl)-3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole and 6-(2-bromo-pyridin-3-yl)-3-morpholine-4-ylmethyl-imidazo [2,1-b] with the mixing of 15mL toluene, stirring is 5 days under refluxing with 0.47mL 4-methoxy-benzyl amine for 1: 1 mixture (600mg) of thiazole.Reaction mixture is cooled to room temperature, passes through CH ₂Cl ₂With the salt water sepn.Separate organic layer, dry (Na ₂SO ₄) and the concentrated crude product that obtains.By chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 95%CH ₂Cl ₂, 4%MeOH and 1%Et ₃N) obtain 200mg (4-methoxyl group-benzyl)-[3-(3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-pyridine-2-yl]-amine.

The preparation of 3-(3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-pyridine-2-base amine:

With (4-methoxyl group-benzyl)-[3-(3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-pyridine-2-yl]-amine (100mg, 0.23mmol) with triethyl silicane (0.11mL, 2 equivalents) together with 2mL CH ₂Cl ₂Mix.Add trifluoracetic acid (1mL), reaction mixture at room temperature stirred 18 hours.Next day, reaction mixture is concentrated.With gained resistates Et ₂O grinds and obtains the tfa salt of the 3-of quantitative yield (3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-pyridine-2-base amine basically.

The preparation of compound 621:

The tfa salt (0.1mmol) of 3-(3-morpholine-4-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-pyridine-2-base amine is mixed with the 1mL pyridine with 0.1mmol 2-quinoxalinyl chlorine.Reaction mixture reacted 10 minutes in microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates and obtain crude product.Use and used the moisture CH of 0.1%TFA buffered ₃The CN mixture by preparation HPLC purifying, obtains tfa salt (MS, the M of 18mg expectation product ⁺+ H=472).

The preparation of N-(4-pyridone-3-yl)-3 nitrobenzamides:

Suspension in EtOH (700mL) and methylene dichloride (50mL) is at H with 4-hydroxy-3-nitropyridine (40g) and 10%Pd/C (4g) ₂(1atm) in stirring at room 4 days.The TLC demonstration reacts completely.Reaction mixture is filtered by the Celite pad, the filtrate vacuum concentration is obtained the red foam crude product (MS confirms for 32g, yield 100%) of 3-amino-4-hydroxy pyridine, it is directly used in next step.

(2.376g, (3.339g, pyridine 18.0mmol) (54.0mL) solution spend the night the stirring of gained mixture to drip the 3-nitrobenzoyl chloride in pyridine 21.6mmol) (36.0mL) solution to 3-amino-4-hydroxy pyridine in 10 ℃.Add Na ₂CO ₃(1.145g 10.8mmol), stirs mixture 1 hour.Solid collected by filtration, with 10%HOAc (30mL * 3) and water (30mL * 3) washing, vacuum-drying obtains the yellow solid (3.70g, yield 66%) of N-(4-pyridone-3-yl)-3 nitrobenzamides. ¹H-NMR (400MHz, DMSO-dB _6B) δ: 6.34 (1H, d, J=7.2Hz), 7.74 (1H, d, J=8.0Hz), 7.84 (1H, t, J=8.0Hz), 8.34 (1H, d, J=7.2Hz), 8.44 (1H, t, J=8.0Hz), 8.66 (1H, s), 8.73 (1H, s), 9.66 (1H, s), 11.65 (1H, br s); MS (ESI): for C ₁₂H ₉N ₃O ₄Calculated value (m/z): 259, measured value: 260[M+1] ⁺

2-(3-nitrophenyl) oxazole is the preparation of [4,5-c] pyridine also:

(1.554g, polyphosphoric acid 6mmol) (12.0mL) solution stirred 6 hours in 150 ℃ with N-(4-pyridone-3-yl)-3-nitrobenzamide.In reaction mixture impouring distilled water, add sodium hydroxide to pH=5.Filter collecting precipitation, be washed to neutrality, vacuum drying oven (50 ℃) drying obtains 2-, and (3-nitrophenyl) oxazole is the yellow solid of [4,5-c] pyridine (1.389g, yield 96%) also.MS (ESI): for C ₁₂H ₇NO ₃Calculated value (m/z): 241, measured value: 242[M+1] ⁺

3-(oxazole is [4,5-c] pyridine-2-yl also) preparation of aniline:

With 2-(3-nitrophenyl) oxazole also [4,5-c] pyridine (1.50g, 6.2mmol), iron powder (1.867g, 31.8mmol) and NH ₄(2.86g is 53.5mmol) at CH for Cl ₃OH/H ₂(4: 1,311.2mL) suspension in refluxed 6 hours O.Mixture is filtered, and with filtrate vacuum-evaporation.Resistates uses the silica gel chromatography purifying (with sherwood oil: EtOAc: Et ₃N=160: 40: 1 wash-outs) obtain also [4,5-c] pyridine-2-yl of 3-(oxazole) white solid (1.107g, yield 85%) of aniline. ¹HNMR (400MHz, DMSO-d ₆) δ: 5.54 (2H, s), 6.82 (1H, d, J=8.0Hz), 7.24 (1H, t, J=8.0Hz), 7.35 (1H, d, J=8.0Hz), 7.44 (1H, s), 7.86 (1H, d, J=5.6Hz), 8.56 (1H, d, J=5.6Hz), 9.07 (1H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of O (m/z): 211, measured value: 212[M+1] ⁺

The general step for preparing compound 296,297,298,311,343,344,345,346,347 and 348:

Acyl chlorides also can commercial acquisition or by being prepared by the following method by corresponding carboxylic acid: the 1.0g carboxylic acid was refluxed 2 hours in 10mL thionyl chloride and 0.1mL DMF.Reaction mixture is cooled to room temperature, the acyl chlorides that concentrating under reduced pressure obtains expecting.With 3-(oxazole [4,5-c] pyridine-2-yl also) aniline (each 0.2mmol) and the suitable mixture of acyl chlorides (each 0.24mmol) in pyridine (2mL) stir under room temperature and spend the night.With reaction mixture H ₂O (each 5mL) dilution.Filter collecting precipitation, grind with MeOH (5mL), drying obtains the storehouse compound, and it is passed through HPLC﹠amp; MS analyzes.With this storehouse compound further by silicagel pad CH ₂Cl ₂/ EtOAc or sherwood oil/EtOAc wash-out purifying.

The also preparation of [4,5-c] pyridine of 2-(3-nitrophenyl) thiazole:

With N-(4-pyridone-3-yl)-3-nitrobenzamide (1.33g, 5.2mmol) and P ₂S ₅(2.40g, 10.4mmol) mixture in pyridine (6.0mL) and right-dimethylbenzene (24mL) stirred 18 hours in 140 ℃.Remove under vacuum while hot and desolvate, resistates obtains the also yellow solid of [4,5-c] pyridine (1.08g, yield 81%) of 2-(3-nitrophenyl) thiazole by the EtOH recrystallization purifying.MS (ESI): for C ₁₂H ₇N ₃O ₂The calculated value of S (m/z): 257, measured value: 258[M+1] ⁺

The preparation of 3-(thiazole is [4,5-c] pyridine-2-yl also) aniline:

With 2-(3-nitrophenyl) thiazole also [4,5-c] pyridine (1.53g, 5.9mmol), NH ₄Cl (2.76g, 51.6mmol), iron powder (1.80g, 32.2mmol), H ₂The mixture of O (30mL) and methyl alcohol (120mL) is at N ₂Under be heated to backflow, kept 5.5 hours.Mixture is filtered, and filtrate is used H ₂O (400mL) dilution.Filter collecting precipitation, vacuum-drying obtains the brown solid (841mg, 63%) of 3-(thiazole is [4,5-c] pyridine-2-yl also) aniline. ¹HNMR (400MHz, DMSO-d ₆) δ: 9.28 (1H, s); 8.52 (1H, s); 8.21 (1H, s); 7.23-7.38 (3H, d), 6.79 (1H, s), 5.51 (2H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of S (m/z): 227, measured value: 228[M+H] P.

The general step for preparing compound 272,273,400,401,402 and 403:

Use 3-(thiazole is [4,5-c] pyridine-2-yl also) aniline as starting raw material and suitable acyl chlorides, adopt and the essentially identical step preparation of above-mentioned preparation compound 343 used steps.

The preparation of N-(4-pyridone-3-yl)-4-nitrobenzamide:

(3.4g, (stirring is spent the night for 4.8g, pyridine 25.7mmol) (77.0ml) solution to drip right-nitrobenzoyl chloride in pyridine 30.9mmol) (51.0mL) solution to 3-amino-4-hydroxy pyridine in 0 ℃.Add Na ₂CO ₃Water (1.7g) (65mL) solution stirs the gained mixture 1 hour.Reaction mixture neutralizes with 10%AcOH.Filter collecting precipitation, with the 10%AcOH washing, vacuum-drying (50 ℃) obtains the light green solid (4.1g, yield 62%) of N-(4-pyridone-3-yl)-4-nitrobenzamide. ¹HNMR (400MHz, DMSO-d ₆) δ: 11.64 (1H, br s), 9.57 (1H, s), 9.07 (1H, s), 8.75 (1H, d, J=4.4Hz), 8.36 (1H, d, J=8.8Hz), 8.20 (1H, d, J=8.8Hz), 7.74 (1H, d, J=4.4Hz), 6.33 (1H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of O (m/z): 211, measured value: 212[M+1] ⁺

2-(4-nitrophenyl) oxazole is the preparation of [4,5-c] pyridine also:

With N-(4-pyridone-3-yl)-4-nitrobenzamide (2.59g, 10.0mmol) and the solution of polyphosphoric acid (20mL) stirred 6 hours in 140 ℃.In reaction mixture impouring distilled water (200mL), add sodium hydroxide to pH=5.Filter collecting precipitation, be washed to neutrality, vacuum-drying obtains 2-, and (4-nitrophenyl) oxazole is the yellow solid of [4,5-c] pyridine (2.261g, yield 94%) also.MS (ESI): for C ₁₂H ₇NO ₃Calculated value (m/z): 241, measured value: 242[M+1] ⁺

4-(oxazole is [4,5-c] pyridine-2-yl also) preparation of aniline:

With 2-(4-nitrophenyl) oxazole also [4,5-c] pyridine (2.261g, 9.3mmol), iron powder (2.814g, 48.0mmol) and NH ₄(4.314g is 80.1mmol) at CH for Cl ₃OH/H ₂O (4: 1,469mL) the middle backflow 6 hours.Mixture is filtered, and with filtrate vacuum-evaporation.Resistates with silica gel chromatography with sherwood oil: ethyl acetate: Et ₃N=160: the wash-out purifying obtained also [4,5-c] pyridine-2-yl of 4-(oxazole in 40: 1) yellow solid (1.215g, yield 62%) of aniline. ¹H NMR (400MHz, DMSO-d ₆) δ: 6.11 (2H, s), 6.69 (2H, d, J=8.4Hz), 7.75 (1H, d, J=5.6Hz), 7.87 (2H, d, J=8.4Hz), 8.46 (1H, d, J=5.6Hz), 8.94 (1H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of O (m/z): 211, measured value: 212[M+1] ⁺

The general step for preparing compound 339,340,341,342,449,410,411 and 412:

Compound 339,340,341,342,449,410,411 and 412 is to use also [4,5-c] pyridine-2-yl of 4-(oxazole) aniline is starting raw material and suitable acyl chlorides, adopts to prepare compound 343 substantially the same steps preparation as previously mentioned.

The also preparation of [4,5-c] pyridine of 2-(4-nitrophenyl) thiazole:

With N-(4-pyridone-3-yl)-4-nitrobenzamide (5.18g, 0.02mol) and P ₂S ₅(8.90g, 0.04mol) mixture in pyridine (25mL) and right-dimethylbenzene (100mL) stirred 18 hours in 140 ℃.Remove under vacuum while hot and desolvate, resistates obtains the also yellow solid of [4,5-c] pyridine (3.00g, yield 59%) of 2-(4-nitrophenyl) thiazole by the EtOH recrystallization purifying.MS (ESI): for C ₁₂H ₇N ₃O ₂The calculated value of S (m/z): 257, measured value: 258[M+1] ⁺

The preparation of 4-(thiazole is [4,5-c] pyridine-2-yl also) aniline:

With 2-(4-nitrophenyl) thiazole also [4,5-c] pyridine (2.57g, 0.01mol), iron powder (2.8g, 0.05mmol) and NH ₄(4.32g is 0.08mol) at CH for Cl ₃OH/H ₂O (4: 1,200mL) the middle backflow 6 hours.Mixture is filtered, and with filtrate vacuum-evaporation.Resistates water (30mL) washing obtains the white solid (1.37g, yield 60%) of 4-(thiazole is [4,5-c] pyridine-2-yl also) aniline.

The general step for preparing compound 322,323,324,325,409 and 450:

Using also [4,5-c] pyridine-2-yl of 4-(oxazole) aniline is as starting raw material and suitable acyl chlorides, prepares compound 322,323,324,325,409 and 450 by preparing compound 343 substantially the same steps as previously mentioned.

The preparation of N-(4-pyridone-3-yl)-5-nitrothiophene-2-methane amide:

(5.000g is 28.9mmol) at SOCl with 5-nitrothiophene-2-formic acid ₂Mixture (40mL) refluxed 2 hours.The SOCl that vacuum-evaporation is excessive ₂, drip 3-amino-4-hydroxy pyridine (2.65g, pyridine 24.1mmol) (150mL) solution.Reaction mixture spends the night in 10 ℃ of stirrings.Add Na ₂CO ₃(1.533g, aqueous solution 14.5mmol) (100mL) is with gained mixture restir hour.Filter collecting precipitation, use 10%Na ₂CO ₃(120mL) washing, vacuum-drying obtains the yellow powder (5.87g, yield 92%) of N-(4-pyridone-3-yl)-5-nitrothiophene-2-methane amide.

2-(the 5-nitrothiophene-also preparation of [4,5-c] pyridine of 2-base) oxazole:

(2.385g, polyphosphoric acid 9.0mmol) (18mL) solution stirred 6 hours in 140 ℃ with N-(4-pyridone-3-yl)-5-nitrothiophene-2-methane amide.In reaction mixture impouring distilled water, add sodium hydroxide to pH=5.Filter collecting precipitation, be washed to neutrality, drying obtains 2-, and (5-nitrothiophene-2-base) oxazole is the yellow solid of [4,5-c] pyridine (1.775g, yield 80%) also.MS (ESI): for C ₁₀H ₅N ₃O ₃The calculated value of S (m/z): 247, measured value: 248[M+1] ⁺

5-(oxazole is [4,5-c] pyridine-2-yl also) preparation of thiophene-2-amine:

With 2-(5-nitrothiophene-2-base) oxazole also [4,5-c] pyridine (1.775g, 7.2mmol), iron powder (2.108g, 36.0mmol) and NH ₄(3.081g is 57.6mmol) at CH for Cl ₃OH/H ₂O (4: 1,360mL) the middle backflow 6 hours.Mixture is filtered, and with filtrate vacuum-evaporation.Resistates with silica gel chromatography with sherwood oil: ethyl acetate: Et ₃N=160: the wash-out purifying obtained also [4,5-c] pyridine-2-yl of 5-(oxazole in 40: 1) yellow solid (1.1g, yield 70%) of thiophene-2-amine. ¹HNMR (400MHz, DMSO-d ₆) δ: 8.83 (1H, s), 8.41 (1H, d, J=4.8Hz), 7.67 (1H, d, J=4.8Hz), 7.57 (1H, d, J=4.4Hz), 6.91 (2H, s), 6.03 (1H, d, J=4.4Hz); MS (ESI): for C ₁₀H ₇N ₃The calculated value of OS (m/z): 217, measured value: 218[M+1] ⁺

Compound 422,423,424,425,426,427 and 428 preparation:

Using also [4,5-c] pyridine-2-yl of 5-(oxazole) thiophene-2-amine is as starting raw material and suitable acyl chlorides, prepares compound 422,423,424,425,426,427 and 428 by preparing compound 343 substantially the same steps as previously mentioned.

The also preparation of [4,5-c] pyridine of 2-(5-nitrothiophene-2-yl) thiazole:

With compound 17 (1.97g, 7.43mmol) and P2S5 (3.30g, 15mmol) mixture in pyridine (30mL) and right-dimethylbenzene (120mL) stirred 18 hours in 140 ℃.Under vacuum, remove while hot and desolvate, resistates by the EtOH recrystallization purifying obtain compound 21 yellow solid (700mg, yield 35%, Lot#:MC0052-050-21).MS (ESI): for C ₁₀H ₅N ₃O ₂S ₂Calculated value (m/z): 263, measured value: 264.1[M+1] ⁺

The preparation of 5-(thiazole [4,5-c] pyridine-2-yl) thiophene-2-amine:

With compound 21 (700mg, 2.66mmol), iron powder (745mg, 13.30mmol) and NH ₄(1.36g is 22mmol) at CH for Cl ₃OH/H ₂O (4: 1,150mL) the middle backflow 6 hours.Mixture is filtered, and with filtrate vacuum-evaporation.With resistates water (30mL) washing, drying obtains the yellow solid (306mg, yield 50%) of compound 22.

Compound 515,516,517,518,519 and 520 preparation:

Using also [4,5-c] pyridine-2-yl of 5-(oxazole) thiophene-2-amine is as starting raw material and suitable acyl chlorides, prepares compound 515,516,517,518,519 and 520 by preparing compound 343 substantially the same steps as previously mentioned.

The preparation of N-(3-pyridone-4-yl)-3-methyl benzamide:

According to Journal of Organic Chemistry (1995), p.5721 the step described in prepares 3-amino-4-hydroxy pyridine.(2.481g, (3.10g, pyridine 16.7mmol) (50mL) solution spend the night the stirring of gained mixture to drip the 3-nitrobenzoyl chloride in pyridine 21.6mmol) (40mL) solution to 3-ammonia-4-pyridone in 10 ℃.Add Na ₂CO ₃(1.0g), with mixture restir 1 hour.Filter collecting precipitation, with 10% acetic acid (30mL * 3) and water (30mL * 3) washing, vacuum-drying obtains the yellow solid (1.057g, yield 43%) of N-(3-pyridone-4-yl)-3-methyl benzamide.

2-(3-nitrophenyl) oxazole is the preparation of [5,4-c] pyridine also:

(1.30g, polyphosphoric acid 5mmol) (7.5mL) solution stirred 6 hours in 150 ℃ with N-(3-pyridone-4-yl)-3-methyl benzamide.In reaction mixture impouring distilled water, add sodium hydroxide to pH=5.Filter collecting precipitation, be washed to neutrality, vacuum drying oven (50 ℃) drying obtains 2-, and (3-nitrophenyl) oxazole is the yellow solid of [5,4-c] pyridine (1.120g, yield 93%) also.

3-(oxazole is [5,4-c] pyridine-2-yl also) preparation of aniline:

With 2-(3-nitrophenyl) oxazole also [5,4-c] pyridine (1.20g, 5mmol), iron powder (1.40g, 25mmol) and NH ₄(2.14g is 40mmol) at CH for Cl ₃OH/H ₂(4: 1,60mL) suspension in refluxed 6 hours O.Reaction mixture is filtered, and with filtrate vacuum-evaporation.In resistates impouring water.Filter collecting precipitation, water (20mL * 3) washing obtains also [5,4-c] pyridine-2-yl of 3-(oxazole) white solid (0.330g, yield 31%) of aniline.

Compound 429,430,431,451,452,453 and 454 preparation:

Using also [5,4-c] pyridine-2-yl of 3-(oxazole) aniline is as starting raw material and suitable acyl chlorides, prepares compound 429,430,431,451,452,453 and 454 by preparing compound 343 substantially the same steps as previously mentioned.

The preparation of N-(3-pyridone-4-yl)-4-nitrobenzamide:

(2.5g, (4.8g, pyridine 25.7mmol) (50mL) solution at room temperature stir and spend the night to drip right-nitrobenzoyl chloride in pyridine 22.7mmol) (88mL) solution to 4-amino-3-pyridone in 10 ℃.In reaction mixture, add Na ₂CO ₃(1.1g, water 10.4mmol) (10mL) solution stirred 1 hour.Add the 10%AcOH neutralization solution.Filter collecting precipitation, with the 10%AcOH washing, drying obtains the yellow powder (2.27g, yield 52%) of N-(3-pyridone-4-yl)-4-nitrobenzamide.MS (ESI): for C ₁₂H ₉N ₃O ₄Calculated value (m/z): 259, measured value: 260[M+H] ⁺

2-(4-nitrophenyl) oxazole is the preparation of [5,4-c] pyridine also:

With N-(3-pyridone-4-yl)-4-nitrobenzamide (260mg, 1mmol) and the mixture of polyphosphoric acid (1.5mL) stirred 6 hours in 150 ℃.In reaction mixture impouring water, add sodium hydroxide to pH=5.Filter collecting precipitation, be washed to neutrality, drying obtains 2-, and (4-nitrophenyl) oxazole is the brown solid of [5,4-c] pyridine (177mg, yield 73%) also. ¹HNMR(400MHz，DMSO-d ₆)δ：9.21(1H，s)，8.62(1H，d，J＝4.8Hz)，8.51(4H，d，J＝18，8.8Hz)，7.95(1H，d，J＝5.2Hz)。

4-(oxazole is [5,4-c] pyridine-2-yl also) preparation of aniline:

With 2-(4-nitrophenyl) oxazole also [5,4-c] pyridine (610mg, 2.5mmol), NH ₄Cl (1.2g, 22.4mmol), iron powder (0.76g, 13.6mmol), H ₂The mixture of O (13mL) and methyl alcohol (51mL) is at N ₂Under be heated to backflow, kept 6 hours.With the mixture vacuum concentration, with the light brown powder (340mg, yield 64%) of silica gel chromatography purifying (with EA/PE=3: 1 wash-out) obtain also [5,4-c] pyridine-2-yl of 4-(oxazole) aniline. ¹H NMR (400MHz, DMSO-d ₆) δ: 8.95 (1H, s); 8.46 (1H, d, J=5.2); 7.92 (2H, d, J=8.8); 7.69 (1H, d, J=5.6), 6.71 (2H, d, J=8.8), 6.19 (2H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of O (m/z): 211, measured value: 212[M+H] ⁺

Compound 408 and 419 preparation:

Using also [5,4-c] pyridine-2-yl of 4-(oxazole) aniline is as starting raw material and suitable acyl chlorides, prepares compound 408 and 419 by preparing compound 343 substantially the same steps as previously mentioned.

The preparation of N-(3-pyridone-4-yl)-5-nitrothiophene-2-methane amide:

With 5-nitrothiophene-2-formic acid (5.0g, 28.9mmol) and SOCl ₂Solution (40mL) refluxed 2 hours.Solvent removed in vacuo adds 4-amino-3-pyridone (2.65g, pyridine 24.1mmol) (150mL) solution then.Reaction mixture spends the night in 10 ℃ of stirrings.Add Na ₂CO ₃(1.53g, water 14.5mmol) (100mL) solution stirred 1 hour, added AcOH then and transferred pH=7.Filter collecting precipitation, with 10%AcOH (30mL * 2) washing, drying obtains the yellow powder (5.0g, yield 78%) of N-(3-pyridone-4-yl)-5-nitrothiophene-2-methane amide.

2-(the 5-nitrothiophene-also preparation of [5,4-c] pyridine of 2-base) oxazole:

(1.1g adds P in pyridine 4.1mmol) (5mL) solution to N-(3-pyridone-4-the yl)-5-nitrothiophene-2-methane amide that stirs ₂O ₅(1.2g, 8.3mmol) and right-dimethylbenzene (21mL).After 160 ℃ of backflows are spent the night, reaction mixture is concentrated under vacuum, resistates is by the CH of silica gel chromatography with 5% ethyl acetate ₂Cl ₂Eluant solution obtains 2-, and (5-nitrothiophene-2-base) oxazole is the brown solid of [5,4-c] pyridine (174mg, yield 17%) also. ¹H NMR(400MHz，CDCl ₃)δ：8.97(1H，s)；8.59(1H，d，J＝5.6)；7.94(1H，d，J＝4.4)；7.86(1H，d，J＝4.4)，7.69(1H，d，J＝5.6，0.8)。

5-(oxazole is [5,4-c] pyridine-2-yl also) preparation of thiophene-2-amine:

With 2-(5-nitrothiophene-2-base) oxazole also [5,4-c] pyridine (170mg, 0.69mmol), NH ₄CI (199mg, 3.73mmol), iron powder (328mg, 5.87mmol), H ₂The mixture of O (10mL) and methyl alcohol (40mL) is at N ₂Under be heated to backflow, kept 6 hours.With the mixture vacuum concentration, add 100mL water then, place 4 ℃ to spend the night.Solid collected by filtration, drying obtain also [5,4-c] pyridine-2-yl of 5-(oxazole) brown solid (52mg, 35%) of thiophene-2-amine. ¹HNMR(400MHz，DMSO-d ₆)δ：8.84(1H，s)；8.40(1H，d，J＝5.2)；7.64(1H，d，J＝4)；7.57(1H，d，J＝5.2)，7.06(2H，s)，1.09(1H，d，J＝4.4)。

Compound 561,562 and 563 preparation:

Using also [5,4-c] pyridine-2-yl of 5-(oxazole) thiophene-2-amine is as starting raw material and suitable acyl chlorides, prepares compound 561,562 and 563 by preparing compound 343 substantially the same steps as previously mentioned.

2-(oxazole is [4,5-c] pyridine-2-yl also) preparation of aniline:

(2.225g, 20.0mmol) (2.740g 20.0mmol) stirred 6 hours in 140 ℃ in polyphosphoric acid (40mL) with the 2-benzaminic acid with 3-amino-4-hydroxy pyridine.In reaction mixture impouring distilled water, add sodium hydroxide to pH=8.Filter collecting precipitation, crude product with silica gel chromatography with sherwood oil: ethyl acetate: Et ₃N (160: 40: 1) wash-out purifying obtains also [4,5-c] pyridine-2-yl of 2-(oxazole) aniline (1.659g, yield 39%). ¹H NMR (400MHz, DMSO-d ₆) δ: 6.68 (1H, t, J=7.6Hz), 6.93 (1H, d, J=8.0Hz), 7.17 (2H, s), 7.30 (1H, t, J=7.6Hz), 7.83 (1H, d, J=5.6Hz), 7.90 (1H, d, J=8.0Hz), 8.55 (1H, d, J=5.6Hz), 9.05 (1H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of O (m/z): 211, measured value: 212[M+1] ⁺

Compound 404,405,406,407,420 and 421 preparation:

Using also [4,5-c] pyridine-2-yl of 2-(oxazole) aniline is as starting raw material and suitable acyl chlorides, prepares compound 404,405,406,407,420 and 421 by preparing compound 343 identical steps as previously mentioned.The also preparation of [4,5-c] pyridine of 2-(2-nitrophenyl) thiazole:

Use 4-hydroxyl-3-aminopyridine and 2-nitrobenzoyl chloride, adopting as previously mentioned similarly, step prepares N-(4-hydroxyl-pyridin-3-yl)-2-nitro-benzamide.General-(4-hydroxyl-pyridin-3-yl)-2-nitro-benzamide (2.6g, 0.01mol) and P ₂S ₅(4.44g, 0.02mol) mixture in pyridine (12.5mL) and right-dimethylbenzene (50mL) stirred 18 hours in 140 ℃.Solvent removed in vacuo, resistates obtains the also yellow solid of [4,5-c] pyridine (1.43g, yield 55%) of 2-(2-nitrophenyl) thiazole by recrystallization purifying.

The 2-thiazole is the preparation of [4,5-c] pyridine-2-base-aniline also:

With 2-(2-nitrophenyl) thiazole also [4,5-c] pyridine (1.170g, 4.6mmol), the Fe powder (1.26g, 22.8mmol) and NH ₄(1.97g is 36.8mol) at CH for Cl ₃OH: H ₂(4: 1,80mL) suspension in refluxed 6 hours O.Mixture is filtered vacuum-evaporation filtrate.In resistates impouring water.Filter collecting precipitation, water (20mL * 3) washing obtains the also yellow solid of [4,5-c] pyridine-2-base-aniline (0.760g, yield 73%) of 2-thiazole.

Compound 317,318,319,320,321 and 349 preparation:

Use 2-(2-nitrophenyl) thiazole also [4,5-c] pyridine prepares compound 317,318,319,320,321 and 349 as starting raw material and suitable acyl chlorides by the substantially the same step for preparing compound 343 as previously mentioned.

2-(oxazole is [5,4-c] pyridine-2-yl also) preparation of aniline:

Will the 3-hydroxyl-4-aminopyridine in the polyphosphoric acid (40mL) (2.220g, 20.0mmol) and the 2-benzaminic acid (2.740g 20.0mmol) stirred 6 hours in 140 ℃.In reaction mixture impouring distilled water, add sodium hydroxide to pH=8.Filter collecting precipitation, further use silica gel chromatography with sherwood oil: ethyl acetate: Et ₃N (160: 40: 1) wash-out purifying obtains also [5,4-c] pyridine-2-yl of 2-(oxazole) yellow solid (1.332g, yield 31%) of aniline. ¹H NMR (400MHz, DMSO-d ₆) δ: 6.70 (1H, t, J=6.8Hz), 6.94 (1H, d, J=8.4Hz), 7.20 (2H, s), 7.33 (1H, t, J=6.8Hz), 7.80 (1H, d, J=5.6Hz), 7.95 (1H, d, J=8.4Hz), 8.53 (1H, d, J=5.6Hz), 9.05 (1H, s); MS (ESI): for C ₁₂H ₉N ₃The calculated value of O (m/z): 211, measured value: 212[M+1] ⁺

Compound 455,456,457,458 and 459 preparation:

Using also [5,4-c] pyridine-2-yl of 2-(oxazole) aniline is as starting raw material and suitable acyl chlorides, prepares compound 455,456,457,458 and 459 by the substantially the same step for preparing compound 343 as previously mentioned.

The preparation of N-(2-chloro-5-picoline-3-yl)-2-nitrobenzamide:

In 0 ℃ to 5-amino-6-chloro-3-picoline (9.54g, drip in pyridine 66.9mmol) (200mL) solution 2-nitrobenzoyl chloride (13.65g, 73.6mmol).Reaction mixture at room temperature stirred 18 hours.With dark mixture water (1500mL) dilution, add saturated sodium bicarbonate solution then to pH=8.Solid collected by filtration, water (30mL * 3) flushing, drying obtains the pale solid (17.70g, yield 91%) of N-(2-chloro-5-picoline-3-yl)-2-nitrobenzamide in baking oven.

The also preparation of [5,4-b] pyridine of 6-methyl-2-(2 nitrophenyl) thiazole:

With N-(2-chloro-5-picoline-3-yl)-2-nitrobenzamide (5.0g, 17.1mmol) and P ₂S ₅(7.6g, 34.2mmol) mixture in pyridine (50mL) and right-dimethylbenzene (200mL) stirred 20 hours in 140 ℃.Hot solution is transferred in another flask solvent removed in vacuo.Resistates obtains the also yellow solid of [5,4-b] pyridine (3.5g, yield 75%) of 6-methyl-2-(2 nitrophenyl) thiazole by the EtOH recrystallization purifying.

The also preparation of [5,4-b] pyridine of 6-(brooethyl)-2-(2-nitrophenyl) thiazole:

With 6-methyl-2-(2 nitrophenyl) thiazole also [5,4-b] pyridine (2.9g, 10.7mmol), N-bromosuccinimide (NBS, 1.91g, 10.7mmol), CCl ₄(200mL) and benzoyl peroxide (0.021g) under argon gas, add in the three-necked bottle (500mL).The gained yellow mixture was refluxed 2 hours.Add NBS (1.91g) and benzoyl peroxide (0.021g) again.After two hours, add NBS (0.95g) and benzoyl peroxide (0.021g) again, mixture is continued to reflux 3 hours.Then mixture is cooled to room temperature.Solution is transferred in another flask, and vacuum concentration obtains also [5,4-b] pyridine crude products (4.0g) of 6-(brooethyl)-2-(2-nitrophenyl) thiazole, and it is directly used in next step.

The preparation of 4-((2-(2-nitrophenyl) thiazole is [5,4-b] pyridine-6-yl also) methyl) piperazine-1-t-butyl formate:

With 6-(brooethyl)-2-(2-nitrophenyl) thiazole also [5,4-b] pyridine crude products (4.0g), BOC-piperazine (1.99g, 10.7mmol), Et ₃N (1.5mL, 10.7mmol) and the solution of acetonitrile (100mL) stirred 4 hours in 50 ℃, under room temperature, stirred 60 hours then.The TLC detection reaction is complete.With the mixture vacuum concentration, with silica gel chromatography purifying (sherwood oil: ethyl acetate: Et ₃N=100: 10: 1) obtains the yellow solid (3.6g, two step yields 74%) of 4-((2-(2-nitrophenyl) thiazole is [5,4-b] pyridine-6-yl also) methyl) piperazine-1-t-butyl formate.

The preparation of 4-((2-(2-aminophenyl) thiazole is [5,4-b] pyridine-6-yl also) methyl) piperazine-1-t-butyl formate:

With 4-((2-(2-nitrophenyl) thiazole is [5,4-b] pyridine-6-yl also) methyl) piperazine-1-t-butyl formate (2.13g, 4.7mmol), NH ₄Cl (2.00g, 37mmol), iron powder (1.31g, 23.5mmol), H ₂The mixture of O (40mL) and methyl alcohol (160mL) is at N ₂Under refluxed 3 hours.Reaction mixture is filtered, and filtrate concentrates under vacuum, with silica gel chromatography purifying (sherwood oil: ethyl acetate: Et ₃N=800: 200: 1) obtains the yellow solid (1.63g, yield 81%) of 4-((2-(2-aminophenyl) thiazole is [5,4-b] pyridine-6-yl also) methyl) piperazine-1-t-butyl formate.

The general step for preparing compound 588,589,590,591,592,593,594,622,646,681,682,683,684,685,686,687,688,689,701,702,722,723,724,725,730,731 and 732:

With amino skeletal (4-((2-(2-aminophenyl) thiazole is [5,4-b] pyridine-6-yl also) methyl) piperazine-1-t-butyl formate, each 0.141mmol) and suitably the mixture of acyl chlorides (0.17mmol) in pyridine (2mL) in the room temperature shaken over night.Then reaction mixture is used saturated NaHCO ₃(each 5mL) dilution.Filter collecting precipitation, grind with MeOH (5mL), drying obtains the storehouse compound of Boc protection, with it with HPLC﹠amp; MS analyzes.Be lower than the storehouse compound of 95% Boc protection for those purity, these compounds are further carried out purifying by silicagel pad with sherwood oil/EtOAc wash-out.

With the compound dissolution of Boc protection in 25%TFA/CH ₂Cl ₂In the solution (1 or 2mL), at room temperature shake, detect with TLC or LC/MS.Then mixture is concentrated under vacuum, use CH ₂Cl ₂(1.0mL * 2) coevaporation under vacuum obtains expecting the tfa salt of product it being passed through ¹H NMR, HPLC and MS analyze.

Compound 690,726,727,728 and 729 preparation:

Except using 3-amino-2-hydroxyl-6-picoline, prepare compound 690,726,727,728 and 729 by the step substantially the same with preparation compound 646 described steps as the starting raw material.The general step for preparing compound 240,608,241,221,280,222,223,225,244,245,246,247,226,303,238,227,304,228,305,306,307,308,309,310,248,249 and 396:

Use 3-thiazole also [5,4-c] pyridine-2-base-aniline is as starting raw material and suitable acyl chlorides, prepares compound 240,608,241,221,280,222,223,225,244,245,246,247,226,303,238,227,304,228,305,306,307,308,309,310,248,249 and 396 by the step substantially the same with preparation compound as described below 241.

To the 3-thiazole also be added in the mixture of [5,4-c] pyridine-2-base aniline in 1.5mL DMF 5-benzofurane-2-carbonyl chloride in the pyridine (0.25mL) (62mg, MW=206.63,0.3mmol) in.React on 40 ℃ and kept 72 hours, detect with TLC.When finishing, reaction adds 5mL H ₂O with gained suspension solid collected by filtration, washes it with water drying then.Crude product is further used preparation TLC (acetone/sherwood oil=1/2) purifying, and uses washing with acetone, obtains white powder (43mg, 36.1%).The product warp ¹HNMR confirms. ¹H NMR(DMSO-d ₆，500MHz)，δ10.50(1H，s)，9.45(1H，s)，8.70(1H，brs)，8.68(1H，d，J＝5.5Hz)，8.13(1H，d，J＝7.8Hz)，8.08(1H，d，J＝5.5Hz)，8.02(2H，d，J＝7.6Hz)，7.93(1H，d，J＝7.7Hz)，7.63(1H，t，J＝7.9Hz)，7.55(3H，m)，7.43(1H，t，J＝7.3Hz)，7.23(1H，d，J＝3.4Hz)。EIMS m/z(％)：397.2(M ⁺)。The general step for preparing compound 466,398,229,230,282,250,231,399,251,283,232,252,284,285,287,234,235,236,237,239,289,288,290,655 and 280:

Use 3-thiazole also [5,4-c] pyridine-2-base-aniline is as starting raw material and suitable SULPHURYL CHLORIDE, prepares compound 466,398,229,230,282,250,231,399,251,283,232,252,284,285,287,234,235,236,237,239,289,288,290,655 and 280 by preparation compound 398 substantially the same steps as described below.

With the 3-thiazole in the 2mL pyridine also [5,4-c] pyridine-2-base aniline (68mg, 0.3mmol) under agitation add dansyl chloride (81mg, 0.3mmol).Reactant kept 24 hours in about 40 ℃.The vaporising under vacuum pyridine adds entry.The gained suspension is filtered,, obtain yellow solid product (29mg, 21.0%) with the THF washing. ¹H NMR(DMSO-d ₆，500MHz)δ9.38(1H，s)，8.64(1H，d，J＝2.8Hz)，8.45(1H，d，J＝8.5Hz)，8.38(1H，d，J＝8.6Hz)，8.30(1H，d，J＝7.1Hz)，8.03(1H，d，J＝5.4Hz)，7.87(1H，s)，7.71(1H，d，J＝7.6Hz)，7.64(2H，m)，7.40(1H，t，J＝7.9Hz)，7.31(1H，d，J＝8.1Hz)，7.26(1H，d，J＝7.6Hz)，2.77(6H，s)。EIMS m/z：460.01(M ⁺，31)。

The general step for preparing compound 599,600,498,610,601,611,485,484,481,612,475,473,472,613 and 491:

Use 3-thiazole also [5,4-c] pyridine-2-base-aniline is as starting raw material and suitable lsothiocyanates, prepares compound 599,600,498,610,601,611,485,484,481,612,475,473,472,613 and 491 by preparation compound 599 substantially the same steps as described below.

3-thiazole in the 1mL pyridine also adds isothiocyanic acid 2 in [5,4-c] pyridine-2-base aniline mixture, and 4-Dimethoxyphenyl ester (59mg, 0.3mmol).Reactant stirs simultaneously in 60 ℃ of maintenances 24 hours, uses the TLC monitoring reaction.In case reaction is finished, just add 5mL H to crude mixture ₂O with gained suspension solid collected by filtration, washes with water then, with preparation TLC (acetone/sherwood oil=1/2) purifying.Isolating solid is further used washing with acetone, the air-dry product 38mg (30.3%) that obtains expecting.The product warp ¹HNMR confirms. ¹H NMR(DMSO-d ₆，500MHz)δ9.40(1H，s)，8.65(1H，d，J＝5.4Hz)，8.55(1H，s)，8.05(1H，d，J＝5.2Hz)，7.90(1H，d，J＝7.4Hz)，7.77(1H，d，J＝7.7Hz)，7.55(1H，t，J＝7.8Hz)，7.47(1H，d，J＝6.6Hz)，6.63(1H，s)，6.54(1H，d，J＝7.8Hz)，3.82(3H，s)，3.77(3H，s)。MS：422.26(M ⁺)。

The general step for preparing compound 604,605 and 607:

Use 3-thiazole also [5,4-c] pyridine-2-base-aniline prepares compound 604,605 and 607 as starting raw material and suitable chloro-formic ester by preparation compound 604 substantially the same steps as described below.

3-thiazole in the 2.5mL pyridine also [5,4-c] pyridine-2-base aniline (68mg, 0.3mmol) add in the mixture N-methyl-N-phenyl amino formyl chloride (50.7mg, 0.3mmol).Reactant kept 48 hours in room temperature.In mixture, add entry (5mL) then, the gained suspension is filtered.The solid of collecting is further with preparation TLC (sherwood oil/acetone=2/1) purifying.The product warp ¹H NMR confirms. ¹H NMR (500MHz, acetone-d ₆) δ 9.34 (1H, s), 8.66 (1H, d, J=5.3Hz), 8.43 (1H, s), 7.97 (1H, d, J=5.4Hz), 7.79 (2H, d, J=7.9Hz), 7.74 (1H, d, J=8.1Hz), 7.50 (2H, t, J=8.1Hz), 7.44 (2H, d, J=8.0Hz), 7.37 (1H, d, J=7.2Hz), 3.36 (3H, s).

The general step for preparing compound 387,609,390,391,462,392,393,436,461,460,596,465 and 463:

Use 2-thiazole also [5,4-c] pyridine-2-base-aniline is as starting raw material and suitable acyl chlorides, prepares compound 387,609,390,391,462,392,393,436,461,460,596,465 and 463 by preparation compound 385 substantially the same steps as described below.

2-thiazole in 1.5mL DMF also be added in [5,4-c] pyridine-2-base aniline mixture 5-benzofurane-2-carbonyl chloride in the pyridine (0.25mL) (62mg, 0.3mmol).Reactant stirs simultaneously in 40 ℃ of maintenances 24 hours, detects with TLC.In case reaction is finished, just in crude mixture, add 5mL H ₂O, and, it is washed subsequently with water drying with gained suspension solid collected by filtration product.Crude product further by preparation TLC (acetone/sherwood oil=1/2) purifying, obtains 38mg product (36.80%).The product warp ¹HNMR confirms: ¹H NMR (500MHz, DMSO-d ₆) δ 8.44 (1H, s), 7.74 (4H, d, J=7.5Hz), 7.41 (4H, t, J=7.7Hz), 7.29 (1H, t, J=7.4Hz), 6.87 (2H, d, J=3.0Hz), 6.75 (2H, d, J=2.6Hz).EIMS m/z：397.2(M ⁺)。

Compound 162 and 163 preparation:

In the microwave phial, add the 2-thiazole also [5,4-c] pyridine-2-base aniline (40mg, 0.2mmol), 3,4, the 5-trimethoxy-benzoyl chloride (40.6mg, 0.2mmol) and the 1mL pyridine.Mixture was carried out microwave radiation 10 minutes under 160 ℃.In solution, add MeOH after the cooling immediately, cause precipitation to form.Cross filter solid, with MeOH washing, the amide product that drying obtains expecting (for the calculated value of C21H17N3O3S: 391.45, [M+H]+measured value: 392.1).

The general step for preparing compound 467,394 and 469:

Use 2-thiazole also [5,4-c] pyridine-2-base-aniline prepares compound 467,394 and 469 as starting raw material and suitable SULPHURYL CHLORIDE by preparation compound 467 substantially the same steps as described below.

To the 2-thiazole also [5,4-c] pyridine-2-base aniline (71mg, 0.3mmol) in the mixture in 1mL THF in room temperature add while stirring SM2 in the 2mL pyridine (68mg, 0.3mmol).Reactant kept 2 days in 60 ℃ of oil baths, monitored to starting raw material with TLC to disappear.Add 5mL water subsequently, the gained suspension is filtered, collect crude product, it by washing with acetone, is obtained thin yellow powder 13mg (10.2%).

¹H NMR(500MHz，DMSO-d ₆)δ9.43(1H，s)，8.70(1H，d，J＝5.5Hz)，8.12(1H，d，J＝5.4Hz)，8.04(1H，d，J＝7.6Hz)，7.58(1H，t，J＝7.5Hz)，7.45(1H，d，J＝8.1Hz)，7.38(1H，t，J＝7.1Hz)，7.17(1H，d，J＝8.3Hz)，7.00(1H，s)，6.90(1H，d，J＝8.4Hz)，3.71(3H，s)，3.46(3H，s)。EIMS m/z：427.17(M ⁺，10)。

The general step for preparing compound 614,615 and 616:

Use 2-thiazole also [5,4-c] pyridine-2-base-aniline prepares compound 614,615 and 616 as starting raw material and suitable lsothiocyanates by preparation compound 614 substantially the same steps as described below.

To the 2-thiazole also [5,4-c] pyridine-2-base aniline (68mg, 0.3mmol), isothiocyanic acid 4-(1H-pyrazol-1-yl) phenylester (60mg, 0.3mmol) and add 8mL ethanol in the mixture of catalytic amount DMAP.Reactant kept 48 hours in 50 ℃.Suspension is filtered, thoroughly wash, obtain 10mg product (7%) with acetone. ¹H NMR(500MHz，DMSO-D6)δ9.43(1H，s)，8.58(1H，d，J＝5.5Hz)，8.47(1H，m)，8.21(1H，d，J＝7.9Hz)，8.19(1H，d，J＝7.4Hz)，7.85(2H，d，J＝8.9Hz)，7.80(1H，d，J＝8.9Hz)，7.75(1H，d，J＝6.7Hz)，7.68(2H，m)，7.61(1H，m)，7.46(1H，m)，6.55(1H，m)。

The general step of preparation compound 597:

Use 2-thiazole also [5,4-c] pyridine-2-base-aniline prepares compound 597 as starting raw material and suitable chloro-formic ester by preparation compound 597 substantially the same steps as described below.

2-thiazole in the 2.5mL pyridine also [5,4-c] pyridine-2-base aniline (68mg, (56mg 0.3mmol), stirred mixture 24 hours under room temperature to add chloroformic acid 4-p-methoxy-phenyl ester in 0.3mmol).Add entry (5mL), the gained mixture is filtered.The crude product of collecting is washed with water, and drying obtains 11mg (12%). ¹H NMR (500MHz, the δ 9.27 of acetone-d6) (1H, s), 8.73 (1H, d, J=5.5Hz), 8.62 (1H, d, J=8.4Hz), 8.02 (1H, d, J=5.5Hz), 7.98 (1H, d, J=7.8Hz), 7.58 (1H, m), 7.23 (3H, m), 6.97 (2H, d, J=8.9Hz), 3.87 (3H, s).

The preparation of 3-(5-dimethylamino methyl-oxazoles are [4,5-b] pyridine-2-yl also)-aniline:

With 5-brooethyl-2-(3-nitro-phenyl)-oxazoles also [4,5-b] pyridine (250mg, 0.75mmol) the THF solution with the 3mL2M dimethylamine is dissolved in 5mL CH ₃Among the CN.Reaction mixture at room temperature stirred 18 hours.Then it is concentrated, with gained resistates and 25mLCH ₂Cl ₂Mix, use the salt water washing.With organic layer drying (Na ₂SO ₄), concentrate and obtain the nitro intermediate of quantitative yield basically.It is mixed with 6mL MeOH and 2mL water with 200mg sodium bisulfide hydrate.Reaction mixture stirred 1 hour under refluxing.Then it is cooled to room temperature, is concentrated into dried.With gained resistates and 100mL 9: 1CH ₂Cl ₂/ MeOH mixture mixes, and filters.Filtrate concentrating obtained 120mg 3-(5-dimethylamino methyl-oxazoles are [4,5-b] pyridine-2-yl also)-aniline (MS, M ⁺+ H=269).

The preparation of compound 165:

(54mg, 0.2mmol) identical as previously mentioned with the 3-dimethylamino Benzoyl chloride use in 1mL pyridine microwave condition reacts to make 3-(5-dimethylamino methyl-oxazole is [4,5-b] pyridine-2-yl also)-aniline.Reaction mixture is cooled to room temperature, concentrates.Use with 1% triethylamine buffered 9: 1CH ₂Cl ₂/ MeOH mixture obtains product (MS, the M that 7mg expects by chromatogram purification ⁺+ H=416).

The preparation of 3-(5-methyl-oxazoles are [4,5-b] pyridine-2-yl also)-aniline:

With 5-methyl-2-(3-nitro-phenyl) oxazole also [4,5-b] pyridine (50mg 0.196mmol) mixes with 6mL MeOH with 2mL water and 66mg sodium sulfhydrate hydrate.Reaction mixture stirred 2 hours under refluxing.Then it is concentrated, use CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain 20mg 3-(5-methyl-oxazoles are [4,5-b] pyridine-2-yl also)-aniline.

The preparation of compound 167:

Make 3-(5-methyl-oxazole is [4,5-b] pyridine-2-yl also)-aniline (20mg, 0.0889mol) with 3-dimethylamino Benzoyl chloride in the 1mL pyridine according to identical as previously mentioned microwave condition reaction.Reaction mixture is cooled to room temperature, concentrates.Use with 9: 1 CH of 1% triethylamine buffered ₂Cl ₂/ MeOH mixture obtains product (MS, the M that 7mg expects by chromatogram purification ⁺+ H=373).

The preparation of 5-(2-nitro-phenyl)-thiazol-2-yl amine:

With typical method, (Aldrich, 5.00g 0.0192mol) mix with 40mL toluene, 40mL ethanol and 20mL water with 2-amino-5-bromo thiazole list hydrobromate.Add 2-nitrophenyl boric acid (3.2g, 0.0192g) and 2.35g[1,1 '-two (diphenylphosphino) ferrocene] two chloro-palladium (II) and CH ₂Cl ₂Mixture (1: 1) and 6.10g anhydrous sodium carbonate.Reaction mixture stirred 18 hours in 90 ℃.Then it is cooled to room temperature, concentrates.The gained resistates is mixed water (3 * 50mL) washings with 500mL EtOAc.Filter organic layer, remove black precipitate.Filtrate is extracted with rare 1N HCl.The water layer that merges is concentrated near doing.The gained resistates by preparation HPLC, is used and used 0.1%TFA buffered acetonitrile solution purifying mixture, obtain 108mg 5-(2-nitro-phenyl)-thiazol-2-yl amine (MS, M ⁺+ H=222).

The preparation of 2-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ethyl formate:

(100mg 0.452mmol) mixes with 10mL methylethylketone and 1.5 equivalent ethyl bromide acetones with 5-(2-nitro-phenyl)-thiazol-2-yl amine.Reaction mixture stirred 5 hours under refluxing.Reaction mixture is cooled to room temperature, concentrates.Crude product chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1 CH ₂Cl ₂/ MeOH), obtain 60mg 2-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ethyl formate (MS, M ⁺+ H=318).

The preparation of 2-(2-amino-phenyl)-imidazo [2,1-b] thiazole-6-methyl-formiate:

(60mg, 0.189mmol) (32mg 0.567mmol) mixes with 3mL MeOH together with sodium sulfhydrate hydrate in 1mL water with 2-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-6-ethyl formate.Reaction mixture stirred 1 hour under refluxing, and monitored with LC/MS.This moment, nitryl group was reduced fully, and the ethyl ester group is converted into corresponding methyl ester derivation.Reaction mixture is cooled to room temperature, concentrates.Water layer CH ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate and obtain the 2-of quantitative yield (2-amino-phenyl)-imidazo [2,1-b] thiazole-6-methyl-formiate (MS, M basically ⁺+ H=274).

The preparation of compound 703:

(27mg, 0.095mmol) with 22mg 3,4, the 5-trimethoxy-benzoyl chloride mixes with the 1mL pyridine together with 2-(2-amino-phenyl)-imidazo [2,1-b] thiazole-6-methyl-formiate.Reaction mixture reacted 10 minutes in microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product uses to contain the water-acetonitrile purifying mixture with the 0.1%TFA buffered by preparation HPLC, obtains 108mg 2-[2-(3,4,5-trimethoxy benzamido)-phenyl]-imidazo [2,1-b] thiazole-6-methyl-formiate (MS, M ⁺+ H=468).

The preparation of compound 704:

With 2-[2-(3,4,5-trimethoxy benzamido)-phenyl]-imidazo [2,1-b] thiazole-6-methyl-formiate (6mg) mixes with 1mL THF.The 1mL aqueous solution that adds sodium hydroxide (10mg).Reaction mixture at room temperature stirred 4 hours, concentrated then.The gained crude product uses to contain the water-acetonitrile purifying mixture with the 0.1%TFA buffered by preparation HPLC, obtains 108mg 2-[2-(3,4,5-trimethoxy benzamido)-phenyl]-imidazo [2,1-b] thiazole-6-formic acid (MS, M ⁺+ H=454).

The preparation of compound 108:

With 4-(3-amino-5-(oxazole is [4,5-b] pyridine-2-yl also) benzoyl) piperazine-1-t-butyl formate (25mg) contains the CH of 25%TFA with 1mL ₂Cl ₂Solution was handled under room temperature 30 minutes.Then it is concentrated, add Et ₂O is settled out product.After the vacuum-drying, obtain expecting tfa salt (MS, the M of product ⁺+ H=324).

2-(methylthio group) oxazole is the preparation of [4,5-b] pyridine also:

According to Chu-Moyer and Berger (J.Org.Chem.1995,60, step 5721-5725) is improved the back through minority and is prepared 2-(methylthio group) oxazole is [4,5-b] pyridine also.(2.8g, 25mmol) (62mL 0.4M) adds ethyl xanthogenate potassium (8.0g, 50mmol, 2 equivalents) in the suspension at EtOH to 2-amino-3-pyridone.Reaction mixture is heated to backflow (78 ℃), stirred 18 hours.Reaction mixture is concentrated into dried, and gained resistates product is dissolved in the water (70mL).To pH5, promptly there are a large amount of solids to separate out with the Glacial acetic acid acidifying.Filter suspension, wash (3x) with water, dried overnight in high-vacuum tube obtains the also brown solid (3.3g, 21.6mmol, 86%) of [4,5-b] pyridine of 2-Liu Dai oxazole.

To 0 ℃ of refrigerative 2-Liu Dai oxazole also [4,5-b] pyridine (3.3g, (54mL 0.4M) adds K to DMF 21.6mmol) in the solution ₂CO ₃(3.0g, 21.6mmol) and methyl iodide (1.6mL, 25.9mmol).After 2.5 hours,, use Et in 0 ℃ of stirring with reaction mixture water (60mL) dilution ₂O (3 * 100mL) extractions.Merge organic layer, water and salt water washing, dry (MgSO ₄), filter, concentrate.(0% to 10%MeOH/CH with silicon-dioxide ₂Cl ₂) purifying, (methylthio group) oxazole is the brown solid (2.5g, 14.7mmol, 68%) of [4,5-b] pyridine also to obtain 2-.MS，M ⁺+H＝167。

The 1-oxazole of Boc protection is the preparation of [4,5-b] pyridine-2-base-piperidines-3-base amine also:

According to Chu-Moyer and Berger (J.Org.Chem.1995,60, step 5721-5725) is improved the also basic amine of [4,5-b] pyridine-2-base-piperidines-3-of back preparation 1-oxazole through minority.To 2-(methylthio group) oxazole also [4,5-b] pyridine (1.9g, add in toluene 11.4mmol) (1.1M) solution 3-Boc-piperidines (2.3g, 11.4mmol).Reaction mixture is heated to 85 ℃ kept 5.5 hours, cooling concentrates then.Resistates is dissolved in CH ₂Cl ₂In, filter, concentrate.(0% to 10%MeOH/CH with the silicon-dioxide purifying ₂Cl ₂) obtain expecting the white solid (2.6g, 8.3mmol, 73%) of product.MS，M ⁺+H＝319。

Between-preparation of pyridyl 6-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine:

(1.12g, 8.2mmol) with 1, (1.77mg, suspension 16.4mmol) are in 8mL PPA, 180 degree heating 2 hours for the 2-diaminobenzene with 6-aminopyridine-2-formic acid.In reaction mixture impouring 250mL frozen water, under vigorous stirring, neutralize with 2N NaOH (cooling off).Filtration gained precipitation is collected pale solid, and it is used the 20mL hot wash, and drying is used 9: 1 CH ₂Cl ₂: the MeOH mixture, by chromatogram purification (MS, M ⁺+ H=211).

The preparation of compound 57:

Will between-pyridyl 6-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine (25mg, 0.118mmol) and 24mg2,3,4-trimethoxy-benzoyl chloride (0.118mmol) mixes with the 1mL pyridine together.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrates.The gained crude product is by chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH), obtain 11mg product (MS, M ⁺+ H=407.1).

Compound 58,59,60,64,69,211 and 70 preparation:

Use suitable aromatic series acyl chlorides, prepare these compounds similarly with preparation compound 57.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in stirred overnight at room temperature or in 160 degree.Then it is cooled to room temperature, concentrating under reduced pressure.The remaining crude product of gained is with the acetonitrile recrystallization purifying or by chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH).

The preparation of compound 71:

In the 2mL phial, will be at [4, the 5-b] pyridine-2-yl also of the 6-(oxazole in the 1mL pyridine) pyridine-2-amine (11mg, 0.05mmol) add 5-isocyanato-benzo [d] [1,3] dioxole (9mg, 0.05mmol).Reactant is heated to 160 ℃ (MW), kept 10 minutes.Get aliquots containig, dilute with MeOH.Remove pyridine under the vacuum.Crude product is suspended in the 5mL acetonitrile, magnetic agitation half an hour filters and collect product, with its dry (MS, M under vacuum subsequently ⁺+ H=376.1).

Compound 72,87 and 147 preparation:

Use suitable aromatic isocyanate or lsothiocyanates, prepare these compounds similarly with preparation compound 71.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in stirred overnight at room temperature or in 160 ℃.Then it is cooled to room temperature, concentrating under reduced pressure.The remaining crude product of gained is with the acetonitrile recrystallization purifying or by chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH).

2-(1,4-Diazesuberane-1-yl) benzo [preparation of d] oxazole:

In under the room temperature in the 40mL phial, to high piperazine (2g, add in acetonitrile solution 20mmol) the 2-chlorobenzene also [d] oxazole (and 760mg, 5mmol).Reaction mixture gradually becomes suspension.Place half an hour, solids removed by filtration is directly used chromatogram purification (Isco, gradient elution, CH with the filtrate of collecting again ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH).Separate the product (MS, the M that obtain the 420mg expectation ⁺+ H=218.1).

The preparation of compound 85:

Described preparation 2-(1, the 4-Diazesuberane-1-yl) benzo [by product of d] oxazole before compound 85 obtains freely.Obtain 24mg product (MS, M ⁺+ H=335.1).

The preparation of compound 88:

In the 2mL phial, and the 2-in the 1mL pyridine (1,4-Diazesuberane-1-yl) benzo [d] oxazole (43mg, 0.2mmol) middle adding 2, the 4-dimethoxy-benzoyl chloride (40mg, mw=230.6,0.2mmol).Reactant is heated to 160 ℃ (MW) to be kept 10 minutes.Then it is chilled to room temperature, concentrates.The gained crude product is by chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH), obtain 60mg product (MS, M ⁺+ H=382.1).

Compound 89,90 and 91 preparation:

Use suitable aromatic series acyl chlorides and isocyanic ester, prepare these compounds similarly with preparation compound 88.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in stirred overnight at room temperature or in 160 ℃.Then it is cooled to room temperature, concentrating under reduced pressure.The remaining crude product of gained is with the acetonitrile recrystallization purifying or with chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH).

The preparation of compound 92:

In the 2mL phial, to 2mL CH ₃2-chlorobenzene among the CN is [d] oxazole (51mg, 0.33mmol) middle 3-(2-methylthiazol-4-yl) aniline (95mg, 0.5mmol, 1.5 equivalents) that adds also.Reactant is heated to 160 ℃ (MW) to be kept 10 minutes.Then it is cooled to room temperature, concentrates.Gained crude product chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH), obtain 71mg product (MS, M ⁺+ H=308.1).

Compound 93,94,95,104 and 105 preparation:

Similar with preparation compound 92, use 3-(2-methylthiazol-4-yl) aniline or 6-(oxazole also [4,5-b] pyridine-2-yl) pyridine-2-amine or 6-(oxazole [4,5-b] pyridine-2-yl also) also [d] oxazole or 2-chlorobenzene be these compounds of [d] thiazole prepared in reaction also for pyridine-2-amine and 2-chlorobenzene.Reaction mixture reacted 10 minutes in the Biotage microwave reactor in 160 ℃.Then it is cooled to room temperature, concentrating under reduced pressure.The remaining crude product of gained is with the acetonitrile recrystallization purifying or with chromatogram purification (Isco, gradient elution, CH ₂Cl ₂To 9: 1CH ₂Cl ₂/ MeOH).

The preparation of compound 142:

With typical method, to 3, the 4-dimethoxy-benzoyl chloride (100mg, mw=200, be added in 0.5mmol) 2-(1H-benzo [d] imidazoles-2-yl) aniline in the 5mL pyridine (105mg, 0.5mmol).Reactant keeps spending the night under room temperature, stirs simultaneously.Remove pyridine then, in crude mixture, add 5mL MeOH.The gained suspension promptly filters the collection pale solid after stirring half an hour, then it is washed drying under reduced pressure with MeOH.The TLC/HPLC/LC-mass spectrum shows that the purity of this product is greater than 95% (MS, M ⁺+ H=374.1).

The preparation of 3-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine:

(1.12g, 8.2mmol) with 1, (1.77mg, suspension 16.4mmol) are in 8mL PPA, and heating is 2 hours under 180 degree for the 2-diaminobenzene with 2-aminopyridine-3-formic acid 2-amino-nicotinic acid.In reaction mixture impouring 250mL frozen water, under vigorous stirring, neutralize with the ice-cold NaOH of 2N.Filtration gained precipitation is used the 20mL hot wash, obtains pure corresponding 3-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine (MS, the M of 1.1 grams ⁺+ H=211.1).

The preparation of 6-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine:

With 6-aminopyridine-2-formic acid (112mg) or 2-aminopyridine-4-formic acid (112mg, 0.82mmol) or 5-aminopyridine-3-formic acid (112mg, 0.82mmol) with 1, (177mg, suspension 1.64mmol) heated (180 degree) 2 hours to the 2-diaminobenzene in 4mL PPA.Reaction mixture separately in the impouring 50mL frozen water, is neutralized with 2NNaOH (cooling off) under vigorous stirring.Filtration gained precipitation is used the 20mL hot wash, obtains product 6-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine (MS, the M of 105mg expectation ⁺+ H=211.1).

The preparation of 3-(1H-benzo [d] imidazoles-2-yl) pyridine-4-amine:

(1.12g, 8.2mmol) with 1, (1.77mg, suspension 16.4mmol) are in 8mL PPA, and heating is 2 hours under 180 degree for the 2-diaminobenzene with 4-aminopyridine-3-formic acid 4-amino-nicotinic acid.In reaction mixture impouring 250mL frozen water, under vigorous stirring, neutralize with the ice-cold NaOH of 2N.Filtration gained precipitation is used the 20mL hot wash, obtains pure corresponding 3-(1H-benzo [d] imidazoles-2-yl) pyridine-2-amine (MS, the M of 1.35 grams ⁺+ H=211.1).

The preparation of 2-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) aniline:

Will (525mg 2.5mmol) be cooled to-78 degree, adds 1mL n-Bu-Li (2.5mmol, 2.5N is in hexane) with syringe then at the 2-among the anhydrous THF of 5mL (1H-benzo [d] imidazoles-2-yl) aniline.Reactant stirred 20 minutes in-78 degree, and adding MeI (360mg, 2.6mmol).Reactant is warming up to room temperature gradually, keeps one hour in room temperature again.The crude reaction thing dilutes with 25mL ether, gained suspension solids removed by filtration.From the filtrate of collecting, remove the back of desolvating and separate crude product, obtain purity greater than 95% 510mg 2-(1-methyl isophthalic acid H-benzo [d] imidazoles-2-yl) aniline (MS, M ⁺+ H=224.1).

Compound 141,143,144,145,146,168,169,175,176,177,257,258,259,260,261,276,313,314,315,507,508,556 and 293 preparation:

Similar with the preparation method of compound 142, prepare these compounds with suitable substituted bicyclic aromatic series aniline and corresponding aroma family acyl chlorides, SULPHURYL CHLORIDE, chloro-formic ester and isocyanate reaction.Reaction mixture spends the night or in 160 ℃ of reactions 10 minutes in the Biotage microwave reactor in stirring under the room temperature.Then it is cooled to room temperature, concentrating under reduced pressure.The remaining crude product of gained uses 9: 1CH with the acetonitrile recrystallization purifying or by chromatogram ₂Cl ₂: the MeOH purifying.

The preparation of compound 503:

To CH ₂Cl ₂3-methoxyl group-4-(20mL) (morpholino methyl) phenylformic acid (502mg, 2mmol) middle add (COCl) ₂(2mL 23mmol), splashes into a droplet DMF then.The gained mixture at room temperature stirred 3 hours.Vacuum-evaporation gets yellow solid.Then this solid is dissolved among the 5mL DMF.(420mg, 2mmol), reaction mixture keeps spending the night under room temperature, stirs simultaneously to add 2-(1H-benzo [d] imidazoles-2-yl) aniline in the 5mL pyridine subsequently.With reactant concentrate thick product, with it further with the anti-phase preparation of Shimadzu HPLC purifying, the product that obtains expecting (103mg), its purity is greater than 98% (MS, M ⁺+ H=443.1).

The preparation of compound 587:

Will the phenylformic acid 3-methoxyl group-4-in the toluene (5mL) ((tetramethyleneimine-1-yl) methyl) ester (249mg, 1mmol) and 2-(1H-benzo [d] imidazoles-2-yl) aniline (209mg 1mmol) is chilled to 0 ℃, adds AlMe then ₃(2mL, 2M, in toluene, 4 equivalents).The gained mixture progressively is warming up to room temperature, and stirring is spent the night.Reactant is cooled to 0 ℃ then, carefully uses the 5mLMeOH quenching.After being warming up to room temperature, the saturated NaHCO of mixture ₃Separate with AcOEt.Be separated into two-layer preceding filtering mixt.Then two of filtrate is separated.Collected organic layer is used Na ₂SO ₄Drying is filtered concentrating under reduced pressure.Product uses Combiflash with amine RediSep post (68-2203-100, Teledyne Isco) (the DCM solution of 0-2%MeOH) purifying.The cut of merge collecting, concentrate 25mg product (MS, M ⁺+ H=427.1).

Compound 557 and 558 preparation:

The preparation method of these compounds is similar to compound 587.Product uses Combiflash with amine RediSep column purification.

The preparation of 3-(chloromethyl)-6-(2-nitrophenyl) imidazo [2,1-b] thiazole:

(1.375g 5mmol) is suspended in 25mL CH with (3-nitro-5-thiazole is [5,4-c] pyridine-2-base-phenyl also)-methyl alcohol ₂Cl ₂In, cool off with ice bath.Thionyl chloride (3.6mL, 10 equivalents), reaction mixture slowly is heated to room temperature.After stirring is spent the night, in reaction mixture, add 100mL ether, filter the gained suspension, collect product (MS, the M of 1.55g expectation ⁺+ H=293.1).

The preparation of compound 626:

With 3-(chloromethyl)-6-(2-nitrophenyl) imidazo [2,1-b] thiazole (292mg, 1mmol), 4-benzyl diethylenediamine-2-ketone (380mg, 2mmol) and NaH (88mg, 2.2 equivalents) be suspended in the 4mL dry DMF.With reactant 100 ℃ of following heated overnight.After being cooled to room temperature, the reaction mixture water is separated with AcOEt.Collected organic layer, drying, evaporate thick product, further get product 4-benzyl-1-((6-(2-nitrophenyl) imidazo [2,1-b] thiazole-3-yl) methyl) piperazine-2-ketone (MS, M that 211mg expects with the reversed-phase HPLC purifying ⁺+ H=448.1).

The preparation of compound 627:

Add 250mg sodium sulfhydrate hydrate in 200mg 1-in 5mL MeOH ((6-(2-nitrophenyl) imidazo [2,1-b] thiazole-3-yl) methyl)-4-benzyl diethylenediamine-2-ketone suspension.Reaction mixture heated 30 minutes down at 135 ℃ (MW).After being cooled to room temperature, mixture is used CH with the dilution of 50mL water ₂Cl ₂Extraction.Merge organic layer, dry (Na ₂SO ₄), concentrate thick product, it further can be got 135mg target product 1-((6-(2-aminophenyl) imidazo [2,1-b] thiazole-3-yl) methyl)-4-benzyl diethylenediamine-2-ketone (MS, M with the reversed-phase HPLC purifying ⁺+ H=418.1).

The preparation of compound 628:

(44mg 0.1mmol) heated 20 minutes down at 160 ℃ (MW) with the mixture of 2-quinoxalinyl chlorine (21mg, 1.1 equivalents) in the 2.5mL pyridine with 1-((6-(2-aminophenyl) imidazo [2,1-b] thiazole-3-yl) methyl)-4-benzyl diethylenediamine-2-ketone.After being cooled to room temperature, remove pyridine, the crude reaction thing is dissolved in methyl alcohol, get product (MS, the M of 22mg expectation with the reversed-phase HPLC purifying ⁺+ H=574.1).

617,618,647,648,676,677,678,679,699,741,742 and 711 preparation:

This compound is to be similar to preparation method's preparation of compound 628.Product reversed-phase HPLC purifying.

The preparation of compound 42:

(1.0g, 9.1mmol), (1.24g is 9.1mmol) with the 12mL polyphosphoric acid for the 3-benzaminic acid to add 2-amino-3-pyridone in the 50mL flask.With mixture heating up to 200 ℃.After 4 hours, cool off reactant a little, use the frozen water quenching then.With the saturated Na of mixture ₂CO ₃Be neutralized to pH7.5.Product extracts with EtOAc, merges organic extraction, uses the salt water washing, through MgSO ₄Dry.Product aminophenyl-oxazoles and pyridine that evaporating solvent obtains expecting.(for the calculated value of C12H9N3O: 211.2, [M+H]+measured value: 212)

Aniline in 6mL DMF (0.375g, 1.8mmol) add in the solution 3-dimethylaminobenzoic acid (0.29g, 1.8mmol), HATU (1.0g, 2.7mmol), HOAt (0.36g, 2.7mmol) and diisopropylethylamine (0.69g, 5.3mmol).Reaction mixture spends the night in 70 ℃ of stirrings.Use CH ₂Cl ₂After the dilution, the saturated NaHCO of organic layer ₃With the salt water washing, through MgSO ₄Dry.Thick material silicon-dioxide chromatogram (0-10%MeOH/CH ₂Cl ₂) the purifying product that obtains expecting.(for the calculated value of C21H18N4O2: 358, [M+H]+measured value: 359)

Compound 19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,43,44,45,46,47,48,49,50,51,52,53,54,55,56,109 and 110 preparation method are similar to compound 42.

The preparation of compound 65:

In the microwave phial, add the 4-oxazole also [4,5-b] pyridine-2-base amine (50mg, 0.2mmol), 4-anisole SULPHURYL CHLORIDE (49mg, 0.2mmol) and the 1mL pyridine.Mixture placed microwave radiation 12 minutes in 160 ℃.Evaporate pyridine then, the gained brown solid is ground with ethanol/methylene.Cross filter solid, with the ethanol/methylene washing, drying obtains expecting the pale powder of product.(for the calculated value of C18H14N4O4S: 382.40, [M+H]+measured value: 383.0).

Compound 61,63,75,76,96,97,98 and 106 adopts the preparation method's preparation that is similar to compound 65.

The preparation of compound 77:

In the 50mL round-bottomed flask, add the 2-amino-phenol (0.24g, 2.2mmol), 2-aminopyridine-4-formic acid (0.30g, 2.2mmol) and the 2mL polyphosphoric acid.Mixture heating up to 200 ℃ stirring 4 hours.Then reactant is used the ice quenching, used saturated Na ₂CO ₃The aqueous solution alkalizes to pH7.5.With the gained sedimentation and filtration, washing, drying obtains expecting the brown solid of product.(for the calculated value of C12H9N3O: 211.23, [M+H]+measured value: 212.1).

In the microwave phial, add 4-benzoxazole-2-base-pyridine-2-base amine (0.050g, 0.2mmol), 3, the 4-dimethoxy-benzoyl chloride (0.047g, 0.2mmol) and the 1mL pyridine.Mixture placed microwave radiation 12 minutes in 160 ℃.The cooling back adds methyl alcohol in mixture, form precipitation.With solid filtering, use methanol wash, drying obtains expecting the red solid of product.(for the calculated value of C21H17N3O4: 375.39, [M+H]+measured value: 376.1)

Compound 78 is to be similar to preparation method's preparation of compound 77.

1-benzo [1,3] dioxole-5-base-3-(4-benzoxazole-2-base-pyridine-2-yl)-urea, the preparation of compound 86:

In the microwave phial, add 4-benzoxazole-2-base-pyridine-2-base amine (0.05g, 0.2mmol), isocyanic acid 3,4-(methylene-dioxy) phenylester (0.04g, 0.2mmol) and the 1mlL pyridine.Mixture placed microwave radiation 15 minutes in 160 ℃.The cooling back forms precipitation.With solid filtering, grind with hot methanol then.Undissolved material is filtered, the precipitation that forms in the filtrated stock, drying obtain expecting product white solid (for the calculated value of C20H14N4O4: 374.36, [M+H]+measured value: 375.1).

2-[1-(4-fluoro-phenyl)-5-methyl isophthalic acid H-imidazol-4 yl]-oxazoles [4,5-b] pyridine also, the preparation of compound 62:

In the 25mL round-bottomed flask, add 1-(4-fluorophenyl)-5-(trifluoromethyl) pyrazole carboxylic acid (0.15g, 0.5mmol), 2-amino-3-pyridone (0.060g, 0.5mmol) and the 1mL polyphosphoric acid.With mixture heating up to 200 ℃, stirred 4 hours.Then reactant is used the ice quenching, used saturated Na ₂CO ₃The aqueous solution alkalizes to pH7.5.

With the gained sedimentation and filtration, use methanol wash.Crude product prepares the TLC plate with silicon-dioxide, with 5% ethanol/methylene wash-out purifying.The product that separates expectation, drying obtain white powder (for the calculated value of C16H8F4N4O: 348.26, [M+H]+measured value: 349.0).

3,4,5-trimethoxy-N-methyl N-(the 2-oxazole is [4,5-b] pyridine-2-base-phenyl also)-benzamide, the preparation of compound 292:

In 3mL DMF 3,4,5-trimethoxy-N-(the 2-oxazole is [4,5-b] pyridine-2-base-phenyl also)-benzamide (0.03g, 0.1mmol) add in the suspension sodium hydride (in mineral oil, 60% disperse thing, 0.006g, 0.2mmol).Mixture stirred under room temperature 30 minutes, became homogeneous.Then to wherein be added dropwise to methyl iodide (0.040g, 0.3mmol, 0.02mL).In room temperature more after an hour after, saturated NH is used in the quenching of reactant water then ₄Cl separates with EtOAc.With organic layer salt water washing, through MgSO ₄Dry.Thick product silicon-dioxide chromatogram purification, the 0-5% ethanol/methylene.The product that separates expectation, for yellow solid (for the calculated value of C23H21N3O5: 419.44, [M+H]+measured value: 420.1)

The preparation of compound 148:

(4.6g, 27.5mmol) (3.0g 27.5mmol) adds under room temperature and mechanical stirring in the polyphosphoric acid (27.5mL) with 2,3 diamino-pyridines with right-nitrobenzoic acid.Reaction mixture is cooled to room temperature in 175 ℃ of stirrings 2 hours, and NaHCO is used in the water quenching ₃Alkalization.Water layer places ambient temperature overnight that precipitation is separated out.Filtration gained precipitation, water, EtOAc and Et ₂The O washing, vacuum-drying obtains expecting the brown solid of product.(for the calculated value of C12H8N4O2: 240.22, [M+H]+measured value: 241).

(550mg adds dimethyl formamide (30mL) in 13.7mmol) to the sodium hydride of using the hexane pre-wash in 0 ℃ under argon atmospher.Add 2-(4-nitrophenyl)-3H-imidazo [4,5-b] pyridine in 0 ℃ in this suspension (3.0g, 12.43mmol), reaction mixture was in stirring at room 1 hour 40 minutes in batches.(2.4mL, 13.7mmol), reaction mixture is in stirring at room 2.5 hours, water quenching to add 2-(chlorine methoxyl group) ethyl trimethoxy silane then.Water layer extracts with EtOAc, merges organic layer, Na ₂SO ₄Drying is filtered vacuum concentration.Thick product SiO ₂Column chromatography gets a cut with hexane/EtOAc (50: 50) to (20: 80) purifying, is the pure isomer and second cut, and its mixture by two kinds of positional isomerss (regioisomer) of 85: 15 is formed.(for the calculated value of C18H22N4O3Si: 370.48, [M+H]+measured value: 371).

In room temperature to the imidazopyridine of SEM protection (1.60g, 4.30mmol) add in the mixture in MeOH (8mL), EtOAc (12mL) and methyl cellosolve (2mL) palladium (0) charcoal (10%w/w, 160mg, 0.15mmol).Reaction mixture places H ₂(vacuum/argon gas three times, vacuum/H in the atmosphere ₂Three times), stirring at room is to transforming (4 hours) fully.Reaction mixture filters with Celite, and filtrate obtains the brown solid of aniline in vacuum concentration.(for the calculated value of C18H24N4OSi: 340.49, [M+H]+measured value: 341).

(150mg 0.44mmol) adds 2,3 to imidazopyridine aniline in 1.5mL DMF in the solution, the 4-trimethoxybenzoic acid (93mg, 0.44mmol), HATU (250mg, 0.7mmol), HOAt (90mg, 0.7mmol) and diisopropylethylamine (171mg, 0.23mL, 1.3mmol).Reaction mixture spends the night in 80 ℃ of stirrings.After the EtOAc dilution, organic layer washes with water, Na ₂SO ₄Drying is filtered vacuum concentration.Then with the gained compound dissolution in the EtOH (1mL) and 5N HCl (1mL) aqueous solution.Reaction mixture is cooled to room temperature in 70 ℃ of stirrings 2.5 hours, with the 2N NaOH aqueous solution and saturated NaNCO ₃Aqueous solution neutralization.Mixture is partly used vacuum concentration, gained sedimentation and filtration, water and Et ₂O washes, the product that vacuum-drying obtains expecting.

Compound 149,150,151,180,181,182,183,184 and 185 is to be similar to the method preparation of compound 148.

The preparation of compound 190:

With 4-ethynyl aniline 15 (1.61g, 13.79mmol) in room temperature add 3-bromo-2-pyridone 33 (2.0g, 11.49mmol), PdCl ₂(PPh ₃) ₂(403mg, 0.574mmol) and CuI (109mg is in degasification triethylamine (60mL) solution 0.572mmol).Reaction mixture degasification 5 minutes was stirred vacuum concentration 6 hours in 100 ℃.Black residue and CH ₂Cl ₂/ MeOH mixes, and filters vacuum concentration.Thick product SiO ₂Column chromatography is with CH ₂Cl ₂/ MeOH (100: 0) to (99: 1) purifying, the product that obtains expecting.(for the calculated value of C13H10N2O: 210.23, [M+H]+measured value: 211)

To N-(4-fluorine [2,3-b] pyridine-2-base-phenyl-2,3-dimethoxy benzamide (30mg, 0.143mmol) and triethylamine (0.02mL, CH 0.143mmol) ₂Cl ₂(1mL) add 2 in the solution, and the 4-dimethoxy-benzoyl chloride (44mg, 0.219mmol).Reaction mixture is in stirred overnight at room temperature.Behind the dilute with water, water layer CH ₂Cl ₂Extraction merges organic layer, NaSO ₄Drying is filtered vacuum concentration.Thick product SiO ₂Column chromatography is with hexane/EtOAc (80: 20 to 50: 50) purifying, and the product that obtains expecting (for the calculated value of C22H18N2O4: 374.39, [M+H]+measured value: 375).

Compound 186,187,188,189,191,192 and 193 is to be similar to the method preparation of compound 190.

The preparation of compound 200:

Adopt Sulfur Letters 1995,18 (2), the step of describing among the 79-95 prepares also [4,5-b] pyridine of 2-(3-nitrophenyl)-thiazole through six steps by the 2-amino-pyridine.In room temperature with palladium (0) charcoal (10%w/w, 40mg, 0.038mmol) add 2-(3-nitrophenyl)-thiazole also [4,5-b] pyridine (403mg, 1.57mmol), in the mixture of toluene (2.5mL), AcOH (2.5mL) and methyl cellosolve (2.5mL).Reaction mixture is placed H ₂(vacuum/argon gas three times, vacuum/H in the atmosphere ₂Three times), in 50 ℃ of stirrings 3 hours, stirred 1.5 hours in 60 ℃.Because reaction is incomplete, (40mg, 0038mmol), reaction mixture stirred 20 hours in 60 ℃ to add the palladium charcoal again.Reaction mixture is cooled to room temperature, filters with Celite, filtrate is in vacuum concentration.Thick product SiO ₂Column chromatography is with EtOAc/ hexane (80: 20) purifying, and the product aniline that obtains expecting is brown solid.(for the calculated value of C12H9N3S: 227.27, [M+H]+measured value: 228.2).

To thiazole also [4,5-b] pyridine-2-base-aniline (40mg, 0.176mmol) and triethylamine (0.02mL, CH 0.143mmol) ₂Cl ₂(1mL) add in the solution 3-dimethylamino Benzoyl chloride (47mg, 0.213mmol).Reaction mixture is in stirred overnight at room temperature.Behind the dilute with water, water layer CH ₂Cl ₂Extraction merges organic layer, NaSO ₄Drying is filtered vacuum concentration.Thick product is with preparing HPLC purifying, the product that obtains expecting.(for the calculated value of C21H18N4OS3: 74.46, [M+H]+measured value: 375).

Compound 152,194,195,196,197,198,199,201 and 202 is to be similar to preparation method's preparation of compound 200.

The preparation of compound 286:

To 5-methyl-2-nitrobenzoic acid (2.0g, 100mL CH 11.0mmol) ₂Cl ₂Add oxalyl chloride (7.0g, 4.8mL, 55.2mmol) and 3 DMF in the solution.With mixture stirring at room 40 minutes, solvent removed in vacuo.The gained resistates places high vacuum, is dissolved in 10mL CH then ₂Cl ₂With this solution add 2-amino-3-pyridone (1.21g, 11.0mmol) and diisopropylethylamine (2.1g, 2.9mL, 100mL CH 16.6mmol) ₂Cl ₂In the solution.Reactant to reacting completely, is used CH in stirring at room then ₂Cl ₂With the salt water sepn.Organic layer salt water washing, MgSO ₄Dry.Thick product silicon-dioxide chromatogram purification, EtOAc/ hexane, the amide product that (20: 80 to 90: 10) obtain expecting.(for the calculated value of C13H11N3O4: 273.25, [M+H]+measured value: 274.1).

(10%w/w, 0.12g) (1.2g is in 50mL MeOH solution 4.4mmol) for slurry adding picolinamide with the palladium charcoal among the 1mL EtOH.Reactant places H ₂In the atmosphere, stirred overnight at room temperature.The mixture nitrogen purge is filtered with Celite then.Vacuum remove the amine that volatile matter obtains expecting (for the calculated value of C13H13N3O2: 243.27, [M+H]+measured value: 244).

(0.2g 0.8mmol) mixes with 1mL PPA, and mixture stirred 2 hours in 150 ℃ with 2-amino-N-(3-pyridone-2-yl)-5-methyl benzamide.Reactant is used saturated Na with the ice quenching ₂CO ₃Alkalization.Filter the gained yellow solid, washing, the aniline that drying obtains expecting.(for the calculated value of C13H11N3O: 225.25, [M+H]+measured value: 226.1).

In the microwave phial, add 4-methyl-2-oxazole also [4,5-b] pyridine-2-base-aniline (40mg, 0.2mmol), 3, the 4-dimethoxy-benzoyl chloride (35mg, 0.2mmol) and the 1mL pyridine.Mixture placed microwave radiation 10 minutes in 160 ℃.Filtration gained precipitation, with the MeOH washing, the acid amides that drying obtains expecting is white solid.(for the calculated value of C22H19N304: 389.41, [M+H]+measured value: 390.1).

The preparation of compound 295:

To 4-(brooethyl)-3-methoxyl methyl benzoate (10.0g, 200mL CH 38.6mmol) ₂Cl ₂Add in the solution morpholine (3.36g, 38.6mmol) and diisopropylethylamine (5.98g, 8.1mL, 46.3mmol).Solution is in stirred overnight at room temperature, then with reactant CH ₂Cl ₂And water sepn.Organic extraction salt water washing, MgSO ₄Dry.Evaporating solvent obtains expecting the viscous solid of product.(for the calculated value of C14H19NO4: 265.31, [M+H]+measured value: 266.1).

(10.4g 39.1mmol) is dissolved among the 150mLTHF, to wherein adding LiOH (4.68g, 195.4mmol) suspension in 75mL water with 4-(morpholino methyl)-3-methoxyl methyl benzoate.Mixture stirred overnight at room temperature, solvent removed in vacuo then.The gained solid is suspended in CH ₂Cl ₂(200mL) and among the MeOH (50mL).Then mixture is filtered the acid product that evaporating solvent obtains expecting from mother liquor by Celite.(for the calculated value of C13H17NO4: 251.28, [M+H]+measured value: 252.1)

(0.1g 0.4mmol) is suspended in CH with phenylformic acid ₂Cl ₂(5mL), to wherein adding oxalyl chloride (0.25g, 2.0mmol, 0.17mL) and 2 DMF.Place room temperature after 1 hour, solvent removed in vacuo placed high vacuum 30 minutes with the gained resistates.Then it is mixed with pyridine (2mL), add also [4,5-b] pyridine-2-base-aniline (0.084g, microwave cast bottle 0.4mmol) of 3-oxazole is housed.Reaction mixture places microwave radiation to keep 10 minutes in 160 ℃.Remove then and desolvate, thick material silicon-dioxide chromatogram (5-10%MeOH/CH ₂Cl ₂) and preparation TLC (5%MeOH/CH ₂Cl ₂) purifying, the amide product that obtains expecting.(for the calculated value of C25H24N4O4:444.5, [M[+H]+measured value: 445.1).

Compound 706,571,572,585,629,630,631,632,636,637,638,642 and 643 is to be similar to preparation method's preparation of compound 295.

The preparation of compound 468:

With 3, the 5-mesitylenic acid (0.3g, 2mmol) and thionyl chloride (8mL) under nitrogen atmosphere, mix, be heated to backflow, kept 3 hours.Excessive thionyl chloride is evaporation fully under vacuum.Then to wherein add the 4-oxazole also [4,5-b] pyridine-2-yl pyridines-2-base amine (0.318g 1.5mmol), the DMAP of anhydrous pyridine (8mL) and catalytic amount, keeps mixture heating up 6 hours in 110 ℃ to refluxing.To wherein adding entry (20mL), compound is extracted to CH ₂Cl ₂(in 2 * 25mL).The organic layer anhydrous Na ₂SO ₄Drying is filtered, and concentrates.Crude compound is with silicon-dioxide (60-120 order), with EtOAc: hexane (1: 5) wash-out purifying, obtain pure acid amides (for the calculated value of C20H16N4O2: 344.38, [M+H]+measured value: 3445.1).

Compound 367,369,375,376,470,482,483,566,567,576,578,579,580 and 639 is to be similar to preparation method's preparation of compound 468.

The preparation of compound 565:

In 10-15 ℃ to the 4-oxazole also [4,5-b] pyridine-2-yl pyridines-2-base amine (0.192g, (1mL, 0.75mmol), reaction mixture was in stirring at room 4 hours to add TMSCl in anhydrous pyridine 0.91mmol) (10mL) solution.

In other round-bottomed flask, under nitrogen atmosphere with trifluoro-methoxy-benzoic acid (0.250g, 1.21mmol) and thionyl chloride (6mL) mix, be heated to backflow, kept 3 hours.The thionyl chloride that vaporising under vacuum is excessive.Add the above-mentioned silanization amine that makes to this reaction mixture under room temperature, mixture heating up kept 6 hours to refluxing.Add entry (20mL), (2 * 25mL) extract compound with methylene dichloride.The organic layer anhydrous Na ₂SO ₄Drying is filtered, and concentrates.The compound crude product with silicon-dioxide (60-120 order) with EtOAc: hexane wash-out purifying obtains pure acid amides.(for the calculated value of C19H11F3N4O3: 400.32, [M+H]+measured value: 400.8).

Compound 577,581,640,641 and 668 preparation method are similar to compound 565.

The preparation of compound 705:

With the 4-oxazole also [4,5-b] pyridine-2-yl pyridines-2-base amine (0.20g, 0.9mmol), (0.9g 0.9mmol) mixes in sealed tube, heats 2 hours down at 220 ℃ for anhydrous pyridine (1mL) and 4-chlorobenzene sulfonyl chloride.The reaction finish after (monitoring) with TLC, reaction mixture is cooled to room temperature, add entry (20mL), with compound be extracted to methylene dichloride (in 2 * 30mL), dry organic layer (Na ₂SO ₄), filter, concentrate.Compound crude product silica column chromatogram purification, obtain pure sulphonamide (for the calculated value of C17H11CIN4O3S: 386.82, [M+H]+measured value: 387.0).

Compound 370,371,372,373,374,471,474,476,477,478,479 and 653 preparation method are similar to compound 705.

The preparation of compound 379:

To the 2-oxazole that stirs also [4,5-b] pyridine-2-base-aniline (0.2g adds 3 in 2mL anhydrous pyridine solution 0.94mmol), 5-two methylsulfonyl chlorides (0.193g, 0.94mmol) and the DMAP of catalytic amount.Mixture stirred 3 hours in 140 ℃.(reaction process is monitored with TLC).Reaction mixture water (20mL) dilution is with ethyl acetate (2 * 25mL) extractions.Merge organic layer, use Na ₂SO ₄Drying, vacuum concentration.Compound crude product silica column chromatogram purification, obtain corresponding sulphonamide (for the calculated value of C20H17N3O3S: 379.44, [M+H]+measured value: 380.0).

Compound 377,378,380,381,382,383,384,486,487,488,489,490,492,493 and 494 preparation method are similar to compound 379.

The preparation of compound 495:

In room temperature to the 2-oxazole that stirs also [4,5-b] pyridine-2-base-aniline (0.15g, (0.16g 0.84mmol), adds the DMAP of catalytic amount then to add chloroformic acid 4-chloro-phenyl-ester in 1.5mL pyridine solution 0.70mmol).Reactant stirred 2 hours under nitrogen atmosphere.(reaction process is monitored with TLC).Reaction mixture water (10mL) dilution, (2 * 25mL) extractions merge organic layer, use anhydrous Na with ethyl acetate ₂SO ₄Drying is filtered vacuum concentration.Compound crude product column chromatography purifying obtains corresponding carbamate.(for the calculated value of C19H12N3O3Cl: 365.7, [M+H]+measured value: 366.0).

Compound 496,497,499,500,501,502,568 and 582 preparation method are similar to compound 495.

The preparation of compound 584:

(0.72g 2.4mmol) is dissolved in the anhydrous methylene chloride and adds pyridines (1 equivalent) in-78 ℃ with triphosgene.Mixture stirred 10 minutes.In this reaction mixture of ten minutes clockwise, be added in 3 among the 2mL DCM, and the 5-xylenol (0.5g, 4mmol), in stirring at room 2 hours.In another round-bottomed flask, with the 2-oxazole also [4,5-b] pyridine-2-base-aniline (0.2g 0.9mmol) is dissolved in the pyridine (20mL), wherein drips the chloroformic acid phenylester of above-mentioned preparation again through 5 fens clockwise in room temperature.The DMAP that adds catalytic amount, reactant stir and spend the night.After the starting raw material completely dissolve (with the TLC monitoring), with reaction mixture water (10mL) dilution, with ethyl acetate (2 * 25mL) extractions.Merge organic layer, use anhydrous Na ₂SO ₄Drying is filtered vacuum concentration.Compound crude product silica column chromatogram purification obtains pure compound.(for the calculated value of C21H17N3O3: 359.38, [M+H]+measured value: 360.0).

Compound 569,570,583,655,656,657,669,670 and 671 preparation method are similar to compound 584.

The preparation of compound 672:

To the 4-trifluoro-methoxy-phenol that stirs (0.1g adds N in dry DMF 0.56mmol) (0.5mL) solution, N-phosphinylidyne diimidazole (0.09g, 0.56mmol).Reactant stirred 30 minutes under nitrogen atmosphere in room temperature.With reaction mixture water (10mL) dilution, be extracted in the ethyl acetate, use anhydrous Na ₂SO ₄Drying is filtered vacuum-evaporation.With this compound dissolving crude product in pyridine (0.5mL), with its add the 2-oxazole that stirs in advance also [4,5-b] pyridine-2-base-aniline (0.075g in pyridine 0.35mmol) (0.5mL) solution, adds the DMAP of catalytic amount then.Mixture was in stirring at room 2 hours.After reaction is finished (monitoring with TLC), reaction mixture water (10mL) dilution is used ethyl acetate extraction, anhydrous Na ₂SO ₄Drying is filtered vacuum concentration.The compound crude product obtains pure compound with the column chromatography purifying.(for the calculated value of C20H12F3N3O4: 415.33, [M+H]+measured value: 415.1).

The preparation of compound 666:

In room temperature under nitrogen atmosphere to the 4-oxazole also [4,5-b] pyridine-2-yl pyridines-2-base amine (0.24g, (0.6mL 4.33mmol), stirs mixture 6 hours to drip trimethylsilyl chloride in pyridine 0.96mmol) (2mL) solution.To wherein add isothiocyanic acid 4-dimethylaminophenyl ester (0.251g, 1.41mol) and the Dimethylamino pyridine of catalytic amount.12 hours (reaction process is monitored with TLC) of reactant backflow.Reaction mixture water (50mL) dilution, (2 * 50mL) extract compound with DCM.With the organic layer drying (Na that merges ₂SO ₄), vacuum-evaporation.Compound crude product silicon-dioxide chromatogram purification obtains corresponding thiocarbamide.(for the calculated value of C20H18N6OS: 390.47, [M+H]+measured value: 391.0).

Compound 573,574,575,658,659,660,661,662,663,664,665,667,673,674 and 675 preparation method are similar to compound 666.

The preparation of compound 634:

To the thiocarbamide (0.040g, DMF 1.05mmol): H that stir ₂Add NH in O (4mL, 2: the 2) solution ₃Solution (30%, 3mL).Mixture was in stirring at room 30 minutes.To wherein adding NaIO ₄Solution (0.033g is in 2mL water) heats reaction mixture 12 hours down at 80 ℃.Add 10%NaOH solution (1mL) in room temperature then.With the sedimentation and filtration of gained, water (2 * 10mL), hexane (2 * 10mL) washings, dry obtain required pure guanidine (for the calculated value of C18H13ClN6O: 364.8, [M+H]+measured value: 364.9).

Compound 633 and 635 preparation method are similar to compound 634.

The preparation of compound 506:

According to prepare the method that the 4-methylmorpholine-the 3-methoxyl methyl benzoate is identical and prepare 4-methylpyrrolidin-3-methoxyl methyl benzoate.

3-oxazole in 1mL toluene also [4,5-b] pyridine-2-base aniline (0.10g, add in suspension 0.5mmol) trimethyl aluminium (2.0M, in toluene, 0.2mL, 0.5mmol).This mixture was in stirring at room 1.5 hours.Then to wherein adding 4-methylpyrrolidin-3-methoxyl methyl benzoate (0.12g, 0.5mmol) slurry in 1mL toluene.Reactant stirred 17 hours under refluxing.After the cooling, mixture CH ₂Cl ₂With the salt water sepn.Water layer CH ₂Cl ₂Extraction merges organic extraction, uses the salt water washing, through MgSO ₄Dry.Thick product silicon-dioxide chromatogram purification, 0 to 10%MeOH/CH ₂Cl ₂Wash-out, and the acid amides that obtains expecting (for the calculated value of C25H24N4O3: 428.50, [M+H]+measured value: 429.1).

The preparation of compound 525:

With 3.27g (30mmol) 2,3 diamino pyridine, 4.53g (30mmol; 1.0 equivalent) 2-nitrobenzaldehyde and 1.92g (60mmol; 2.0 equivalent) the sulphur thorough mixing is heated to 120 ℃ together.Mixture becomes black liquor, restir 3 hours.After being cooled to room temperature, solid residue is dissolved in the hot ethanol (400mL), filters.Concentrated filtrate, resistates obtains the pyridine-imidazole product with flash chromatography purifying (gradient elution, hexane/ethyl acetate 1: 1 to 0: 100).(for the calculated value of C12H8N4O2: 240.2, [M+H]+measured value: 242).

In 100mL two neck bottles, under nitrogen with 604mg (13.8mmol; 1.1 equivalent) (2 * 5mL) washings are suspended in the dry DMF (30mL) sodium hydride (55%, in paraffin) with anhydrous hexane.Add 3.02g (12.6mmol) imidazoles 22 in 0 ℃ in batches, cause gas to be emitted, and form dark red brown solution.Mixture stirred 30 minutes in 0 ℃, in stirring at room 30 minutes, was cooled to 0 ℃, dripped 2.45ml (13.8mmol, 1.1 equivalents) 2-(chlorine methoxyl group) ethyl-trimethyl silane.After the stirring at room 5.5 hours, the brown suspension of this tangerine is added saturated Na ₂CO ₃In the mixture of the aqueous solution (150mL), water (300mL), ethyl acetate (200mL) and salt solution (50mL).(4 * 100mL) extractions merge organic layer to water layer usefulness ethyl acetate, the mixture of usefulness salt solution and water (1: 3; 2 * 100mL) and salt solution (50mL) washing, dry (NaSO ₄), concentrate.Resistates obtains three kinds of isomer: 1.90g (5.13mmol, 41%), the 1.31g (3.55mmol of product with flash chromatography purifying (gradient elution, hexane/ethyl acetate 1: 2 to 0: 100); 28%) and 895mg (2.41mmol; 19%).(for the calculated value of C18H22N4O3Si: 370.1, [M+H]+measured value: 371.2).

In the presence of 10% palladium charcoal (190mg), under environmental stress and temperature, 2-(2-nitrophenyl) imidazopyridine 1.87g (5.05mmol) is dissolved in ethyl acetate (27ml) and the methyl alcohol (18mL), kept 4 hours.Aniline with flash chromatography (hexane/ethyl acetate 1: 1) purifying crude product obtains expecting is yellow-green colour oily matter.(for the calculated value of C18H224N4OSi: 340.1, [M+H]+measured value: 341.2).

With 2-[3-(2-trimethyl silyl-ethoxyl methyl)-3H-imidazo [4,5-b] pyridine-2-yl] aniline (85.1mg; 0.25mmol) and at anhydrous CH ₂Cl ₂(2mL) 3,4-dimethoxy-benzoyl chloride (60.2mg; 1.2 equivalent) and 38 μ L (1.1 equivalent) NEt ₃Reaction, by flash chromatography (hexane/ethyl acetate 2: 1), the acid amides that obtains expecting is colourless, highly viscous arborescens thing then, it solidifies when adding ethanol.(for the calculated value of C27H32N4O4Si: 504.2, [M+H]+measured value: 505).

Compound 521,522,523,524,526,527,528,529,530,531,532,533,534,535,536,537,538,539 and 540 preparation method are similar to compound 525.

The preparation of compound 253:

Press typical method, will (104mg, 0.5mmol) with 2, (100mg 0.5mmol) stirs the 4-dimethoxy-benzoyl chloride at the 2-in the 4mL pyridine (2-aminophenyl) indoles.Reactant at room temperature stirs and spends the night.Finish by LC-MS affirmation reaction, add 15mL water.The gained suspension stirred and supersound process to obtaining white precipitate.Filter and collect white solid, washing, air-dry.Product flash chromatography on silica gel purifying is with CH ₂Cl ₂As eluent (0 to 10% methyl alcohol gradient).TLC/HPLC/LC-Mass shows that it is pure product (MS, M ⁺+ H=373.1).

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 253 to prepare compound 254,255 and 256.

The preparation of compound 262:

Press typical method, with the 4-in the 3mL pyridine (1H-benzimidazolyl-2 radicals-yl)-aniline (and 83mg 0.4mmol) adds 2, the 4-dimethoxy-benzoyl chloride (80mg, 0.4mmol).Reactant is in stirred overnight at room temperature.Finish with LC-MS affirmation reaction, add 15mL water.The gained suspension stirs 5 hours after-filtration and collects pale solid, it is washed with water drying under reduced pressure.Product flash chromatography on silica gel purifying is with CH ₂Cl ₂As eluent (0 to 10% methyl alcohol gradient).TLC/HPLC/LC-Mass shows that it is pure product (MS, M ⁺+ H=374.1).

Use suitable acyl chlorides, adopt the preparation method be similar to compound 262 to prepare compound 263,264 and 294, with the acetonitrile recrystallization purifying or with the CH of normal-phase chromatography with 9: 1 ₂Cl ₂: the MeOH mixture is as the eluent purifying.

The preparation of compound 332:

Prepare compound 332 by typical method, (400umol 68mg) is dissolved in the 2mL pyridine with 2-pyridin-3-yl-aniline in phial.Under agitation add 3, and the 4-dimethoxy-benzoyl chloride (400umol, 80mg).Solution is in stirred overnight at room temperature.Add 20mL H then ₂O, gained white emulsion spend the night in the ultrasonic stirring down of intermittence and generate white precipitate in settled solutions.Cross filter solid, air-dry.With silica gel with CH ₂Cl ₂Purifying (methyl alcohol gradient 0 to 10%) is concentrated into driedly, obtains the white solid of product.(MS，M ⁺+H＝335.1)。

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 332 to prepare compound 331 and 333.Under the situation of compound 331 and 333, by being extracted to CH ₂Cl ₂The thick product of middle separation.

The preparation of compound 334:

Prepare compound 332 by typical method, (400umol 70mg) is dissolved in the 2mL pyridine with 2-pyridin-3-yl-aniline in phial.Under agitation add 2, and the 4-dimethoxy-benzoyl chloride (400umol, 80mg).Solution is in stirred overnight at room temperature.Add 20mL H then ₂O, gained white emulsion spend the night in the ultrasonic stirring down of intermittence and generate white precipitate in settled solutions.Cross filter solid, air-dry.With silica gel with CH ₂Cl ₂Purifying (methyl alcohol gradient 0 to 10%) is concentrated into driedly, obtains the white solid of product.(MS，M ⁺+H＝340.1)。

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 332 to prepare compound 335 and 336.Under the situation of compound 335, by being extracted to CH ₂Cl ₂The thick product of middle separation.

The preparation of compound 413:

Prepare compound 413 by typical method, (300umol 66mg) is dissolved in the 2mL pyridine with 2-pyridin-3-yl-aniline in phial.Under agitation add 2, and the 4-dimethoxy-benzoyl chloride (300umol, 60mg).Solution is in stirred overnight at room temperature, is concentrated into driedly, and (2 * 5mL) handle (chase) obtains the thick product of orange solids with pentane.Thick product obtains the product (77mg) of expectation with silica gel chromatography purifying (0% to 70% in pentane ethyl acetate).(MS，M ⁺+H＝385.1)。

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 413 to prepare compound 414,415 and 416.

The preparation of 2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine:

(7.65g, 31.3mmol) (2.95g 31.3mmol) is dissolved in acetone (50mL), is heated to backflow with the 2-aminopyridine with 2-bromo-2 '-nitro-acetophenone.After 10 minutes, except violent boiling, there is light yellow/white precipitate to generate.Continue to reflux 3 hours, be cooled to room temperature.By evaporation volume is reduced 1/2, the solid collected by filtration intermediate is with acetone (20mL) washing, air-dry (7.26g intermediate).Intermediate (7.20g) is dissolved in MeOH (100mL), adds HBr (4, catalyzer), be heated to backflow.With the TLC monitoring reaction (CH of 10%MeOH ₂Cl ₂Solution).After 70 minutes, reaction mixture is cooled to room temperature, is adjusted to pH=12, concentrate and remove methyl alcohol with 1M NaOH.Filter and collect yellow product, washing, air-dry.Obtain 5.54g (74%) 2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine, be yellow crystals solid (MS, M ⁺+ H=240.1).

The preparation of 2-imidazo [1,2-a] pyridine-2-base aniline:

Prepare 2-imidazo [1,2-a] pyridine-2-base aniline with two kinds of reduction methods.

1) catalytic hydrogenation.With 2-(2-nitro-phenyl)-(250mg 1.04mmol) is dissolved among the THF (15mL) imidazo [1,2-a] pyridine.In flask, add 20mg 10% palladium charcoal, behind the logical nitrogen, at H ₂Stir under balloon (1atm) the O/W condition.With HPLC or the TLC monitoring reaction (CH of 5%MeOH ₂Cl ₂Solution).Reaction mixture removes by filter catalyzer with the Celite bed, and (2 * 10mL) washing beds merge organic layer, are concentrated into dried amber oil with THF.By careful rotary evaporation 50% aqueous ethanolic solution, filter and collect acquisition white solid product (MS, M ⁺+ H=210.1).

2) sulfide reduction.In round-bottomed flask, add 2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine (250mg, 1.04mmol), sodium sulfhydrate (351mg, 6.24mmol), methyl alcohol (6mL) and water (2mL).Reaction mixture refluxed is spent the night.TLC shows the (CH of 5%MeOH that reacts completely ₂Cl ₂Solution).Mixture is cooled to room temperature, is concentrated into driedly, in white/yellow salt, add entry (1mL), CH ₂Cl ₂(10mL) and MeOH (1mL).Layering is with water layer CH ₂Cl ₂(2 * 10mL) strip.Merge organic layer, through NaSO ₄Drying is concentrated into and does the acquisition product, is brown solid (MS, M ⁺+ H=210.1).

The preparation of compound 265:

Prepare compound 265 according to typical method, in the cast bottle with 2-imidazo [1,2-a] pyridine-(400umol 84mg) is dissolved in the 3mL pyridine 2-base-aniline.Under agitation add 2, and the 4-dimethoxy-benzoyl chloride (400umol, 80mg).Solution at room temperature stirred spend the night.Add 15mL H then ₂O, the gained white emulsion occurred white precipitate in 5 hours ultrasonic the stirring down of intermittence in settled solution.Cross filter solid, air-dry.With silica gel with CH ₂Cl ₂(methyl alcohol gradient 0 to 10%) wash-out purifying is concentrated into driedly, grinds with pentane and to obtain product, is pale solid (MS, M ⁺+ H=374.1).

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 265 to prepare compound 266,267 and 268.

The preparation of 2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine-3-formaldehyde:

(2.7g 37mmol), was cooled to 0 ℃, slowly added POCl through 5 minutes to add DMF in the exsiccant flask ₃Solution was warming up to room temperature again in 0 ℃ of stirring 10 minutes through 1 hour.In being cooled to 0 ℃ dark red solution again, add 2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine (1.0g, DMF 4.18mmol) (8mL) solution.Reactant was stirred 5.5 hours; LC-MS shows that some product generates.Add the Vilsmeier mixture again (by 2.7g DMF and 1.47g POCl ₃Preparation), reactant stirs and to spend the night, and is heated to 50 ℃ then and keeps and finished to reaction in 3 hours.Reactant is cooled to room temperature, is poured on ice, transfer pH=7 with 1N NaOH.Product is extracted into CH ₂Cl ₂(in 3 * 50mL), use the salt water washing, through Na ₂SO ₄Drying concentrates and obtains product, is white solid (1.03g, yield 92%).(MS，M ⁺+H＝268.0)。

The preparation of compound 316:

(700mg adds NaBH in methyl alcohol 2.62mmol) (30mL) suspension to 2-(2-nitro-phenyl)-imidazo [1, the 2-a] pyridine that is cooled to 0 ℃ ₄(99mg, methyl alcohol 2.62mmol) (2mL) solution.After 15 minutes, solution is warming up to room temperature in 0 ℃ of stirring, stirred 1.5 hours.Transfer pH to 6 with 4N HCl, concentrated solution is removed methyl alcohol.Filter and collect yellow solid, washing, thorough drying obtains product, is yellow solid (539mg, yield 76%).(MS，M ⁺+H＝270.1)。

The preparation of 3-chloromethyl-2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine:

To [2-(2-nitro-phenyl)-imidazo [1,2-a] pyridin-3-yl]-methyl alcohol (500mg, CH 1.86mmol) ₂Cl ₂(25mL) thionyl chloride (662mg, 3 equivalents) in the suspension.Reactant is in stirring at room 3.5 hours, is concentrated into driedly, adds CH ₂Cl ₂, drying under reduced pressure obtains the product of quantitative yield, is white solid.(MS, M ⁺+ H=270.1 reacts with diluent water.

2-(3-dimethylamino methyl)-imidazo [1,2-a] pyridine-2-yl)-aniline must prepare:

To 3-chloromethyl-2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine (324mg, CH 1.0mmol) that is cooled to 0 ℃ ₂Cl ₂(20mL) drip triethylamine (303mg, 3 equivalents) in the suspension, added at twice through 5 hours then the 2M dimethylamine THF solution (8mmol, 4mL).Reaction mixture is concentrated into dried, is dissolved in CH ₂Cl ₂(20mL), water, salt water washing are through Na ₂SO ₄Drying concentrates, with the CH of chromatography with 9: 1 ₂Cl ₂/ MeOH purifying mixture.Enriched fraction is dissolved in THF (15mL), at H ₂Spend the night with 10%Pd/C (10mg) stirring under the balloon condition.Reaction mixture is filtered by Celite, concentrate and obtain product, be yellow solid (164mg).(MS，M ⁺+H＝267.1)。

The preparation of compound 350:

Prepare compound 350 by typical method, will be at the 2-in the 2ml pyridine (3-dimethylamino methyl)-imidazo [1,2-a] pyridine-2-yl)-(200umol, 53mg) with 3, (200umol is 40mg) in stirred overnight at room temperature for the 4-dimethoxy-benzoyl chloride for aniline.Reaction mixture is passed through to add 10mL H ₂The O quenching concentrates, by the CH of chromatography with 90: 9: 1 ₂Cl ₂/ methyl alcohol/triethylamine purifying mixture.With pentane grind product, be brown solid.Can utilize other silica gel column chromatography (100%EtOAc) and/or the preparation TLC (CH of 5%MeOH ₂Cl ₂Solution w/7MNH ₃) the higher purity of acquisition.(MS，M ⁺+H＝431.1)。

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 350 to prepare compound 351.

4-[2-(2-amino-phenyl)-imidazo [1,2-a] pyridin-3-yl methyl)-preparation of piperazine-1-t-butyl formate:

To 3-chloromethyl-2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine (298mg, CH 0.92mmol) that is cooled to 0 ℃ ₂Cl ₂(15mL) drip triethylamine (297mg, 3 equivalents) in the suspension, added at twice through 24 hours then the 1-Boc-piperazine (1.3 equivalents, 221mg).Reaction mixture is concentrated into dried, with chromatography with 9: 1 CH ₂Cl ₂/ MeOH purifying mixture.Enriched fraction is dissolved in ethanol (20mL), at H ₂Stirred 48 hours with 10%Pd/C (10mg) under the atmosphere.Reaction mixture is filtered by Celite, concentrate, dry under high vacuum, obtain the product that 250mg expects.(MS，M ⁺+H＝408.2)

The preparation of compound 359:

Prepare compound 359 by typical method, will be at the 4-[2-in the 2mL pyridine (2-amino-phenyl)-imidazo [1,2-a] pyridin-3-yl methyl]-piperazine-1-t-butyl formate (150umol, 61mg) and 2, (150umol is 30mg) in stirring at room 3 hours for the 4-dimethoxy-benzoyl chloride.Reactant 1mLH ₂The O quenching concentrates, by silica gel chromatography purifying (0 to 5%MeOH CH ₂Cl ₂Solution).Enriched fraction is used TFA/CH ₂Cl ₂Handled 5 hours, and be concentrated into driedly, use CH ₂Cl ₂(2 * 10mL), pumping high vacuum grinds with 1: 1 pentane/ether, obtains the white solid of two tfa salts, (46mg) to handle (chase).(MS，M ⁺+H＝472.1)

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 359 to prepare compound 362 and 364.

The preparation of 2-(2-nitro-phenyl)-imidazo [1,2-a] pyrimidine:

(5g, 20.4mmol) (1.94g 20.4mmol) is dissolved in acetone (50mL), is heated to backflow with the 2-aminopyridine with 2-bromo-2 '-nitro-acetophenone.There is shallow white precipitate to generate after 60 minutes.Continue to reflux 5.5 hours, be cooled to room temperature.By evaporation volume is reduced 1/2, the solid collected by filtration intermediate is with acetone (20mL) washing, air-dry (2.84g intermediate).Collect second part of product by concentrating the mother liquor that merges, resistates was refluxed 1.5 hours in fresh acetone (20mL).Through overcooling, by evaporation volume is reduced 1/2, collect the 3.11g solid.The solid intermediate (5.95g) that merges is dissolved in MeOH (70mL), adds 5 dense HBr, refluxed 2 hours.After the cooling, volume is reduced 1/2, add entry (40mL), transfer solution to alkalescence (pH=10) with 1N NaOH.Rotary evaporation is removed the methyl alcohol that the product crystallization produces.Filtering product, washing, air-dry product (MS, the M that obtains the 5.03g expectation ⁺+ H=241.0).

2-imidazo [1,2-a] pyrimidine-2-base-aniline must prepare:

With 2-(2-nitro-phenyl)-imidazo [1,2-a] pyrimidine (2g, 8.33mmol) and NaHS (2.8g, 6 equivalents) in 25% aqueous methanol (40mL) aqueous solution, reflux and spend the night.Reaction mixture is cooled to room temperature, is concentrated into dried.Add methyl alcohol (10mL) and water (30mL), use CH ₂Cl ₂(3 * 100mL) extracted products.Merge organic layer, be concentrated into driedly, use 10%MeOH: CH ₂Cl ₂Handle, dry down in 45 ℃ of high vacuum conditions, obtain product, be orange solids (1.34g, yield 76%).(MS，M ⁺+H＝211.1)

The preparation of compound 437:

Prepare compound 437 by typical method, will (200umol, 42mg) and 2, (200umol be 40mg) in stirred overnight at room temperature for the 4-dimethoxy-benzoyl chloride at the 2-imidazo in the 2mL pyridine [1,2-a] pyrimidine-2-base-aniline.Be concentrated into reaction mixture dried morning next day, uses CH ₂Cl ₂Handle with pentane.Carry out purifying with silica gel with 30% to 70%EtOAc pentane solution gradient elution.(MS，M ⁺+H＝375.1)

Use suitable acyl chlorides, adopt the method that is similar to compound 437 to prepare compound 438,439,504 and 505.

The preparation of 2-(5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyridine-2-yl)-aniline:

In the exsiccant flask, add 2-(2-nitro-phenyl)-imidazo [1,2-a] pyridine (239mg, 1mmol), 10%Pd/C (15mg), ethanol (25mL), water (1.5mL) and 4M HCl (0.5mL).Inflated with nitrogen was finished until reaction with other Pd/C catalyzer (15mg) and reinforced the stirring down of 4N HCl (4.5mL) under 1atm hydrogen condition in 5 days.Reaction mixture is filtered by Celite, use saturated NaHCO ₃Solution is neutralized to pH=6.Ethanol, water layer CH are removed in the solution rotating evaporation ₂Cl ₂(2 * 5mL) extractions, with the organic layer that merges through Na ₂SO ₄Drying concentrates the product that obtains quantitative yield, is oily matter (205mg).(MS，M ⁺+H＝214.1)

The preparation of compound 545:

In phial, add 2-(5,6,7,8-tetrahydrochysene-imidazo [1,2-a] pyridine-2-yl)-aniline (200umol, 42mg) and triethylamine (3.5 equivalents, anhydrous CH 100ul) ₂Cl ₂(3ml) solution under agitation adds 3 then, and the 4-dimethoxy-benzoyl chloride (200umol, 40mg).In stirred overnight at room temperature, be concentrated into driedly reactant, with 0% to 100%EtOAc pentane solution gradient elution purifying, obtain white solid product grinding the back with pentane with silica gel.(MS，M ⁺+H＝378.1)

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 545 to prepare compound 546,547 and 548.

The preparation of compound 541:

(125mg 500umol) is dissolved in anhydrous CH with 3-methoxyl group-4-morpholine-4-ylmethyl-phenylformic acid in phial ₂Cl ₂(5ml), add oxalyl chloride (0.5mL, 11 equivalents) and 1 DMF.Stir and after 3 hours reactant is concentrated into driedly, obtain acyl chlorides.In this acyl chlorides, add 2-imidazo [1,2-a] pyridine-2-base-aniline (500mmol, anhydrous pyridine 104mg) (5mL) solution.Stir and after 2 hours reaction mixture is concentrated into driedly, be suspended in EtOAc, with 50% saturated NaHCO ₃Solution washing.Water layer is stripped with EtOAc, merge organic layer, through Na ₂SO ₄Drying concentrates, and obtains the yellow solid crude product.Column chromatogram chromatography (40g silicon-dioxide, 0% to 5%MeOH CH ₂Cl ₂Solution gradient), concentrate, with methyl alcohol grind white solid product (57mg).(MS，M ⁺+H＝443.1)

Use 2-imidazo [1,2-a] pyrimidine-2-base-aniline, adopt the preparation method who is similar to compound 541 to prepare compound 542.

The preparation of 2-(3-tetramethyleneimine-1-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-aniline:

Will be at CH ₂Cl ₂[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl alcohol (5ml) (110mg, 0.4mmol) and triethylamine (56ul, 1 equivalent) be cooled to 0 ℃.Drip methylsulfonyl chloride (31ul, 1 equivalent),, be warming up to room temperature, stirred 15 minutes in 0 ℃ of stirring 10 minutes.Reactant by adding the salt solution quenching, is used CH ₂Cl ₂The extraction methanesulfonates is through Na ₂SO ₄Drying concentrates.Resistates is dissolved in the acetonitrile (3mL), adds triethylamine (31ul, 1 equivalent), add tetramethyleneimine (66ul, 2 equivalents) then.Reaction mixture was stirred 2 hours, concentrate, handle with pentane.Column chromatogram chromatography is used CH ₂Cl ₂(0 to 4%MeOH gradient) wash-out gets 6-(2-nitro-phenyl)-3-tetramethyleneimine-1-ylmethyl-imidazo [2,1-b] thiazole.This material is dissolved in methyl alcohol (16ml), adds water (4ml) solution of sodium sulfhydrate (112mg, 5 equivalents).Reaction mixture add again NaHS (2 * 112mg), refluxed 2 days.With the concentrated methyl alcohol, aqueous solution CH removed of reactant ₂Cl ₂(3 * 40ml) extractions.Organic layer Na ₂SO ₄Drying concentrates to such an extent that product is yellow film, 109mg.(MS，M ⁺+H＝299.1)

The preparation of compound 620:

With the 2ml pyridine solution and 3,4 of 2-(3-tetramethyleneimine-1-ylmethyl-imidazo [2,1-b] thiazole-6-yl)-aniline (200umol), (200umol 46mg) stirs the 5-trimethoxy-benzoyl chloride.With solution stirring 3 hours, be concentrated into driedly, handle with methyl alcohol, by preparation-HPLC purifying.The cut freeze-drying is got the 36mg product, be THA salt.(MS，M ⁺+H＝493.1)

Use suitable acyl chlorides, adopt the preparation method who is similar to compound 620 to prepare compound 619.

The preparation of 6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-ethyl formate:

Press typical method, (1.0g, 5.8mmol) (1.42g 5.8mmol) mixes with the 30mL methylethylketone together with 2-bromo-2 '-nitro-acetophenone with ethyl (2-amino-thiazolyl--4-yl)-methyl acetate.With reaction mixture refluxed 1 hour, spend the night in 90 ℃ of stirrings.Then it is cooled to room temperature, concentrate red oil.It is dissolved in methyl alcohol to impel the product precipitation, adds water and get emulsion.Rotary evaporation is removed methyl alcohol, and emulsified water solution is placed separating funnel.Use Na ₂CO ₃Transfer pH to 9, mixture CH ₂Cl ₂(3 * 50ml) extractions.Merge organic layer, through Na ₂SO ₄Drying, concentrate red oil, silica gel chromatography purifying (CH ₂Cl ₂Add 0 to 5%MeOH gradient elution).The acquisition product is red solid (0.59g, a yield 32%).(MS，M ⁺+H＝318.0)

The preparation of [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-acetate:

Will be 2: (466mg 1.47mmol) mixes with 4 equivalent NaOH (234mg) 6-in the 1THF/ water (2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-ethyl formate.Reaction mixture is heated to 50 ℃ to be kept 3 hours.Reaction mixture is concentrated into dried, with resistates water-soluble (20mL), uses CH ₂Cl ₂Washing, water layer is transferred pH=3 with 4N HCl.Solid collected by filtration, washing, air-dry that product acid is brown solid (442mg, yield 99%) (MS, M ⁺+ H=304.0)

The preparation of compound 649:

In phial, (30mg, 100umol), N methyl piperazine (10mg, 1.0 equivalents), N, N-diisopropyl ethyl amine (52uL, 3.0 equivalents) is dissolved in CH with [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-acetate ₂Cl ₂In reaction mixture, add HOAT (16mg, 1.2 equivalents) and EDCI (29mg, 1.5 equivalents) successively.Reactant stirs and spends the night.Add 50% saturated NaHCO ₃(2ml) and use CH ₂Cl ₂(after 3 * 3ml) extractions, with organic layer Na ₂SO ₄Drying concentrates.Grind to such an extent that the product acid amides is a brown solid with pentane.

The acid amides that the last step was made is dissolved in methyl alcohol (4ml) and NaHS (34mg, 6 equivalents), uses microwave heating 30 minutes down at 150 ℃.In reaction-ure mixture, add MgSO ₄, filter the back and concentrate, use CH ₂Cl ₂(2x) handle, obtain the aniline of expectation, be red membranoid substance.

The aniline that the last step was made is dissolved in the pyridine (2ml), adds 2-quinoxalinyl chlorine (38mg, 2.0 equivalents) solid.After stirring is spent the night, reactant being concentrated into dried, getting title compound with preparation-HPLC purifying, is orange solids (32.2mg, three step yields 44%).(MS，M ⁺+H＝512.2)

The preparation of compound 650:

In phial, add 4-[6-(2-amino-phenyl)-imidazo [2,1-b] thiazole-3-ylmethyl]-piperazine-1-t-butyl formate (82mg, 0.2mmol), triethylamine (56ul, 2 equivalents) and anhydrous CH ₂Cl ₂(3ml).Add 2-quinoxalinyl chlorine (40mg, 1.0 equivalents) solid.Reaction mixture was stirred 18 hours, concentrate, use CH ₂Cl ₂Handle.With silica gel with CH ₂Cl ₂(95: 4: 1 CH ₂Cl ₂: MeOH: Et ₃The N gradient) the wash-out purifying gets the yellow solid of compound 650.(MS，M ⁺+H＝570.2)

The preparation of compound 651:

With compound 650 (105mg, 0.185mmol) with 30% at CH ₂Cl ₂TFA (4ml) handled 2 hours, used CH ₂Cl ₂(3x) and ether (3x) handle, obtain the crude product of compound 441.Half (92umol) and Et with this material ₃N (70ul) is dissolved in CH together ₂Cl ₂(5ml), be cooled to 0 ℃.Add aceticanhydride (10ul, 1 equivalent), reaction mixture was warming up to room temperature through 1 hour.By adding the quenching of first alcohol and water, be concentrated into dried reactant.With anti-phase preparation HPLC purifying, freeze-drying gets the tfa salt of compound 651.(MS，M ⁺+H＝512.2)

2-[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-the alcoholic acid preparation:

(300mg 1.0mmol) is suspended among the THF (20ml), at room temperature stirs 1 hour with NMM (110ul, 1 equivalent) with [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-acetate.Reaction mixture is cooled to 0 ℃, adds isobutyl chlorocarbonate (131ul, 1 equivalent), reaction mixture was in 0 ℃ of stirring 2 hours, and this moment, mixed acid anhydride formed fully.Drip NaBH in 0 ℃ ₄(38mg) mixture in water (5ml) is warming up to room temperature, stirs 1 hour.Reactant can not complete reaction under 1 equivalent condition, therefore adds 3 equivalent NaBH again ₄Therefore afterreaction was incomplete in 1 hour, reaction mixture was concentrated into driedly, added fresh THF, added NaBH then ₄(1 equivalent), stirring is spent the night.LC-MS shows and to react completely, and mixture is concentrated into dried, adds CH ₂Cl ₂(50ml) and water (20ml).Treat layering, water layer CH ₂Cl ₂(3 * 50ml) extractions merge organic layer, use Na ₂SO ₄Drying is concentrated into dried.Product concentrates, by CH with silica gel purification (pentane with 15% to 100%EtOAc gradient) ₃CN: H ₂O freeze-drying (160mg, yield 55%).(MS，M ⁺+H＝290.0)

4-{2-[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-ethyl }-preparation of piperazine-1-t-butyl formate:

With 2-[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-(40mg 0.14mmol) is dissolved in anhydrous CH to ethanol ₂Cl ₂, be cooled to 0 ℃.Add triethylamine (19ul, 1 equivalent) and methylsulfonyl chloride (11ul, 1 equivalent) successively.Reaction mixture is warming up to room temperature, stirred 30 minutes.LC-MS shows that reaction is incomplete, adds triethylamine (19ul, 1 equivalent) and methylsulfonyl chloride (11ul, 1 equivalent) again.Reaction mixture by adding the quenching of 2ml salt solution, is used CH ₂Cl ₂(2 * 2ml) extractions are through Na ₂SO ₄Drying, concentrate methanesulfonates, be yellow membranoid substance.

Methanesulfonates is dissolved in anhydrous acetonitrile (2ml) and triethylamine (38ul, 2 equivalents), stirs with N-Boc-piperazine (26mg, 2 equivalents) and spend the night, reaction mixture still only is a methanesulfonates.Add sodium iodide (41mg) in the reaction mixture, stirred 6 days, with anti-phase preparation HPLC purifying.With cut NaHCO ₃(saturated) alkalization concentrates and removes CH ₃CN, water layer CH ₂Cl ₂Extraction.Organic layer is dry to be concentrated to such an extent that product is yellow membranoid substance.(MS，M ⁺+H＝458.2)

The preparation of compound 680:

In the microwave test tube, add 4-{2-[6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-ethyl }-piperazine-1-t-butyl formate (24mg, 0.05mmol), NaHS (30mg, 10 equivalents) and 5ml methyl alcohol.With reaction mixture 150 ℃ of following microwave heatings 30 minutes.Reaction is carried out but is incomplete.Add 30mgNaHS again, 160 ℃ of following microwave heating reaction mixtures 30 minutes.Add 15mg NaHS once more, 160 ℃ of following microwave heating reaction mixtures 20 minutes.Solids removed by filtration, solution MgSO ₄Drying, concentrate the amine intermediate.This amine (0.05mmol) and pyridine (3ml) and 2-quinoxalinyl chlorine (20mg, 2 equivalents) are mixed, 160 ℃ of following microwave heatings 10 minutes.Reactive moieties is finished, therefore add two equivalent 2-quinoxalinyl chlorine (20mg) again after, with reactant 160 ℃ of following microwave heatings 20 minutes.Reaction mixture is concentrated into dried, with silica gel chromatography purifying (CH ₂Cl ₂Wash-out, 0 to 5%MeOH gradient).With resistates 25%TFA/CH ₂Cl ₂Handled 3 hours, and concentrated, with anti-phase preparation HPLC purifying.(MS，M ⁺+H＝484.2)。

The preparation of 3-chloromethyl-6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole:

(1.0g slowly adds thionyl chloride (2ml, 7.5 equivalents) in anhydrous methylene chloride 3.63mmol) (15ml) solution to [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl alcohol that stirs.Solution becomes homogeneous, has yellow mercury oxide to generate then.After 5 minutes, add the DMF (1) of catalytic amount, mixture was stirred 1 hour, be concentrated into driedly, use CH successively ₂Cl ₂(2x), ether (1x) is handled drying under reduced pressure.Obtain the 1.53g yellow solid, be speculated as quantitative yield.(MS，M ⁺+H＝294.0)

The preparation of compound 700:

Reset: will (126mg is 0.300mmol) 110 ℃ of following microwave heatings 30 minutes at the 3-chloromethyl-6-in 2ml 1-methyl-piperazine (2-nitro-phenyl)-imidazo [2,1-b] thiazole.Reaction mixture is concentrated into dried, with methyl alcohol handle thick 3-(4-methyl-piperazine-1-ylmethyl)-6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole.

Nitroreduction: above-mentioned resistates is dissolved in ethanol (20ml), under agitation adds 10% palladium charcoal.Bleed and pour nitrogen (3x), H again ₂Stirred 18 hours under balloon (1atm) condition.Reaction mixture filters with Celite, is concentrated into driedly, uses CH ₂Cl ₂Handle acquisition amine with pentane, be red oil.

The formation of acid amides: will go up the amine that makes of step and be dissolved in pyridine (3ml), and its adding will be equipped with in the microwave test tube of 2-quinoxalinyl chlorine (64mg, 1.1 equivalents), 160 ℃ of following microwave heatings 30 minutes.Reaction only finishes 50%, therefore adds another part 2-quinoxalinyl chlorine again, continues 160 ℃ of heating 30 minutes.Reaction mixture is concentrated into dried, with anti-phase preparation HPLC purifying.(MS，M ⁺+H＝512.2)

Use suitable amine, adopt the preparation method who is similar to compound 700 to prepare compound 714,715,716 and 717.(the Boc blocking group passes through the CH with 25%TFA before purifying ₂Cl ₂Solution-treated is removed.)

The preparation of compound 718:

(0.342g 1mmol) is dissolved in 3: 1 ethanol: THF (80ml) with 6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-ethyl formate.Add 10%Pd/C (30mg) in reaction mixture, reaction mixture stirred 7 days under H2 balloon (1atm) condition, and regularly added catalyzer.Reaction mixture filters with Celite, concentrate as for, with pentane handle aniline, be orange solids, 289mg.

The part aniline of last step preparation (56mg 200umol) is dissolved in pyridine (4ml), with 2-quinoxalinyl chlorine (46mg, 1.2 equivalents) in stirred overnight at room temperature.Reaction mixture ethanol quenching is concentrated into driedly, uses CH ₂Cl ₂/ pentane is handled.Resistates is dissolved in CH ₂Cl ₂, with 50% saturated NaHCO ₃Solution washing is through Na ₂SO ₄Dry.Product is with the silica gel purification (CH with 0 to 5% methyl alcohol gradient ₂Cl ₂).(MS，M ⁺+H＝444.1)

Use [6-(2-nitro-phenyl)-imidazo [2,1-b] thiazole-3-yl]-methyl acetate as starting raw material, adopt the method identical to prepare compound 720 with compound 718.

The preparation of compound 719:

With 6-{2-[(quinoxaline-2-carbonyl)-amino]-phenyl }-imidazo [2,1-b] thiazole-3-ethyl formate is dissolved in 1: 10 THF: methyl alcohol (33ml), stir with the 1MNaOH aqueous solution (4ml) and to spend the night.Finish with the LC-MS monitoring reaction.Reaction mixture concentrated remove organism, add entry (20ml).With alkalescence (pH=13) water layer CH ₂Cl ₂(2 * 20ml) washings.Water layer is used CH with 4M HCl acidifying (pH=2) ₂Cl ₂(3 * 20ml) extractions.Merge organic layer, through Na ₂SO ₄Drying is filtered, concentrate, with pentane grind the product of expectation, be orange solids.(MS，M ⁺+H＝416.0)

Use similar methyl esters as starting raw material, adopt the preparation method identical to prepare compound 721 with compound 719.

The preparation of compound 745:

Reset: with 3-chloromethyl-6-(2-nitro-phenyl)-imidazo [2,1-b] thiazoles (0.200mmol), imidazoles (68mg, 5 equivalents) and the triethylamine (140ul) in acetonitrile (3ml) 110 ℃ of microwave heatings 30 minutes.Reaction mixture is concentrated into dried.

Nitroreduction: the resistates that will go up the step is dissolved in methyl alcohol (6ml), adds the mixture of NaHS (67mg, 6 equivalents) in water (1ml), and reactant spends the night in 60 ℃ of stirrings.Add another part NaHS (67mg, 6 equivalents) morning next day, reactant is heated to 85 ℃ kept 3 hours.With reactant cooling, be concentrated into driedly, use CH ₂Cl ₂With the water dilution, use CH ₂Cl ₂(2 * 40ml) extractions.Merge organic layer, dry (Na ₂SO ₄), concentrate.

The formation of acid amides: will go up the amine that makes of step and be dissolved in pyridine (3ml) and 2-quinoxalinyl chlorine (46mg, 1.2 equivalents) in stirring at room 3 hours.Reaction mixture is concentrated into dried, with anti-phase preparation HPLC purifying.Lyophilize gets HCl salt with HCl.(MS，M ⁺+H＝452.1)

The evaluation of embodiment 2:Sirtuin conditioning agent

The activity of SIRT1 conditioning agent is identified in use based on fluorescence polarization or mass spectral assay method.Identical assay method can be used for identifying the proteic conditioning agent of any sirtuin.The fluorescence polarization determination method is used a kind of based in the segmental two kinds of different peptides of known sirtuin deacetylation target-p53.Compound 1-18 detects with the substrate that contains the peptide 1 with following 14 amino-acid residues: GQSTSSHSK (Ac) NleSTEG (SEQ ID NO:1), and wherein K (Ac) is the acetylize lysine residue, Nle is a nor-leucine.This peptide at C-end mark, is held mark with vitamin H at N-with fluorophor MR121 (exciting 635nm/ emission 680nm).The sequence of peptide substrates is based on the p53 after the multiple modification.Particularly, different with acetylize Methionin, all arginine and leucine residues are all replaced by Serine, make peptide be not easy to by the trypsinase cracking under the situation that does not have deacetylation.In addition, because methionine(Met) is easy to oxidation in synthetic and purge process, therefore the natural methionine residue that is present in this sequence is substituted with nor-leucine.Compound 19-56 detects with the substrate that contains the peptide 2 with following 20 amino-acid residues: EE-K (vitamin H)-GQSTSSHSK (Ac) NleSTEG-K (MR121)-EE-NH ₂(SEQ ID NO:2), wherein K (vitamin H) is the biotinylation lysine residue, and K (Ac) is the acetylize lysine residue, and Nle is a nor-leucine, the lysine residue of K (MR121) for modifying with the MR121 fluorophor.This peptide at C-end mark, is held mark with vitamin H at N-with fluorophor MR121 (exciting 635nm/ emission 680nm).The sequence of peptide substrates is based on the p53 after the multiple modification.Particularly, different with the acetylize lysine residue, all arginine and leucine residues are all replaced by Serine, make peptide be not easy to by the trypsinase cracking under the situation that does not have deacetylation.In addition, because methionine(Met) is easy to oxidation in synthetic and purge process, therefore the natural methionine residue that is present in this sequence is replaced with nor-leucine.As selectable substrate in the mensuration process; following peptide 3 is used to detection compound 19 to 56:Ac-EE-K (vitamin H)-GQSTSSHSK (Ac) NleSTEG-K (5TMR)-EE-NH2 (SEQ ID NO:3) equally; wherein K (Ac) is the acetylize lysine residue, and Nle is a nor-leucine.This peptide is held mark with fluorophor 5TMR (exciting 540nm/ emission 580nm) at C-.The sequence of peptide substrates also is based on the p53 after the multiple modification.In addition, because methionine(Met) is easy to oxidation in synthetic and purge process, therefore the natural methionine residue that is present in this sequence is replaced with nor-leucine.

Peptide substrates is at NAD ⁺There is contact sirtuin albumen down, makes substrate deacetylated, the cracking sensitivity that causes it that trypsinase is caused.Add trypsinase then, react, discharge MR121 or 5TMR fragment to finishing (being that deacetylated substrate is cleaved).Add streptavidin then in reactant, it can be in conjunction with the non-fluorescence part (as containing the vitamin H fragment) of not cracking substrate (as any residual acetylize substrate) and cleavage of peptide substrate.Observed fluorescence polarization signal for the full-length peptide substrate that is bonded to streptavidin is better than observed for the MR121 that discharges or the fluorescence polarization signal of 5TMR C-end fragment.Fluorescence polarization that obtains thus and deacetylated level be inversely proportional to (being inversely proportional to) as signal and surtuin protein-active.Suitable excite the microtest plate fluorescence polarization reader (Molecular Devices Spectramax MD) with emission filter to read the result by having.

Use the fluorescence polarization determination method operating process of peptide 1 as follows: with 0.5 μ M peptide substrates and 150 μ M β NAD ⁺With 0.1 μ g/ml SIRT1 (25mM Tutofusin tris-acetate (Tris-acetate) pH8,137mM Na-Ac, 2.7mM K-Ac in reaction buffer, 1mM Mg-Ac, 0.05% tween 20,0.1% pluronic F127 (Pluronic F127), 10mM CaCl ₂, 5mM DTT, 0.025%BSA, 0.15mM niacinamide) and in 37 ℃ of hatchings 60 minutes.Test compounds 1-18 is dissolved among the DMSO, adds in the reactant with 11 kinds of concentration among 0.7 μ M to the 100 μ M.

Use the fluorescence polarization determination method of peptide 2 can be by following operation: with 0.5 μ M peptide substrates and 120 μ M β NAD ⁺With 3nM SIRT1 (25mM Tutofusin tris-acetate (Tris-acetate) pH8,137mMNa-Ac, 2.7mM K-Ac in reaction buffer, 1mM Mg-Ac, 0.05% tween 20,0.1% pluronic F127 (Pluronic F127), 10mM CaCl ₂, 5mM DTT is 0.025%BSA) in 25 ℃ of hatchings 20 minutes.Test compounds 19-56 is dissolved among the DMSO, to add in the reactant behind 3 times of 10 kinds of concentration dilutions among 300 μ M to the 0.15 μ M.

With after the SIRT1 hatching, adding niacinamide to ultimate density in reactant is 3mM, stopping deacetylated reaction, and adds 0.5 μ g/mL trypsinase with the deacetylated substrate of cracking.Reactant was hatched 30 minutes in 37 ℃ in the presence of 1 μ M streptavidin.Fluorescence polarization is exciting (650nm) and emission (680nm) wavelength to detect.Measure the sirtuin protein-active level under the different concns test compounds existence condition then, can compare with there not being the sirtuin protein-active level under the test compounds condition, and/or compare with sirtuin protein-active level in negative control as described below (as the inhibition level) and positive control (as activation levels).

For the fluorescence polarization determination method, suppressing the active controlled trial of sirtuin is to carry out as negative control (as allowing that detecting maximum sirtuin suppresses) by add 1 μ L 500mM niacinamide when reaction is initial.The active controlled trial of activation sirtuin is to carry out with the baseline (as detecting gauged sirtuin activity) that reaches the deacetylated effect of substrate by 1 μ LDMSO with 3nM sirtuin albumen and replacement compound.

Use the peptide of following 20 amino-acid residues: Ac-EE-K (vitamin H)-GQSTSSHSK (Ac) NleSTEG-K (5TMR)-EE-NH2 (SEQ ID NO:3) based on mass spectral assay method, wherein K (Ac) is the acetylize lysine residue, and Nle is a nor-leucine.This peptide is held mark with fluorophor 5TMR (exciting 540nm/ emission 580nm) at C-.The p53 of the sequence of peptide substrates after based on multiple modification.In addition, because methionine(Met) is easy to oxidation in synthetic and purge process, therefore the natural methionine residue that is present in this sequence is replaced with nor-leucine.

Mass spectrometry is pressed following operation: with 0.5 μ M peptide substrates and 120 μ M β NAD ⁺With 10nM SIRT1 (50mM Tutofusin tris-acetate (Tris-acetate) pH8,137mMNaCl, 2.7mM KCl, 1mM MgCl in reaction buffer ₂, 5mM DTT is 0.05%BSA) in 25 ℃ of hatchings 25 minutes.Test compounds can be by adding in the reactant as previously mentioned.The SirT1 gene clone is gone into to contain in the carrier of T7-promotor, be transformed among the BL21 (DE3).After SIRT1 hatching 25 minutes, add 10 μ L10% formic acid with stopped reaction.With the reactant sealing, and the mass spectroscopy after freezing being used for.The degree of acetylation (as starting raw material) that the quality of detection peptide substrate is compared with deacetylated peptide (product) with accurate mensuration.

For based on mass spectral assay method, suppressing the active controlled trial of sirtuin is to carry out as negative control (as allowing that detecting maximum sirtuin suppresses) by add 1 μ L 500mM niacinamide when reaction is initial.Activating the active controlled trial of sirtuin is by carrying out with 10nM sirtuin albumen and the amount that the 1 μ LDMSO that replaces compound detects the substrate deacetylation that put preset time in measuring linearity range.The used time point of this time point and test compounds is identical, and in linearity range, terminal point is represented rate variations.

For above-mentioned each mensuration, SIRT1 albumen is expressed and purifying as follows.The SirT1 gene clone is gone into to contain in the carrier of T7-promotor, be transformed among the BL21 (DE3).By with as the 1mM IPTG of N-end His-tag fusion rotein in 18 ℃ of overnight incubation, under 30000xg, gather, with protein expression.Cell is with molten born of the same parents' damping fluid (50mM Tris-HCl, 2mM three [2-propyloic] phosphine (TCEP), 10 μ M ZnCl ₂, 200mMNaCl) the N,O-Diacetylmuramidase dissolving in, further supersound process made dissolving fully in 10 minutes.Albumen mixes with Ni-NTA post (Amersham) purifying, the cut that will contain pure protein, and is concentrated, handles with screening post (Sephadex S20026/60 sphere).Collection contains the peak of soluble protein, handles with ion exchange column (MonoQ).Gradient elution (200mM-500mM NaCl) gets pure protein.This albumen is concentrated, with dialysis buffer liquid (20mMTris-HCl, 2mM TCEP) dialysed overnight.Five equilibrium albumen is refrigerated to further use in-80 ℃.

The Sirtuin of activation SIRT1 regulates compound and identifies with aforesaid assay method, and is as shown in table 4 below.The Sirtuin that suppresses SIRT1 regulates compound and identifies with aforesaid assay method, and is as shown in table 5 below.The ED of activating compounds in fluorescence polarization determination method (FP) or mass spectrometry (MS) ₅₀Value A ' (ED ₅₀=＜5 μ M), A (ED ₅₀=5-50 μ M), B (ED ₅₀=51-100 μ M), C (ED ₅₀=101-150 μ M) and D (ED ₅₀=＞150 μ M) expression.NT represents that compound does not detect with described measuring method.NA represents compound non-activity in described measuring method.Multiplication activation (fold activation), as measuring with MS, by A (multiplication activation＞250%), B (multiplication activation＜250%) or C (not having the multiplication activation) expression.The ED of trans-resveratrol activation SIRT1 ₅₀Be 16 μ M, trans-resveratrol is about 200% to the multiplication activation of SIRT1 in MS measures.Similarly, the IC that suppresses compound ₅₀Value is by A (IC ₅₀=＜50 μ M), B (IC ₅₀=51-100 μ M), C (IC ₅₀=101-150 μ M) and D (IC ₅₀=＞150 μ M) expression.

Table 4.Sirt1 activator

Table 5.Sirt1 inhibitor

Embodiment 3: use SIRT3 to identify the Sirtuin conditioning agent

Identify SIRT3 conditioning agent activity with the fluorescence polarization determination method.Available same measuring method is identified any sirtuin protein modulators.This assay method utilization is taken off the segmental peptide substrates of acetyl target-histone H 4 based on known sirtuin.This substrate contains the peptide with following 14 amino-acid residues: vitamin H-GASSHSK (Ac) VLK (MR121) (SEQ ID NO:4), and wherein K (Ac) is the acetylize lysine residue.This peptide at C-end mark, is held mark with vitamin H at N-with fluorophor MR121 (exciting 635nm/ emission 680nm).

Peptide substrates is at NAD ⁺There is contact sirtuin albumen down, makes substrate deacetylated, the cracking sensitivity that causes it that trypsinase is caused.Add trypsinase then, react, discharge the MR121 fragment to finishing (cleaved) as deacetylated substrate.Add streptavidin then in reactant, it can be in conjunction with the non-fluorescence part (promptly containing the vitamin H fragment) of not cracking substrate (being any residual acetylize substrate) and cleavage of peptide substrate.Observed fluorescence polarization signal for the full-length peptide substrate that is bonded to streptavidin is better than observed fluorescence polarization signal for the MR121C-end fragment that discharges.Therefore resulting fluorescence polarization and deacetylated level be inversely proportional to (being inversely proportional to) as signal and surtuin protein-active.Suitable excite the microtest plate fluorescence polarization reader (Molecular DevicesSpectramax MD) with emission filter to read the result by having.

The fluorescence polarization determination method can be by following operation: with 0.5 μ M peptide substrates and 50 μ M β NAD ⁺With 2nMSIRT3 at reaction buffer (25mM Tutofusin tris-acetate (Tris-acetate) pH8,137mM Na-Ac, 2.7mM K-Ac, 1mM Mg-Ac, 0.1% pluronic F127 (PluronicF127), 10mM CaCl ₂, 1mM TCEP, 0.025%BSA) in, in 37 ℃ the hatching 60 minutes.Test compounds is dissolved among the DMSO, adds in the reactant with 11 kinds of concentration among 0.7 μ M to the 100 μ M.The SIRT3 albumen that uses in the mensuration is corresponding to the people SIRT3 amino-acid residue 102-399 with N-end His-tag.The overexpression in E.coli of this albumen is with standard technique purifying on the nickel chelate column.After SIRT3 hatching 60 minutes, adding niacinamide to ultimate density in reactant is 3mM, stopping deacetylated effect, and adds 0.5 μ g/mL trypsinase with the deacetylated substrate of cracking.Reactant was hatched 30 minutes in 37 ℃ under 1mM streptavidin existence condition.Fluorescence polarization is exciting detection under (650nm) and emission (680nm) wavelength.Measure the sirtuin protein-active level under the different concns test compounds existence condition then, can compare with there not being the sirtuin protein-active level under the test compounds condition, and/or compare with sirtuin protein-active level in negative control as described below (as the inhibition level) and positive control (as activation levels).

Suppressing the active controlled trial of sirtuin is to be undertaken by add 30mM niacinamide (as allowing that detecting maximum sirtuin suppresses) when reaction is initial.The active controlled trial of activation sirtuin is by carrying out with the baseline (as detecting gauged sirtuin activity) that reaches the deacetylated effect of substrate with 0.5 μ g/mL sirtuin albumen.

The Sirtuin of activation SIRT3 regulates compound and identifies with aforesaid measuring method, and is as shown in table 6 below.The Sirtuin that suppresses SIRT3 regulates compound and identifies with aforesaid measuring method, and is as shown in table 7 below.The ED of activating compounds ₅₀Value A (ED ₅₀=＜50 μ M), B (ED ₅₀=51-100 μ M), C (ED ₅₀=101-150 μ M) and D (ED ₅₀=＞150 μ M) expression.The ED of trans-resveratrol activation SIRT3 ₅₀＞300 μ M.Similarly, the IC that suppresses compound ₅₀Value is by A (IC ₅₀=＜50 μ M), B (IC ₅₀=51-100 μ M), C (IC ₅₀=101-150 μ M) and D (IC ₅₀=＞150 μ M) expression.

Table 6

Table 7

Embodiment 4: based on the Sirtuin determination of activity of cell

(Fat mobilization assay) measured in fat mobilization.With the 3T3L1 cell with 2mL 30000 cells/ml by 24 orifice plates be inoculated in Dulbecco improvement Eagle substratum (Dulbecco ' s Modified EagleMedium, DMEM)/10% in the newborn calf serum.Then each hole is made its differentiation by adding the 100nM rosiglitazone.Not breaking up cellular control unit is maintained in the mensuration process in the fresh DMEM/10% newborn calf serum.The 48th hour (2 days), cause lipogenesis by adding DMEM/10% foetal calf serum/0.5mM 3-isobutyl-1-methylxanthine (IBMX)/1 μ M dexamethasone.The 96th hour (4 days),, in each hole, add 2ml DMEM/10% foetal calf serum and 10 μ g/ml Regular Insulin or 100nM rosiglitazone and further impel lipogenesis by removing medium.In the 144th hour (6 days) and the 192nd hour (8 days), all Kong Jun replace with the DMEM/10% foetal calf serum.

The 240th hour (beginning the 10th day from initial cell inoculation), triplicate added the test compounds in the concentration range in each hole, and added the 100nM rosiglitazone.The undifferentiated cell in three holes still places the DMEM/10% new-born calf serum, and the differentiation control cells in three holes then places fresh DMEM/10% newborn calf serum and 100nM rosiglitazone.As the positive control of fat mobilization, the working concentration scope is 100 μ M to 0.4 μ M, dilution triple trans-resveratrol (SIRT1 activator).

The 312nd hour (13 days), remove medium, cell PBS washed twice.Comprise in each hole that does not have the blank of cell group and to add 0.5mL oil red O solution (by Adipogenesis Assay Kit, Cat.#ECM950, Chemicon International, Temecula, CA provides).Plate is removed oil red O stain solution then in room temperature hatching 15 minutes, and each hole is washed 3 times with 1mL washing lotion (Adipogenesis Assay Kit).Remove direct viewing after the last washing lotion, scanning or take dyed plate.Extraction dyestuff (Adipogenesis Assay Kit) uses microplate reader (plate reader) in the 520nm quantitative analysis.Result quantitatively directly perceived as shown in figure 16.

First spinal ganglion (Primary dorsal root ganglion, DGR) measure by cytoprotective.Test compounds detects (Araki et al. (2004) Science305 (5686): 1010-3) by described aixs cylinder protection measuring method.In brief, will under 1nM nerve growth factor existence condition, cultivate from E12.5 embryo's mouse DGR explant.By in the substratum medium, adding 5 FU 5 fluorouracil non-neuronal cell is removed from substratum.Test compounds is cut off in aixs cylinder and was added in preceding 12 to 24 hours.Removing pericaryon in external (DIV) with the 18-puncture needle at 10-20 days denervates prominent.

Embodiment 5: based on the assay method of ATP cell

This embodiment has described the influence of SIRT1 activator-trans-resveratrol pair cell ATP level in the NCI-H358 cell.The cell ATP level is cellular metabolism speed and expansion ground, the indirect measurement of mitochondrial function.Because the activation of SIRT1 is relevant with the plastosome biology generation of increase in the body, the purpose of this research is whether increased mitochondrial function by the cell ATP level as the index determining trans-resveratrol.The ATP test combines with the cell viability test, so the horizontal recoverable viable cell of cell ATP level.The cell ATP level is measured with ATPLite 1 Step Kit (PerkinElmer), cell viability Premeabilisation of cells dyestuff, AlamarBlue ^TMMeasure.

Cell ATP is determined as multiple assay, needs to measure the ATP level and the vigor of given cell sample.This test is carried out in 96 hole assay plate, and data are represented with [ATP]/vigor form in every hole in the assay plate.

ATPLite 1Step ^TMKit is the single step photogenic cell based assays method that is used to detect ATP.This test kit comprises freeze dried substrate mixture, is made up of D-fluorescein and fluorescence worm (Photinus pyrali) enzyme luciferase.In addition, contain the reassembly buffer liquid based on washing composition in this test kit, it causes membranolysis.Luciferase in the test mixing thing produces bioluminescence according to following signal catalytic reaction free cell ATP and the reaction between the D-fluorescein.The light quantity that produces is directly proportional with cell ATP concentration.

AlamarBlue ^TMAssay method is for using the single step assay method of soluble non-toxic cell infiltration dyestuff, and the Premeabilisation of cells dyestuff adds in the cell growth medium.This dyestuff carries out electron reduction in viable cell, but does not carry out electron reduction in dead cell.The vat dyes product produces fluorescent signal, can detect (exciting 545nm and emission 575nm) by the fluorescent plate analyser.The fluorescence volume that produces in given hole is directly proportional with the number of viable cell.Obtain the vigor signal by this mensuration, in order to proofread and correct ATPLite 1Step ^TMATP signal in the measurement result.

Test substrate in the preparation cell ATP assay method: trans-resveratrol is weighed, place brown phial.This material is dissolved in 100% vehicle (DMSO), and making ultimate density is 10mM (stoste), and stoste is used the 100%DMSO serial dilution as described in SOP 7.10.The ultimate density of trans-resveratrol is 0.008,0.023,0.069,0.206,0.617,1.852,5.556,16.667,50 and 150 μ M in the compound plate.

The influence of trans-resveratrol pair cell ATP level in the NCI-H358 cell is measured by described cell ATP assay method.Experimental design is summarized in Fig. 1.In this assay method, the NCI-H358 cell (is obtained ATCC) to be inoculated in 96 hole microplates (10 from American Tissue Culture Collection ⁴Cells/well).The NCI-H358 growth medium adds 10%FBS, 100mg/mL Streptomycin sulphate and 100 units/mL penicillin by RPMI 1640 substratum and forms.Three repetitive cell microplates are with the trans-resveratrol (0.008,0.023,0.069,0.206,0.617,1.852,5.556,16.667,50 and 150 μ M) or the 15 μ L vehicle (DMSO of 10 concentration of 15 μ L, ultimate density is 0.5%, and every plate repeats 12 times) handle.In under the cell growth conditions compound treatment after 48 hours, being shifted out plate from brooder, every hole adds 15 μ LAlamarBlue ^TMDyestuff.Cell microplate and dyestuff were hatched 2 hours under growth conditions, measured fluorescence with the plate analysis instrument subsequently.Remove and contain AlamarBlue ^TMMedium, plate is washed with 100 μ L PBS in every hole.Remove washing lotion, add 200 μ L 1xATPLite 1Step reagent in every hole.Measure luminous with the plate analysis instrument then.Every hole ATP signal with luminous sweep measuring is proofreaied and correct by the corresponding cell energy value of being measured by the fluorescent scanning instrument, thereby obtains the average A TP level (ATP/vCell) of each viable cell unit.ATP/vCell with each processing is normalized to its average medium thing ATP/vCell of cell microplate separately then, thereby obtains standardized ATP/vCell (standard A TP/vCell).At last, the standard A TP/vCell of each individual curing is average by the plate repeat number, thus obtain average ATP/vCell.The trans-resveratrol dosage of increase cell ATP level has the standard A TP/vCell greater than 1.0.Make maximum 50% the resveratrol concentration (EC50ATP) that increases of standard A TP/vCell with S shape dose-response curve model by the optimum fit curve assay determination.

Measure with the trans-resveratrol of 10 kinds of concentration or only with the ATP level of the cell of vehicle processing.Each ATP level is normalized to the cell viability in respective handling hole, thereby obtains the ATP/vCell value.Subsequently each ATP/vCell value is normalized to its average medium thing ATP/vCell value of cell microplate separately.

Data are standard A TP/vCell (arbitrary unit).Fig. 2 is best-fit, the S shape dose-response curve of 10 kinds of its corresponding standard A TP/vCell values of concentration trans-resveratrol of plotting.These values are three plate multiple mean values.Trans-resveratrol increases cell ATP level in the NCI-H358 cell in dosage dependence mode.The maximum of cell ATP level increases to 3 times, comes across situation about handling with 50 μ M trans-resveratrols.By measuring, the EC50ATP of trans-resveratrol is 29 μ M.

Embodiment 6: with ATP cell based experiment sieving test compounds

A large amount of compounds screen its influence to the ATP level by embodiment 5 described testing method.The result is as shown in table 8.Increase the ED of the compound of ATP level in the cell ₅₀Value representation is A (ED ₅₀=＜50 μ M), B (ED ₅₀=51-100 μ M), C (ED ₅₀=101-150 μ M) and D (ED ₅₀=＞150 μ M).NA represents that compound is with described method mensuration.Similarly, reduce the IC of the compound of ATP level in the cell ₅₀Value representation is A (IC ₅₀=＜50 μ M), B (IC ₅₀=51-100 μ M), C (IC ₅₀=101-150 μ M) and D (IC ₅₀=＞150 μ M).

Table 8

Equivalent

The invention provides sirtuin activating compounds and its using method or the like.Specific embodiments of the invention are discussed, above-mentioned specification sheets is an illustrative, and nonrestrictive.To those skilled in the art, after having read this specification sheets, many variations of the present invention are obvious.Four corner of the present invention should be determined with reference to the four corner of claim and equivalent thereof and specification sheets and described variation thereof.

Be incorporated herein by reference

All publications and patent that this paper addresses, comprise following clauses and subclauses at this by it all is incorporated herein by reference, as each publication or patent all clearly and respectively indicate be incorporated herein by reference.If contradiction with the application, comprises that any definition of this paper is as the criterion to some extent.

Also have, what all be incorporated herein by reference has any polynucleotide and a peptide sequence, it has been quoted from and has entered the accession number that public database is associated, as by The Institute for Genomic Research (TIGR) (www.tigr.org) and/or the database (www.ncbi.nlm.nih.gov) kept of the National Center for Biotechnology Information (NCBI).

What be incorporated herein by reference in addition, is: the open WO 2005/002672 of PCT; 2005/002555; With 2004/016726.

Claims

1. a following formula: compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Each Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃Be independently selected from N, CR ²⁰Or CR ₁'; And

Each Z ₁₄, Z ₁₅And Z ₁₆Be independently selected from N, NR ₁', S, O, CR ²⁰Or CR ₁',

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', O or S;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Zero to a R ₁' for choosing the C that replaces wantonly ₁-C ₃The straight or branched alkyl;

Each R ²⁰All be independently selected from H or solubilizing group;

R ²¹Be selected from:

-NR ₁′-C(O)-、-NR ₁′-S(O) ₂-、-NR ₁′-C(O)-NR ₁′-、-NR ₁′-C(S)-NR ₁′-、-NR ₁′-C(S)-NR ₁′-CR ₁ ′R ₁′-、-NR ₁′-C(O)-CR ₁ ′R ₁′-NR ₁′-、-NR ₁′-C(＝NR ₁′)-NR ₁′-、-C(O)-NR ₁′-、-C(O)-NR ₁′-S(O) ₂-、-NR ₁′-、-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′＝CR ₁′-、-NR ₁′-S(O) ₂-NR ₁′-、-NR ₁′-C(O)-NR ₁′-S(O) ₂-、-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-、-CR ₁′R ₁′-C(O)-NR ₁′-、-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-、-NR ₁′-C(＝N-CN)-NR ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-O-、-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁′R ₁′-O-、-NR ₁′-S(O) ₂-CR ₁′R ₁′-、-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R′ ₁-CR ₁′R′ ₁-、-NR ₁′-C(S)-NR ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-、-NR ₁′-C(O)-O-、

Each R ₁' be independently selected from H or choose the C that replaces wantonly ₁-C ₃The straight or branched alkyl; And

R ³¹Be selected from optional monocycle or the bicyclic aryl that replaces, or optional monocycle or the bicyclic heteroaryl that replaces, condition is: work as R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ²¹For-NR ₁'-S (O) ₂-time, R ³¹Not 4-p-methoxy-phenyl or 4-tert-butyl-phenyl.

2. the compound of claim 1, described compound has the following formula structure:

Wherein:

R ²⁰Be selected from H or solubilizing group;

R ²¹Be selected from-NH-C (O)-or-NH-C (O)-CH ₂-; And

R ³¹Be selected from optional monocycle or the bicyclic aryl that replaces, or optional monocycle or the bicyclic heteroaryl that replaces.

3. the compound of claim 1, wherein R ¹⁹Be selected from phenyl, pyridyl, thienyl or furyl.

4. the compound of claim 3, wherein R ¹⁹Be the optional phenyl that replaces.

5. according to the compound of claim 1, wherein:

R ²⁰Be selected from H ,-CH ₂-N (CH ₃) ₂,

6. according to the compound of claim 1, wherein:

R ³¹Be selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidyl, thienyl, naphthyl, benzopyrazoles base, benzofuryl, quinolyl, quinoxalinyl or benzothienyl, and R wherein ³¹It is optional the replacement.

7. according to the compound of claim 1, R wherein ²¹Be selected from

-NH-C (O)-or-NH-C (O)-CH ₂-.

8. a following formula: compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', O or S;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰All be independently selected from H or solubilizing group;

R ^20aBe independently selected from H or solubilizing group;

R ²¹Be selected from:

-NR ₁′-C(O)-、-NR ₁′-S(O) ₂-、-NR ₁′-C(O)-NR ₁′-、-NR ₁′-C(S)-NR ₁′-、-NR ₁′-C(S)-NR ₁′-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-、-NR ₁′-C(＝NR ₁′)-NR ₁′-、-C(O)-NR ₁′-、-C(O)-NR ₁′-S(O) ₂-、-NR ₁′-、-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′＝CR ₁′-、-NR ₁′-S(O) ₂-NR ₁′-、-NR ₁′-C(O)-NR ₁′-S(O) ₂-、-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-、-CR ₁′R ₁′-C(O)-NR ₁′-、-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-、-NR ₁′-C(＝N-CN)-NR ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-O-、-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁′R ₁′-O-、-NR ₁′-S(O) ₂-CR ₁′R ₁′-、-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R′ ₁-CR ₁′R′ ₁-、-NR ₁′-C(S)-NR ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-、-NR ₁′-C(O)-O-、

Wherein:

R ³¹Be selected from optional monocycle or the bicyclic aryl that replaces, or optional monocycle or the bicyclic heteroaryl that replaces, R wherein worked as ¹⁹For

And Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃When respectively doing for oneself CH, R ^20aBe solubilizing group.

9. the compound of claim 8, wherein R ¹⁹Be selected from phenyl, pyridyl, thienyl or furyl.

10. the compound of claim 9, wherein R ¹⁹Be the optional phenyl that replaces.

11. compound according to Claim 8, wherein:

R ^20aBe selected from H ,-CH ₂-N (CH ₃) ₂,

12. compound according to Claim 8, wherein:

13. compound according to Claim 8, wherein R ²¹Be selected from:

-NH-C (O)-or-NH-C (O)-CH ₂-.

14. a following formula: compound or its salt:

Wherein:

R ²¹Be selected from:

Wherein:

R ³²Be optional monocycle or the bicyclic heteroaryl that replaces, or the optional bicyclic aryl that replaces, wherein:

Work as R ²¹For-NH-C (O)-CH ₂-time, R ³²It or not unsubstituted thiophene-2-base;

Work as R ²¹For-NH-C (O)-time, R ³²It or not furans-2-base, 5-bromo furan-2-base or 2-phenyl-4-methylthiazol-5-base;

Work as R ²¹For-NH-S (O) ₂-time, R ³²It or not unsubstituted naphthyl or 5-chloro thiophene-2-base.

15. according to the compound of claim 14, wherein:

R ³²Be selected from pyrryl, pyrazolyl, pyrazinyl, furyl, pyridyl, pyrimidyl or thienyl, and R ³²For optional that replace and for randomly by the phenyl ring condensed.

16. according to the compound of claim 14, wherein:

R ²¹Be selected from:

Wherein:

R ³²Be selected from benzofuryl, methyl furan base, benzothienyl, pyridyl, pyrazinyl, pyrimidyl, pyrazolyl, wherein said methyl furan base, pyridyl, pyrazinyl, pyrimidyl or pyrazolyl are randomly by phenyl ring condensed and R wherein ³²For optional that replace or further replaced.

17. a following formula: compound or its salt:

Wherein:

R ²¹Be selected from:

-NR ₁'-C (O)-,-NR ₁'-S (O) ₂-,-NR ₁'-C (O)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-NR ₁'-,-NR ₁'-C (=NR ₁')-NR ₁'-,-C (O)-NR ₁'-,-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-,-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-,-NR ₁'-S (O) ₂-NR ₁'-,-NR ₁'-C (O)-NR ₁'-S (O) ₂-,-NR ₁'-CR ₁' R ₁'-C (O)-NR ₁'-,-CR ₁' R ₁'-C (O)-NR ₁'-,-NR ₁'-C (O)-CR ₁'=CR ₁'-CR ₁' R ₁'-,-NR ₁'-C (=N-CN)-NR ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-O-,-NR ₁'-C (O)-CR ₁' R ₁'-CR ₁' R ₁'-O-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-,-NR ₁'-S (O) ₂-CR ₁' R ₁'-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ₁'-,-NR ₁'-C (O)-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (S)-NR ₁'-CR ₁' R ' ₁-CR ₁' R ' ₁-,-NR ₁'-C (O)-O-,

Each R wherein ₁' be independently selected from H or choose the C that replaces wantonly ₁-C ₃The straight or branched alkyl; And

R ³³Be the optional phenyl that replaces, wherein:

Work as R ²¹For-NR ₁'-C (O)-time, R ₁' not H;

Work as R ²¹For-NH-C (O)-CH ₂Or-NH-C (O)-CH ₂During-O-, R ³³Not unsubstituted phenyl or 4-halogenophenyl; And

Work as R ²¹For-NH-S (O) ₂-time, R ³³It or not unsubstituted phenyl, 2,4-or 3,4-3,5-dimethylphenyl, 2,4-dimethyl-5-p-methoxy-phenyl, 2-methoxyl group-3,4-dichloro-phenyl, 2-methoxyl group, 5-bromo phenyl-3,4-dioxy ethylidene base phenyl, 3,4-Dimethoxyphenyl, 3,4-dichloro-phenyl, 3,4-3,5-dimethylphenyl, 3-or 4-aminomethyl phenyl, 4-alkoxyl phenyl, 4-Phenoxyphenyl, 4-halogenophenyl, 4-xenyl or 4-acetylamino phenyl.

18. according to the compound of claim 17, wherein R ²¹Be selected from:

-NH-C (O)-or-NH-C (O)-CH ₂-.

19. a following formula: compound or its salt:

Wherein:

R ²¹Be selected from-NH-C (O)-or-NH-C (O)-CH ₂-; And

R ³³By the phenyl that following radicals replaced:

A) one-N (CH ₃) ₂Group;

B) a CN group on 3;

C) one-S (CH ₃) group; Or

D) 3 of bridgings and 4

20. composition that comprises following formula: compound or its salt:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰All be independently selected from H or solubilizing group;

R ²¹Be selected from:

R ³¹Be selected from optional monocycle or the bicyclic aryl that replaces, or optional monocycle or the bicyclic heteroaryl that replaces, condition is:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

Work as R ¹⁹For

And R ²¹For-NR ₁'-S (O) ₂-time, R ³¹Not 4-p-methoxy-phenyl or 4-tert-butyl-phenyl; And

Work as R ¹⁹For

Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃The CH that respectively does for oneself, R ²⁰Be H and R ²¹For-NHC (O)-time, R ³¹Not the optional phenyl that replaces,

Wherein said composition is pyrogen-free.

21. one kind comprises each compound compositions of claim 1-19, wherein said composition is pyrogen-free.

22. a pharmaceutical composition, it comprises:

A) a kind of following formula: compound or its pharmacy acceptable salt or its prodrug:

Wherein,

R ¹⁹Be selected from:

Wherein:

Each Z ₁₄, Z ₁₅And Z ₁₆Be independently selected from N, NR ₁', S, O, CR ²⁰Or CR ₁', wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰All be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

Work as R ¹⁹For

Work as R ¹⁹For

Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃The CH that respectively does for oneself, R ²⁰Be H and R ²¹For-NHC (O)-time, R ³¹It or not the optional phenyl that replaces; With

B) pharmaceutically acceptable carrier or thinner.

23. a pharmaceutical composition, it comprises each compound of pharmaceutically acceptable carrier or thinner and claim 1-19.

24. the medicine through packing, it comprises following formula: compound or its pharmacy acceptable salt or its prodrug:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

Work as R ¹⁹For

Work as R ¹⁹For

Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃The CH that respectively does for oneself, R ²⁰Be H and R ²¹For-NHC (O)-time, R ³¹It or not the optional phenyl that replaces.

25. one kind through the packing medicine, its comprise claim 1-19 each compound and use described compound to regulate the explanation of sirtuin.

26. a method that is used to promote the eukaryotic cell survival, described method comprise described cell and following formula: compound or its pharmacy acceptable salt or its prodrug are contacted:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

Work as R ¹⁹For Z ₁₀, Z ₁₁, Z ₁₂And Z ₁₃The CH that respectively does for oneself, R ²⁰Be H and R ²¹For-NHC (O)-time, R ³¹It or not the optional phenyl that replaces.

27. the method for claim 26, wherein said compound increases the life-span of described cell.

28. the method for claim 26, wherein said compound strengthens the ability of described cell anti-stress.

29. the method for claim 28 wherein saidly stress be following one or more: heat-shocked, infiltration stress, dna damage, insufficient salt level, insufficient nitrogen level or insufficient nutrient level.

30. the method for claim 28, wherein said compound simulation nutrient restriction is to the effect of described cell.

31. the method for claim 28, wherein said eukaryotic cell is a mammalian cell.

32. one kind be used for the treatment of or object of prevention in necrocytosis or the old and feeble relevant disease or the method for obstacle, it comprises that the object that needs are arranged treats following formula: compound or its pharmacy acceptable salt or its prodrug of significant quantity:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰All be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or And

Work as R ¹⁹For

33. the method for claim 32, wherein said and old and feeble relevant disease is apoplexy, cardiovascular disorder, sacroiliitis, hypertension or alzheimer's disease.

34. one kind be used for the treatment of or object of prevention in insulin resistance, metabolism syndrome, diabetes or its complication or be used for increase the method for the insulin sensitivity of object, described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

Work as R ¹⁹For

35. a method that is used to reduce object body weight or object of prevention weight increase, described method comprise following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

Work as R ¹⁹For

36. the method for claim 35, wherein said object do not reduce heat exhaustion under the situation that does not have the sirtuin activating compounds, it is active to increase or its two be bonded to and be enough to cause the degree that loses weight.

37. one kind be used to prevent before the method for adipocyte differentiation, described method comprises adipocyte before described and following formula: compound or its pharmacy acceptable salt or its prodrug is contacted:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For And R ²¹For-NR ₁'-S (O) ₂-time, R ³¹Not 4-p-methoxy-phenyl or 4-tert-butyl-phenyl; And

Work as R ¹⁹For

38. a method that is used to prolong object lifetime, described method comprise following formula: compound or its pharmacy acceptable salt or its prodrug that gives object treatment significant quantity:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or And

Work as R ¹⁹For

39. one kind be used for the treatment of or object of prevention in the method for neurodegeneration obstacle, described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

And

Work as R ¹⁹For

Work as R ¹⁹For

40. the method for claim 39, wherein said neurodegeneration obstacle is selected from: alzheimer's disease (AD), Parkinson's disease (PD), Huntington Chorea (HD), amyotrophic lateral sclerosis (ALS; Luo Gaihe league (unit of length) disease), diffusivity Lu Yi body disease, tarantism-acanthocytosis, primary lateral bundle sclerosis, multiple sclerosis (MS) and friedreich's ataxia.

41. one kind be used for the treatment of or object of prevention in the method for blood coagulation disorder, described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

And

42. the method for claim 41, wherein said blood coagulation disorder is selected from thromboembolism, venous thrombosis, pulmonary infarction, apoplexy, myocardial infarction, miscarriage, lack relevant thrombophilia with Antithrombin III, the C hypoproteinosis, the S hypoproteinosis is to the proteic resistance of activatory C, dysfibrinogenemia, the fibrinolysis obstacle, homocystinuria, gestation, inflammatory diseases, the myelosis disease, arteriosclerosis, angina, disseminated inravascular coagulation, thrombocytopenic purpura,thrombotic, cancer metastasis, drepanocytosis, glomerulonephritis, drug-induced thrombocytopenia and the therapeutic clot dissolution or the operation as angioplasty or intra-operative or obstruction more afterwards.

43. a method that is used for the treatment of or prevents eye disease or obstacle, described method comprise following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

And

Work as R ¹⁹For

Work as R ¹⁹For

44. the method for claim 43, wherein said eye disease or obstacle are impaired vision, glaucoma, optic neuritis, macular degeneration or anterior ischemic optic neuropathy.

45. being the damages by optic nerve or central nervous system, the method for claim 44, wherein said impaired vision caused.

46. the method for claim 45, wherein said damage are caused by high intraocular pressure, optic nerve swelling or local asphyxia.

47. the method for claim 44, wherein said impaired vision is caused by retina injury.

48. the method for claim 46, wherein said damage be by flow to amphiblestroid circulatory disorders or macula lutea break cause.

49. a method that is used for the treatment of or prevents the DPN that is caused by chemotherapeutics, described method comprise following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

Work as R ¹⁹For

50. the method for claim 49, wherein said chemotherapeutics comprises catharanthus alkaloid or cis-platinum.

51. one kind is used for the treatment of or the method for the DPN of prevention and local asphyxia incident or disease-related, described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or And

Work as R ¹⁹For

Work as R ¹⁹For

52. the method for claim 51, wherein said local asphyxia incident are apoplexy, coronary heart disease (comprising congestive heart failure or myocardial infarction), apoplexy, pulmonary emphysema, hemorrhagic shock, arrhythmia (for example auricular fibrillation), peripheral vascular disease or transplant relevant damage.

53. a method that is used for the treatment of or prevents polyglutamic acid amides disease, described method comprise following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

-NR ₁′-C(O)-、-NR ₁′-S(O) ₂-、-NR ₁′-C(O)-NR ₁′-、-NR ₁′-C(S)-NR ₁′-、-NR ₁′-C(S)-NR ₁′-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-NR ₁′-、-NR ₁′-C(＝NR ₁′)-NR ₁′-、-C(O)-NR ₁′-、-C(O)-NR ₁′-S(O) ₂-、-NR ₁′-、-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′＝CR ₁′-、-NR ₁′-S(O) ₂-NR ₁′-、-NR ₁′-C(O)-NR ₁′-S(O) ₂-、-NR ₁′-CR ₁′R ₁′-C(O)-NR ₁′-、-CR ₁′R ₁′-C(O)-NR ₁′-、-NR ₁′-C(O)-CR ₁′＝CR ₁′-CR ₁′R ₁′-、-NR ₁′-C(＝N-CN)-NR ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-O-、-NR ₁′-C(O)-CR ₁′R ₁′-CR ₁′R ₁′-O-、-NR ₁′-S(O) ₂-CR ₁′R ₁′-、-NR ₁′-S(O) ₂-CR ₁′R ₁′-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R ₁′-、-NR ₁′-C(O)-CR ₁′R′ ₁-CR ₁′R′ ₁-、-NR ₁′-C(S)-N ₁′-CR ₁′R′ ₁-CR ₁′R′ ₁-、-NR ₁′-C(O)-O-、

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

Work as R ¹⁹For

54. being spinal cord bulbar muscular atrophy disease (kennedy's disease), Huntington Chorea, dentate nucleus rubrum pallidum Louis, the method for claim 53, wherein said polyglutamic acid amides disease examine atrophy (Hao River syndrome) (dentatorubralpallidoluysian atrophy (Haw River syndrome)), 1 type spinocebellar ataxia, 2 type spinocebellar ataxias, 3 type spinocebellar ataxias (Ma-Yue disease), 6 type spinocebellar ataxias, 7 type spinocebellar ataxias or 17 type spinocebellar ataxias.

55. the method for claim 53, wherein said method also comprise the HDAC I/II inhibitor for the treatment of significant quantity.

56. one kind be used for the treatment of can from the enhanced mitochondria activity, benefit object in the method for disease or obstacle, described method comprises that the object that needs are arranged treats following formula: compound or its pharmacy acceptable salt or its prodrug of significant quantity:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

57. also comprising, the method for claim 56, described method give one or more following materials of described object: VITAMIN, cofactor or antioxidant.

58. also comprising, the method for claim 56, described method give one or more following materials of described object: ubiquinone ₁₀, L-carnitine, VitB1, riboflavin, niacinamide, folic acid, vitamin-E, selenium, Thioctic Acid or prednisone.

59. the method for claim 56, described method comprise that also giving described object alleviates the reagent of the symptom of described disease or obstacle with one or more.

60. the method for claim 59, wherein said reagent alleviates epileptic seizures, neuropathic pain or heart dysfunction.

61. the method for claim 59, wherein said obstacle is relevant with the administration of the pharmaceutical agents that reduces mitochondria activity.

62. the method for claim 61, wherein said pharmaceutical agents are reverse transcriptase inhibitors, proteinase inhibitor or dihydroorate dehydrogenase (DHOD) inhibitor.

63. one kind is used for strengthening exercise performance or muscular endurance, lessen fatigue or increasing the method for recovering from fatigue, described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

Work as R ¹⁹For

64. the method for claim 63 is wherein said to liking the sportsmen.

65. the method for claim 63, wherein said fatigue is relevant with the administration of chemotherapeutic agent.

66. a method that is used for the treatment of or prevents illness, exercise performance or muscular endurance reduce in this illness, and described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

Work as R ¹⁹For

67. being muscular dystrophy, neuromuscular disorder, McArdle, myasthenia gravis, muscle injury, multiple sclerosis, amyotrophic lateral sclerosis or age related skeletal muscle, the method for claim 66, wherein said illness reduce disease.

68. one kind is used for the treatment of or the method for the muscle tissue damage that prevention is relevant with anoxic or local asphyxia, described method comprises following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or

And

Work as R ¹⁹For

69. a method that is used for improving the muscle ATP level of object, described method comprise at least a following formula: compound or its pharmacy acceptable salt or its prodrug of the object treatment significant quantity that needs are arranged:

Wherein:

R ¹⁹Be selected from:

Wherein:

Z ₁₀, Z ₁₁, Z ₁₂Or Z ₁₃In zero to two be N;

Z ₁₄, Z ₁₅And Z ₁₆In at least one be N, NR ₁', S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to one be S or O;

Z ₁₄, Z ₁₅And Z ₁₆In zero to two be N or NR ₁';

Zero to a R ²⁰Be solubilizing group; And

Each R ²⁰Be independently selected from H or solubilizing group;

R ²¹Be selected from:

Work as R ¹⁹For

And R ²¹For-NR ₁'-C (O)-time, R ³¹Be not the 4-cyano-phenyl or And

Work as R ¹⁹For

Work as R ¹⁹For

70. each method among the claim 26-69, wherein said compound increase at least a in proteic level of sirtuin or the activity.

71. the method for claim 70, wherein said compound increase the proteic deacetylase activity of described sirtuin.

72. the method for claim 70, wherein said sirtuin albumen is mammalian proteins.

73. the method for claim 70, wherein said sirtuin albumen is people SIRT1.

74. the method for claim 70, wherein said sirtuin albumen is people SIRT3.

75. the method for claim 70; wherein said compound is effectively increasing under SIRT1 and/or the active compound concentration of the proteic deacetylation of SIRT3, does not have one or more following activity basically: suppress the PI3-kinases, suppress aldose reductase, suppress Tyrosylprotein kinase, trans-activation EGFR Tyrosylprotein kinase, coronary artery expansion or spasmolysis activity.

76. a method that is used to promote the eukaryotic cell survival, described method comprise each compound or its pharmacy acceptable salt or its prodrug of described cell and at least a claim 1-19 contacted.

77. the method for claim 76, wherein said compound increases the life-span of described cell.

78. the method for claim 76, wherein said compound strengthens the anti-stress ability of described cell.

79. the method for claim 78, wherein said stress be following one or more: heat-shocked, infiltration stress, dna damage, insufficient salt level, insufficient nitrogen level or insufficient nutrient level.

80. the method for claim 78, wherein said compound simulation nutrient restriction is to the effect of described cell.

81. the method for claim 78, wherein said eukaryotic cell are mammalian cell.

82. one kind be used for the treatment of or object of prevention in necrocytosis or the old and feeble relevant disease or the method for obstacle, described method comprises that the object that needs are arranged treats each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of significant quantity.

83. the method for claim 82, wherein said and old and feeble relevant disease is apoplexy, cardiovascular disorder, sacroiliitis, hypertension or alzheimer's disease.

84. one kind be used for the treatment of or object of prevention in insulin resistance, metabolism syndrome, diabetes or its complication or be used for increase the method for the insulin sensitivity of object, described method comprises each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

85. a method that is used to reduce object body weight or object of prevention weight increase, described method comprise each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

86. the method for claim 85, wherein said object do not reduce heat exhaustion under the situation that does not have the sirtuin activating compounds, it is active to increase or its two be bonded to and be enough to cause the degree that loses weight.

87. one kind be used to prevent before the method for adipocyte differentiation, described method comprises each compound or its pharmacy acceptable salt or its prodrug of adipocyte before described and at least a claim 1-19 is contacted.

88. a method that is used to prolong object lifetime, described method comprise each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 that gives object treatment significant quantity.

89. one kind be used for the treatment of or object of prevention in the method for neurodegeneration obstacle, described method comprises each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

90. the method for claim 89, wherein said neurodegeneration obstacle is selected from: alzheimer's disease (AD), Parkinson's disease (PD), Huntington Chorea (HD), amyotrophic lateral sclerosis (ALS; Luo Gaihe league (unit of length) disease), diffusivity Lu Yi body disease, tarantism-acanthocytosis, primary lateral bundle sclerosis, multiple sclerosis (MS) and friedreich's ataxia.

91. one kind be used for the treatment of or object of prevention in the method for blood coagulation disorder, described method comprises each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

92. the method for claim 91, wherein said blood coagulation disorder is selected from thromboembolism, venous thrombosis, pulmonary infarction, apoplexy, myocardial infarction, miscarriage, lack relevant thrombophilia with Antithrombin III, the C hypoproteinosis, the S hypoproteinosis is to the proteic resistance of activatory C, dysfibrinogenemia, the fibrinolysis obstacle, homocystinuria, gestation, inflammatory diseases, the myelosis disease, arteriosclerosis, angina, disseminated inravascular coagulation, thrombocytopenic purpura,thrombotic, cancer metastasis, drepanocytosis, glomerulonephritis, drug-induced thrombocytopenia and the therapeutic clot dissolution or the operation as angioplasty or intra-operative or obstruction more afterwards.

93. a method that is used for the treatment of or prevents eye disease or obstacle, described method comprise each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

94. the method for claim 93, wherein said eye disease or obstacle are selected from impaired vision, glaucoma, optic neuritis, macular degeneration or anterior ischemic optic neuropathy.

95. being the damages by optic nerve or central nervous system, the method for claim 94, wherein said impaired vision caused.

96. the method for claim 95, wherein said damage are caused by high intraocular pressure, optic nerve swelling or local asphyxia.

97. the method for claim 94, wherein said impaired vision is caused by retina injury.

98. the method for claim 97, wherein said damage be by flow to amphiblestroid circulatory disorders or macula lutea break cause.

99. a method that is used for the treatment of or prevents the DPN that is caused by chemotherapeutics, described method comprise each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

100. the method for claim 99, wherein said chemotherapeutics comprises catharanthus alkaloid or cis-platinum.

101. one kind is used for the treatment of or the method for the DPN of prevention and local asphyxia incident or disease-related, described method comprises each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

102. the method for claim 101, wherein said local asphyxia incident are apoplexy, coronary heart disease (comprising congestive heart failure or myocardial infarction), apoplexy, pulmonary emphysema, hemorrhagic shock, arrhythmia (for example auricular fibrillation), peripheral vascular disease or transplant relevant damage.

103. a method that is used for the treatment of or prevents polyglutamic acid amides disease, described method comprise each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

104. being spinal cord bulbar muscular atrophy disease (kennedy's disease), Huntington Chorea, dentate nucleus rubrum pallidum Louis, the method for claim 103, wherein said polyglutamic acid amides disease examine atrophy (Hao River syndrome), 1 type spinocebellar ataxia, 2 type spinocebellar ataxias, 3 type spinocebellar ataxias (Ma-Yue disease), 6 type spinocebellar ataxias, 7 type spinocebellar ataxias or 17 type spinocebellar ataxias.

105. the method for claim 103, wherein said method also comprise the HDAC I/II inhibitor for the treatment of significant quantity.

106. one kind be used for the treatment of can from the enhanced mitochondria activity, benefit object in disease or the method for obstacle, described method comprises that the object that needs are arranged treats each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of significant quantity.

107. also comprising, the method for claim 106, described method give one or more following materials of described object: VITAMIN, cofactor or antioxidant.

108. also comprising, the method for claim 106, described method give one or more following materials of described object: ubiquinone ₁₀, L-carnitine, VitB1, riboflavin, niacinamide, folic acid, vitamin-E, selenium, Thioctic Acid or prednisone.

109. the method for claim 106, described method also comprise give described object one or more alleviate the reagent of the symptom of described disease or obstacle.

110. the method for claim 109, wherein said reagent alleviates epileptic seizures, neuropathic pain or heart dysfunction.

111. the method for claim 106, wherein said obstacle is relevant with the administration of the pharmaceutical agents that reduces mitochondria activity.

112. the method for claim 111, wherein said pharmaceutical agents are reverse transcriptase inhibitors, proteinase inhibitor or dihydroorate dehydrogenase (DHOD) inhibitor.

113. one kind is used for strengthening exercise performance or muscular endurance, lessen fatigue or increasing the method for recovering from fatigue, described method comprises each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

114. the method for claim 113 is wherein said to liking the sportsmen.

115. the method for claim 113, wherein said fatigue is relevant with the administration of chemotherapeutic agent.

116. method that is used for the treatment of or prevents illness, exercise performance or muscular endurance reduce in this illness, and described method comprises that the object that needs are arranged treats each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of significant quantity.

117. being muscular dystrophy, neuromuscular disorder, McArdle, myasthenia gravis, muscle injury, multiple sclerosis, amyotrophic lateral sclerosis or age related skeletal muscle, the method for claim 116, wherein said illness reduce disease.

118. one kind is used for the treatment of or the method for the muscle tissue damage that prevention is relevant with anoxic or local asphyxia, described method comprises each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

119. a method that is used for improving the muscle ATP level of object, described method comprise each compound or its pharmacy acceptable salt or its prodrug of at least a claim 1-19 of the object treatment significant quantity that needs are arranged.

120. each method of claim 76-119, wherein said compound increase at least a in proteic level of sirtuin or the activity.

121. the method for claim 120, wherein said compound increase the proteic deacetylase activity of described sirtuin.

122. the method for claim 120, wherein said sirtuin albumen is mammalian proteins.

123. the method for claim 120, wherein said sirtuin albumen is people SIRT1.

124. the method for claim 120, wherein said sirtuin albumen is people SIRT3.

125. the method for claim 120; wherein said compound is effectively increasing under SIRT1 and/or the active compound concentration of the proteic deacetylation of SIRT3, does not have one or more following activity basically: suppress the PI3-kinases, suppress aldose reductase, suppress Tyrosylprotein kinase, trans-activation EGFR Tyrosylprotein kinase, coronary artery expansion or spasmolysis activity.