CN101506154B - Compounds for treating proliferative disorders - Google Patents
Compounds for treating proliferative disorders Download PDFInfo
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- CN101506154B CN101506154B CN200780031010.XA CN200780031010A CN101506154B CN 101506154 B CN101506154 B CN 101506154B CN 200780031010 A CN200780031010 A CN 200780031010A CN 101506154 B CN101506154 B CN 101506154B
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- 0 CN(C(c1ccccc1)=*)NC(CS(NN(C)C(c1ccccc1)=*)(=O)=O)=O Chemical compound CN(C(c1ccccc1)=*)NC(CS(NN(C)C(c1ccccc1)=*)(=O)=O)=O 0.000 description 2
- JJZFQYXZSXBTEC-UHFFFAOYSA-N CN(C(c1ccccc1)=S)N Chemical compound CN(C(c1ccccc1)=S)N JJZFQYXZSXBTEC-UHFFFAOYSA-N 0.000 description 1
- RQXQVUSDWAJVOF-UHFFFAOYSA-N CN(C(c1ccccc1)=S)N(P(N1N(C)C(c2ccccc2)=S)(Oc2ccccc2)=O)P1(Oc1ccccc1)=O Chemical compound CN(C(c1ccccc1)=S)N(P(N1N(C)C(c2ccccc2)=S)(Oc2ccccc2)=O)P1(Oc1ccccc1)=O RQXQVUSDWAJVOF-UHFFFAOYSA-N 0.000 description 1
Abstract
Disclosed are compounds and methods, of using compounds of the invention for treating a subject with a proliferative disorder, such as cancer, and methods for treating disorders responsive to Hsp70 induction and/or natural killer induction. Also, disclosed are pharmaceutical compositions comprising compounds of the invention and a pharmaceutically acceptable carrier.
Description
Related application
Subject application advocates U.S. Provisional Application case the 60/839th, No. 034 (carrying Shen on August 21st, 2006) and U.S. Provisional Application case the 60/841st, the interests of No. 408 (carrying Shen on August 31st, 2006).The entire teachings of above application case includes in herein with way of reference.
Background of invention
In fact in all prokaryotic organism and eukaryotic cells, all have found heat shock protein(HSP) (HSP), in those cells, they support the folding of nascent polypeptide, prevention protein aggregation, and assist other protein to cross over the transport of film.Protein (being called together " Hsp70 ") in Hsp70 family is played the part of one side Cell protection after Environmental pressure and is avoided mortality infringement, and the dual role of cell for immune mediating molten born of the same parents' sexual assault determined by target on the other hand.The performance of the increase of Hsp70 in tenuigenin has been notified protection under stress and has been permitted various kinds of cell, its be by the prevention wrong folding of cytoplasmic protein, gathering, with sex change and suppress various apoptosis approach (people such as Mosser, Mol Cell Biol.2000 October; 20 (19): 7146-7159; Yenari, Adv Exp Med Biol, 2002,513,281-299; Kiang and Tsokos, Pharmacol Ther.1998; 80 (2): 182-201).But membrane-binding Hsp70 is provided for the target structure of the molten born of the same parents' sexual assault mediated by natural killer cell.
Cell can due to temperature; Injury (wound); Heredopathia; Metabolic defect; Apoptosis; Infect; Toxin; Radiation; Oxide compound; Surplus/the shortage of nutrient or metabolic product; And fellow and suffer pressure.Such as, in technical field, known primary cellular defect in following various medical conditions can experience protectiveness effect to Hsp70 reaction.
Cause comprising Alzheimer's disease (Alzheimers ' disease) (people such as Zhang, J.Neuroscience, 2004,24 (23), 5315-5321; Klettner, Drug News Perspect, 200417 (5), 299-306); Huntington chorea (Huntington ' s disease) (Klettner, ibid); Parkinson's disease (Parkinson ' sdisease) (people such as Auluck, Science, 2002,295 (5556), 865-868); And the neurodegenerative protein mistake folding/gathering illness of fellow.Other neurodegenerative illnesss comprise spinal cord/bulbar muscular atrophy (Sobue, Nihon Shinkei Seishin Yakurigaku Zasshi, 2001,21 (1), 21-25); With Familial amyotrophic inclined side sclerosis (people such as Howland, Proc Nat Acad Sci USA, 2002,99 (3), 1604-1609; Sobue, ibid; The people such as Vleminck, J Neuropathol Exp Neurol, 2002,61 (11), 968-974).
Local asphyxia has an impact to the various tissues comprising following person to relevant oxidative damage: neurone and neuroglia (people such as Carmel, Exp Neurol, 2004,185 (1) 81-96; Renshaw and Warburton, Front Biosci, 2004,9,110-116; Yenari, Adv Exp Med Biol, 2002,513,281-299; Kelly and Yenari, Curr Res Med Opin, 2002,18 Suppl 2, s55-60; The people such as Lee, Exp Neurol, 2001,170 (1), 129-139; Klettner, ibid; Klettner and Herdegen, Br J Pharmacol, 2003,138 (5), 1004-1012); Cardiac muscle (people such as Marber, M.S., (1995) J.Clin.Invest.95:1446-1456; The people such as Plumier, J.C. (1995) J.Clin.Invest.95:1854-1860; The people such as Radford, N.B. (1996) Proc.Natl.Acad.Sci.USA 93 (6): 2339-2342; The people such as Voss, Am J Physiol Heart Circ Physiol 285:H687-H692,2003); Liver organization (people such as Doi, Hepatogastroenterology.2001 Mar-Apr; 48 (38): 533-40; The people such as Gao, World J Gastroenterol 2004; 10 (7): 1019-1027); Skeletal muscle (people such as Lepore, Cell Stress & Chaperones, 2001,6 (2), 93-96); Renal tissue (people such as Chen, Kidney Int.1999; 56:1270-1273; The people such as Beck, Am J Physiol Renal Physiol 279:F203-F215,2000.); Tissue (people such as Hiratsuka, the J Heart Lung Transplant.1998Dec of lung; 17 (12): 1238-46); Tissue (people such as Bellmann, the J Clin Invest.1995 June of pancreas; 95 (6): 2840-2845) and fellow.
Damage neuronic outbreak (seizure) illness and comprise (such as) Epileptic fits (Yenari, ibid; The people such as Blondeau, Neuroscience 2002,109 (2), 231-241); Or chemical induced outbreak people such as (, Neurosurgery, 2003,53 (5), 1179-1187) Tsuchiya.
Thermal pressure comprises hyperpyrexia illness, such as fever, heatstroke and fellow (Barclay and Robertson, J Neurobiol, 200356 (4), 360-271; The people such as Sato, Brain Res, 1996,740 (1-2), 117-123); With hypothermy (Kandor and Goldberg, Proc Natl Acad Sci US A.1997 May 13; 94 (10): 4978-4981).
Aging illness (Minowada, G. and Welch, W.J., (1995) J.Clin.Invest.95:3-12 comprising such as atherosclerosis (it has an impact to smooth muscle cell); The people such as Johnson, A.J., (1995) Arterio.Thromb.Vasc.Biol.15 (1): 27-36).
Other illnesss comprise (such as) from the radiation damage (Simon of UV-light to tissue (such as muroid fibroblast), M.M. people is waited, (1995) J.Clin.Res.95 (3): 926-933), with to the light loss of retina cell evil (people such as Yu, Molecular Vision 2001; 7:48-56).
Mechanicalness that wound comprises (such as) injures, such as in glaucoma to the pressures compromises of ganglia retinae people such as (, Invest Opthalmol Vis Sci, 2003,44 (5), 1982-1992) Ishii.
Poisoning illness comprises the pharmaceutical chemicals of such as following person or taking of pharmaceutical chemicals: methamphetamine (Malberg & Seiden, Poster " MDMA Administration Induces Expression ofHSP70 in the Rat Brain " Society for Neuroscience Annual Meeting, New Orleans, LA, October 25-30,1997); Anti-retroviral HIV therapy (people such as Keswani, AnnalsNeurology, 2002,53 (1), 57-64); Heavy metal, amino acid analogue, chemical oxidizing agent, ethanol, L-glutamic acid, with other toxin (Ashburner, M. and Bonner, J.J., (1979) Cell:17:241-254; Lindquist, S., (1986) Ann.Rev.Biochem.55:1151-1191; Craig, E.A., (1985) Crit.Rev.Biochem.18 (3): 239-280; The people such as Morimoto, in: The Biologyof Heat Shock Proteins and Molecular Chaperone, (1994) pp.417-455.ColdSpring Harbor Laboratory Press.Cold Spring Harbor, N.Y.); And fellow.
Therefore, have for increasing the performance of Hsp70 with the demand for the treatment of to the novel method of the disease that Hsp70 responds.
The outer Hsp70 and membrane-binding Hsp70 of showed cell plays the part of pivotal player in congenital immune activation.Shown monocyte and can secrete front inflammatory cells Jie element to solubility Hsp70 albumen test, display membrane-binding Hsp70 can be provided for the target structure of the molten born of the same parents' sexual assault by natural killer cell.
NK cell (NK) cell, a kind of white cell, known is the important composition key element of a body immune system.Because the limited function of NK cell is without previous immunogenic spontaneous cytotoxicity, the First Line of the defence of NK cell in immunity system, and it is believed that it plays the part of certain role in attack cancer cell and infectious diseases.Many illnesss (such as immunological incompetence disease, aging, toxin exposure, endometriosis and fellow) can make affected person have the NK cytoactive of reduction or parafunctional NK cell.
Such as, affected person may have minimizing or defective NK cytoactive in (such as) following illness: chronic fatigue syndrome (chronic fatigue immune dysfunction syndrome) or Epstein-Barr virus, post-viral fatigue syndrome, syndrome or host-transplant disease (host-graftdisease) after transplanting, be exposed to medicine, such as carcinostatic agents or nitric oxide synthase inhibitors, weather aging, with various immunological incompetence illness, such as serious combined immunological incomplete (severe combinedimmunodeficiency), variability immunological incompetence disease group (variable immunodeficiency syndrome), and fellow (Caligiuri M, Murray C, Buchwald D, Levine H, Cheney P, Peterson D, Komaroff AL, Ritz J, Phenotypic and functional deficiencyof natural killer cells in patients with chronic fatigue syndrome.Journal ofImmunology 1987, 139:3306-13, Morrison LJA, Behan WHM, Behan PO, Changes in natural killer cell phenotype in patients with post-viral fatiguesyndrome.Clinical and Experimental Immunology 1991, 83:441-6, Klingemann, HG, Relevance and Potential of Natural Killer Cells in Stem Cell TransplantationBiology of Blood and Marrow Transplantation 2000, 6:90-99, Ruggeri L, CapanniM, Mancusi A, Aversa F, Martelli MF, Velardi A, Natural killer cells as atherapeutic tool in mismatched transplantation.Best Pract Res Clin Haematol.2004 Sep, 17 (3): 427-38, Cifone MG, Ulisse S, Santoni A, Natural killer cells andnitric oxide.Int Immunopharmacol.2001 Aug, 1 (8): 1513-24, Plackett TP, Boehmer ED, Faunce DE, Kovacs EJ, Aging and innate immune cells.J LeukocBiol.2004 Aug, 76 (2): 291-9.Epub 2004 Mar 23, Alpdogan O, van den Brink MR, IL-7 and IL-15:therapeutic cytokines for immunodeficiency.Trends Immunol.2005 Jan, 26 (1): 56-64, Heusel JW, Ballas ZK, Natural killer cells:emergingconcepts in immunity to infection and implications for assessment ofimmunodeficiency.Curr Opin Pediatr.2003 Dec, 15 (6): 586-93, Hacein-Bey-AbinaS, Fischer A, Cavazzana-Calvo M, Gene therapy of X-linked severe combinedimmunodeficiency.Int J Hematol.2002 Nov, 76 (4): 295-8, Baumert E, SchlesierM, Wolff-Vorbeck G, Peter HH, Alterations in lymphocyte subsets in variableimmunodeficiency syndrome Immun Infekt.1992 Jul, 20 (3): 73-5).
Known NK cell has the activity of the infectious pathogeny body (such as bacterium, virus, fungi, protozoon parasite, associativity infect (such as, associativity bacillary/viral infection) and fellow) of antagonism numerous species.It is believed that NK cell is important especially in the operation infected with (in this place's pathogeny body in affected time multiplexed cell system) in cell, the substantial part of such as virus and other pathogeny bodies many that can form intracellular infection.
Such as, existing report points out that the infection of the fungi of numerous species can be determined by NK cellular targets, such as Cryptococcus neoformans (Cryptococcus neoformans), dermatophytes, such as trichophyton purpureatum (Trichophytonrubrum), Candida albicans (Candida albicans), thick ball mould (Coccidioides immitis), the secondary ball mould of Brazil (Paracoccidioides brasiliensis), or fellow (Hidore MR, Mislan TW, Murphy JW, Responses of murine natural killer cells to binding of the fungaltarget Cryptococcus neoformans Infect Immun.1991 Apr, 59 (4): 1489-99, AkibaH, Motoki Y, Satoh M, Iwatsuki K, Kaneko F, Recalcitrant trichophyticgranuloma associated with NK-cell deficiency in a SLE patient treated withcorticosteroid.Eur J Dermatol.2001 Jan-Feb, 11 (1): 58-62, Mathews HL, Witek-Janusek L, Antifungal activity of interleukin-2-activated natural killer (NK1.1+) lymphocytes against Candida albicans.J Med Microbiol.1998Nov, 47 (11): 1007-14, Ampel NM, Bejarano GC, Galgiani JN, Killing ofCoccidioides immitis by human peripheral blood mononuclear cells.InfectImmun.1992 Oct, 60 (10): 4200-4, Jimenez BE, Murphy JW, In vitro effects ofnatural killer cells against Paracoccidioides brasiliensis yeast phase.Infect Immun.1984 Nov, 46 (2): 552-8.).
NK cell also target determines bacterium, particularly Intracellular bacterial (such as, mycobacterium tuberculosis (Mycobacterium tuberculosis), mycobacterium avium (Mycobacterium avium), increasing property of monocyte Lee Salmonella (Listeria monocytogenes)), many different virus (such as Human Immunodeficiency virus, simplexvirus, hepatitis, and fellow), and viral/bacillary common-infect (EsinS, Batoni G, Kallenius G, Gaines H, Campa M, Svenson SB, Andersson R, Wigzell H, Proliferation of distinct human T cell subsets in response to live, killed or soluble extracts of Mycobacterium tuberculosis and Myco.avium.ClinExp Immunol.1996 Jun, 104 (3): 419-25, Kaufmann SH, Immunity to intracellularbacteria.Annu Rev Immunol.1993, 11:129-63, See DM, Khemka P, Sahl L, Bui T, Tilles JG, The role of natural killer cells in viral infections.Scand JImmunol.1997 Sep, 46 (3): 217-24, Brenner BG, Dascal A, Margolese RG, Wainberg MA, Natural killer cell function in patients with acquiredimmunodeficiency syndrome and related diseases.J Leukoc Biol.1989Jul, 46 (1): 75-83, Kottilil S, Natural killer cells in HIV-1 infection:role of NKcell-mediated non-cytolytic mechanisms in pathogenesis of HIV-1 infection.Indian J Exp Biol.2003 Nov, 41 (11): 1219-25, Herman RB, Koziel MJ, Naturalkiller cells and hepatitis C:is losing inhibition the key to clearance? ClinGastroenterol Hepatol.2004 Dec, 2 (12): 1061-3, Beadling C, Slifka MK, How doviral infections predispose patients to bacterial infections? Curr Opin Infect Dis. 2004 Jun, 17 (3): 185-91).
In addition, NK cell and protozoal infect (comprise bend worm disease, trypanosomiasis, Li Shiman body are sick, malaria) (particularly intracellular infection) fights (Korbel DS, Finney OC, Riley EM, Naturalkiller cells and innate immunity to protozoan pathogens.Int J Parasitol.2004Dec; 34 (13-14): 1517-28; Ahmed JS, Mehlhorn H, Review:the cellular basis of theimmunity to and immunopathogenesis of tropical theileriosis.Parasitol Res.1999Jul; 85 (7): 539-49; Osman M, Lausten SB, E1-Sefi T, Boghdadi I, Rashed MY, Jensen SL, Biliary parasites, Dig Surg.1998; 15 (4): 287-96; Gazzinelli RT, Denkers EY, Sher A, Host resistance to Toxoplasma gondii:model for studyingthe selective induction of cell-mediated immunity by intracellular parasites.InfectAgents Dis.1993 Jun; 2 (3): 139-49; Askonas BA, Bancroft GJ, Interaction ofAfrican trypanosomes with the immune system.Philos Trans R Soc Lond B BiolSci.1984 Nov 13; 307 (1131): 41-9; Allison AC, Eugui EM, The role ofcell-mediated immune responses in resistance to malaria, with special reference tooxidant stress.Annu Rev Immunol.1983; 1:361-92).
Show NK cell and played the part of certain role in the cancer cell of attacking performance membrane-binding Hsp70.It is believed that membrane-binding Hsp70 is bonded to the CD94 acceptor on the surface of NK cell, and make them produce the ferment with secretion a large amount, granzyme (granzyme) B, its be considered to can by with membrane-binding Hsp70 interaction and enter tumour cell and apoptosis-induced (see Radons and Multhoff, Exerc.Immunol.Rev. (2005), 11:17-33).Therefore, have to for increasing NK cytoactive with Therapeutic cancer and the urgent demand of effective treatment of NK being brought out to the other diseases responded.
Summary of the invention
Some compound of the present invention can induce Hsp70 to produce in cell, and increases the level of Hsp70 in tenuigenin and on the surface of cell whereby.In addition, some compound of the present invention has cytotoxicity to cancer cell (comprising multi-drug resistance cancer cell system), and improve the anti-proliferate and apoptosis activity (such as, antitumour activity) of eliminating cancer victory (Taxol) and Taxan (taxane) analogue.
In one embodiment, compound of the present invention is by formula (I):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein:
R
1with R
2the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, halogen, nitro, cyano group, guanidine radicals ,-OR independently
17,-NR
19r
20,-C (O) R
17,-C (O) OR
17,-OC (O) R
17,-C (O) NR
19r
20,-NR
18c (O) R
17,-OP (O) (OR
17)
2,-SP (O) (OR
17)
2,-SR
17,-S (O)
pr
17,-OS (O)
pr
17,-S (O)
poR
17,-NR
18s (O)
pr
17, or-S (O)
pnR
19r
20.
R
3with R
4-H independently, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted or the heteroaryl that is optionally substituted;
R
5with R
6-H independently, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted or the heteroaryl that is optionally substituted;
R
13be covalent linkage or be substituted or the C1-C6 alkylen group that is unsubstituted;
R
17with R
18(at every turn occur) (independently) be-H, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, the aralkyl be optionally substituted or the heteroaralkyl that is optionally substituted;
R
19with R
20(occur) is-H at every turn independently, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, the aralkyl be optionally substituted or the heteroaralkyl that is optionally substituted; Or R
19with R
20(together with the nitrogen that they connect) forms the heterocyclic radical be optionally substituted or the heteroaryl be optionally substituted; And
P is 1 or 2.
In the embodiment of formula (I) compound, work as R
13-CH
2-, R
3with R
4all be phenyl and R
5with R
6when being all-H, then R
1with R
2it is not all phenyl.
In the embodiment of formula (I) compound, work as R
13-CH
2-, R
3with R
4all be phenyl and R
5with R
6when being all-H, then R
1with R
2it is not all methyl.
In another embodiment, compound of the present invention is representated by formula (II):
Wherein:
R
7with R
8-H or the alkyl be optionally substituted independently of one another, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical that is optionally substituted, or R
7be-H and R
8the aryl be optionally substituted or the heteroaryl be optionally substituted; And R
1, R
2, R
3, and R
4defined such as formula (I).
In another embodiment, compound of the present invention is by formula (III) or (IV):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein:
X
1, X
2, X
3, and X
4group independently selected from being made up of following person:
Z
1, Z
2, Z
3, and Z
4o or S independently of one another;
R
9, R
10, and R
11-H ,-NR independently of one another
19r
20, halogen ,-OR
17, the optionally alkyl, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted or the heteroaryl be optionally substituted that are substituted; And
R
1, R
2, R
3, R
4, R
5, R
6, and R
13defined such as formula (I).
In the embodiment of formula (III) compound, R
1with R
2not-OH ,-SH or-NH
2.
In another embodiment, compound of the present invention is representated by formula (V):
Wherein R
1, R
2, R
3, and R
4defined such as formula (I), X
3with X
4defined such as formula (III), and R
7with R
8defined such as formula (II).
In another embodiment, compound of the present invention is representated by formula (VI):
Wherein R
1, R
2, R
3, and R
4defined such as formula (I), X
1with X
2defined such as formula (IV), and R
7with R
8defined such as formula (II).
In another embodiment, compound of the present invention is by formula (VII):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein:
Each Z is O or S independently;
X
5be-S (O)-,-S (O)
2-,-P (O) (OR
12-S)-, (O)
2r
13s (O)
2-,-S (O)
2oS (O)
2-,-S (O)
2sS (O)
2-,-S (O)
2n (R
5) S (O)
2-,-P (O) (OR
12) R
13p (O) (OR
12)-, P (O) (OR
12) OP (O) (OR
12)-,-P (O) (OR
12) SP (O) (OR
12)-or-P (O) (OR
12) N (R
5) P (O) (OR
12)-;
R
12-H independently, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted or halogen; And R
1, R
2, R
3, R
4, R
5, R
6, and R
13defined such as formula (I).
In the embodiment of formula (VII) compound, work as Z
3or Z
4when being O, then R
1or R
2not-OR
17.In the embodiment of formula (VII) compound, when z iso, then R
1or R
2not-OR
17or-NR
19r
20.
In another embodiment, compound of the present invention is representated by formula (VIII) or (IX):
Wherein R
1, R
2, R
3, and R
4defined such as formula (I), R
7with R
8defined such as formula (II), and R
12defined such as formula (VII).
In another embodiment, compound of the present invention is by formula (X):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein X
6-O-,-S-,-N (R
5)-or-C (R
5)
2-; X
9with X
10-C (R independently
5)-; R
1, R
2, R
3, and R
4defined such as formula (I).Z defined such as formula (VII).
In another embodiment, compound of the present invention is by formula (XI):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein X
6-O-,-S-,-N (R
5)-or-C (R
5)
2-, X
7with X
8-O-,-S-,-N (R independently
5)-or-C (R
5)
2-, and R
2, R
3, and R
4defined such as formula (I).X
9with X
10defined such as formula (X).
In another embodiment, compound of the present invention is by formula (XII):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein X
11with X
12-C (R independently
5)-or-N-, its condition is X
11or X
12at least one is-N-.X
7with X
8defined such as formula (XI).R
1, R
2, R
3, and R
4defined such as formula (I).Z defined such as formula (VII).
In another embodiment, compound of the present invention is by formula (XIII):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein:
X
13be-C (O)-;-S (O)-,-S (O)
2-,-P (O) (OR
12-S)-, (O)
2r
13s (O)
2-,-S (O)
2oS (O)
2-,-S (O)
2sS (O)
2-,-S (O)
2n (R
5) S (O)
2-,-P (O) (OR
12) R
13p (O) (OR
12)-, P (O) (OR
12) OP (O) (OR
12)-,-P (O) (OR
12) SP (O) (OR
12)-,-C (O) R
13s (O)
2-,-C (O) C (=NNHR
26) C (O)-,-S (O)
2nR
27c (O)-or-P (O) (OR
12) N (R
5) P (O) (OR
12)-.R
5with R
6-H independently, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted or the heteroaryl that is optionally substituted, or R
5with R
6(nitrogen be connected with them and X
13together) form following ring structure:
R
26the alkyl be optionally substituted or the phenyl group be optionally substituted.R
27the alkyl group being-H or being optionally substituted.R
1, R
2, R
3, R
4, R
12with R
13defined such as formula (I).
In the embodiment of formula (XIII) compound, work as R
3, R
4, R
5, and R
6when being all-H, then R
1or R
2not-OR
17,-NR
19r
20,-NR
18c (O) R
17, or phenyl.
In another embodiment, compound of the present invention is by formula (XIV):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein:
X
14be-C (O)-;-S (O)-,-S (O)
2-,-P (O) (OR
12)-; R
22with R
23-N (R independently of one another
5)-N (R
5)-C (R
5)
2-or-C (R
5)
2-N (R
5)-N (R
5)-; And R
1with R
2defined such as formula (I).
In the embodiment of formula (XIV) compound, when two Z groups are all O and X
14be-C (O)-time, then R
1or R
2not-OR
17.
In another embodiment, compound of the present invention is by formula (XV):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
24with R
25-H independently, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted or the heteroaryl that is optionally substituted.R
1, R
2, R
3, R
4, R
5, R
6defined such as formula (I) with Z.X
14defined such as formula (XIV).
In another embodiment, compound of the present invention is by formula (XVI):
Or representated by its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
5, R
6, defined such as formula (I) with Z.X
14defined such as formula (XIV).R
24with R
25defined such as formula (XV).
Another embodiment of the invention is pharmaceutical composition, and it comprises compound of the present invention or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, and pharmaceutically acceptable supporting agent or thinner.This pharmaceutical composition can be used in treatment, such as, as anti-proliferate agent (such as, carcinostatic agent).In addition, this pharmaceutical composition can be used for bringing out to Hsp70 the disease responded with treatment in treatment, such as, or this pharmaceutical composition can be used for bringing out to natural killer cell the disease responded, bacterial infection, fungal infection, viral infection or parasitic infection with treatment in treatment.
The present invention also provides treatment to have the method for the individuality of proliferative disease (such as cancer).The method comprises the compound of the present invention or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug that give this individual effective dose.Compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug) single-form of (that is, as giving individual unique anti-proliferate medicine) for the treatment of can be given or be total to-give with one or more other cancer therapy drugs.In one embodiment, compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug) is and eliminates cancer and win
or taxanes derivative gives together.
The present invention also provides the purposes of compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug), and it is the pharmaceuticals for the manufacture of the object for treating proliferative disease (such as cancer) in individuality.
The present invention also provides treatment to have the method for the individuality of Hsp70 response disorderly (such as Alzheimer's disease, Huntington chorea, Parkinson's disease and amyotrophic lateral sclerosis).The method comprises the compound of the present invention or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug that give this individual effective dose.
The present invention also provides the purposes of compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug), and it brings out to Hsp70 the disease (such as Alzheimer's disease, Huntington chorea, Parkinson's disease and amyotrophic lateral sclerosis) responded for the manufacture of for treating in individuality.
The present invention is also provided for the method that treatment has the individuality of natural killer cell response disorderly (such as bacterial infection, fungal infection, viral infection or parasitic infection).The method comprises the compound of the present invention or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug that give this individual effective dose.
The present invention also provides the purposes of compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug), and it is for the manufacture of the pharmaceuticals for treating the object of natural killer cell being brought out to the disease (such as bacterial infection, fungal infection, viral infection or parasitic infection) responded in individuality.
The present invention also provides the method preparing compound of the present invention.The method comprises the following steps
Compound of the present invention or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug can be used for treatment proliferative disease (such as cancer, comprise the cancer becoming multi-drug resistance), it is used alone or uses in conjunction with other carcinostatic agents.Therefore, compound of the present invention in the failure of other drug regime or can be used for the treatment of cancer when becoming invalid.In addition, when compound of the present invention uses in conjunction with other cancer therapy drugs (such as eliminating cancer victory or taxanes analogue), be effective especially.
Accompanying drawing explanation
Fig. 1 eliminates cancer victory
the structure of (Paclitaxel).
Fig. 2 is that gram cancer is easy
the structure of (Docetaxel).
Fig. 3-23 separately description eliminates cancer victory especially
the structure of analogue.
Figure 24 be comprise that autohemagglutination polymer backbone stretches out eliminate cancer victory
the structure of the polymkeric substance of analogue group.This polymkeric substance is the trimer of three as directed monomeric units.
Detailed Description Of The Invention
In one embodiment, the invention provides the compound as following the formula (I) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
5, R
6, and R
13as defined above.
In the embodiment of formula (I) compound, work as R
13-CH
2-, R
3with R
4all be phenyl and R
5with R
6when being all-H, then R
1with R
2it is not all phenyl.
In the embodiment of formula (I) compound, work as R
13-CH
2-, R
3with R
4all be phenyl and R
5with R
6when being all-H, then R
1with R
2it is not all methyl.
In one embodiment, the invention provides the compound as following the formula (II) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
7, and R
8as defined above.
In one embodiment, the invention provides as following the formula (III) proposed and the compound of formula (IV):
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
5, R
6, R
13, Z
1, Z
2, Z
3, Z
4, X
1, X
2, X
3, and X
4as defined above.
In the embodiment of formula (III) compound, R
1with R
2not-OH ,-SH or-NH
2.
In one embodiment, the invention provides the compound as following the formula (V) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
7, R
8, X
3with X
4as defined above.
In one embodiment, the invention provides the compound as following the formula (VI) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
7, R
8, X
1with X
2as defined above.
In one embodiment, the invention provides the compound as following the formula (VII) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein: R
1, R
2, R
3, R
4, R
5, R
6, and X
5as defined above.
In the embodiment of formula (VII) compound, work as Z
3or Z
4when being O, then R
1or R
2not-OR
17.In the embodiment of formula (VII) compound, when z iso, then R
1or R
2not-OR
17or-NR
19r
20.
In one embodiment, the invention provides the compound as following the formula (VIII) that proposes or (IX):
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
7, R
8with R
12as defined above.
In one embodiment, the invention provides the compound as following the formula (X) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein X
6, R
1, R
2, R
3, R
4, with Z be as defined above.
In the embodiment of formula (X) compound, when z iso, R
1or R
2not-OR
17.
In one embodiment, the invention provides the compound as following the formula (XI) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, X
6, X
7, X
8, R
2, R
3, and R
4as defined above.
In one embodiment, the invention provides the compound as following the formula (XII) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein X
11, X
12, X
7, X
8, R
1, R
2, R
3, R
4as defined above with Z.
In the embodiment of formula (XII) compound, X
11or X
12at least one is-N-.
In the embodiment of formula (XII) compound, when two Z groups are all O, then R
1or R
2not-OR
17.
In the embodiment of formula (XII) compound, when two Z groups are all O and X
7with X
8all-CH
2-time, then R
1or R
2not-NR
19r
20, or phenyl.
In one embodiment, the invention provides the compound as following the formula (XIII) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein:
X
13, R
1, R
2, R
3, and R
4as defined above.
In the embodiment of formula (XIII) compound, work as R
3, R
4, R
5, and R
6when being all-H, then R
1or R
2not-OR
17,-NR
19r
20,-NR
18c (O) R
17, or phenyl.
In one embodiment, the invention provides the compound as following the formula (XIV) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein X
14, R
22, R
23, R
1with R
2as defined above.
In the embodiment of formula (XIV) compound, when two Z groups are all O and X
14be-C (O)-time, then R
1or R
2not-OR
17.
In one embodiment, the invention provides the compound as following the formula (XV) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, R
24, R
25, R
1, R
2, R
3, R
4, R
5, R
6, Z and X
14as defined above.
In one embodiment, the invention provides the compound as following the formula (XVI) proposed:
Or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug, wherein R
1, R
2, R
3, R
4, R
5, R
6, Z, X
14, R
24with R
25as defined above.
In the embodiment of another compound representated by formula (I)-(XVI), R
1with R
2each aryl be optionally substituted naturally or the heteroaryl be optionally substituted.On the one hand, R
1with R
2each phenyl group that is that be substituted naturally or that be unsubstituted.On the one hand, R
1with R
2it is all phenyl.On the other hand, R
1with R
2it is all 4-cyano-phenyl.On the other hand, R
1with R
2it is all 4-p-methoxy-phenyl.More on the one hand, R
1with R
2it is all 2,5-Dimethoxyphenyl.On the other hand, R
1with R
2it is all 3-cyano-phenyl.More on the one hand, R
1with R
2it is all 3-fluorophenyl.On the other hand, R
1with R
2it is all 4-chloro-phenyl-.More on the one hand, R
1with R
2it is all 2-Dimethoxyphenyl.On the other hand, R
1with R
2it is all 3-p-methoxy-phenyl.On the one hand, R
1with R
2it is all 2,3-Dimethoxyphenyl.On the other hand, R
1with R
2it is all 2,5-difluorophenyl.More on the one hand, R
1with R
2it is all 2,5-dichlorophenyl.On the other hand, R
1with R
2it is all 2,5-3,5-dimethylphenyl.
In the embodiment of another compound representated by formula (I)-(XVI), R
1with R
2all the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical that is optionally substituted.On the one hand, R
1with R
2all optionally with the C3-C8 group of naphthene base that at least one alkyl group replaces.On the other hand, R
1with R
2all cyclopropyl or 1-methylcyclopropyl groups.On the one hand, R
1with R
2it is all cyclopropyl.More on the one hand, R
1with R
2it is all 1-methylcyclopropyl groups.On the other hand, R
1with R
2it is all 2-methylcyclopropyl groups.On the one hand, R
1with R
2it is all 2-phenycyclopropyl.On the other hand, R
1with R
2it is all 1-phenycyclopropyl.More on the one hand, R
1with R
2it is all cyclobutyl.On the other hand, R
1with R
2it is all cyclopentyl.On the other hand, R
1with R
2it is all cyclohexyl.More on the one hand, R
1with R
2it is all methyl.On the other hand, R
1with R
2it is all methyl.On the one hand, R
1with R
2it is all the tertiary butyl.On the other hand, R
1with R
2it is ethyl.More on the one hand, R
1with R
2it is all n-propyl.On the other hand, R
1with R
2it is alkylhalide group.
In the embodiment of another compound representated by formula (I)-(XVI), R
1with R
2all halogen, nitro, cyano group, guanidine radicals ,-OR
17,-NR
19r
20,-C (O) R
17,-C (O) OR
17,-OC (O) R
17,-C (O) NR
19r
20,-NR
18c (O) R
17,-OP (O) (OR
17)
2,-SP (O) (OR
17)
2,-SR
17,-S (O)
pr
17,-OS (O)
pr
17,-S (O)
poR
17,-NR
18s (O)
pr
17, or-S (O)
pnR
19r
20.On the one hand, R
1with R
2all-OR
17.On the one hand, R
1with R
2all-NR
19r
20.
In the embodiment of another compound representated by formula (I)-(XIII), (XV) or (XVI), R
3with R
4the alkyl be respectively optionally substituted naturally, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted.On the one hand, R
3with R
4each alkyl group naturally.On the other hand, R
3with R
4each methyl or ethyl naturally.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII), (X), (XIII), (XV) or (XVI), R
5be-H and R
6-H, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical that is optionally substituted.On the one hand, R
6-H or methyl.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII), (X), (XIII), (XV) or (XVI), R
1with R
2each aryl be optionally substituted naturally or the heteroaryl be optionally substituted; And R
3with R
4the alkyl be respectively optionally substituted naturally, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII), (X), (XIII), (XV) or (XVI), R
5be-H and R
6-H, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical that is optionally substituted; And R
3with R
4each alkyl group naturally.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII), (X), (XIII), (XV) or (XVI), R
1with R
2each phenyl group that is that be substituted naturally or that be unsubstituted and R
3with R
4each methyl or ethyl naturally.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII), (X), (XIII), (XV) or (XVI), R
1with R
2all the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical that is optionally substituted; R
5-H; And R
6-H or the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical that is optionally substituted.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII), (X), (XIII), (XV) or (XVI), R
1with R
2all optionally with the C3-C8 group of naphthene base that at least one alkyl group replaces; R
3with R
4it is all alkyl group; And R
6-H or methyl.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII) or (XIII), R
13it is covalent linkage.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII) or (XIII), R
13-CH
2cH
2cH
2-or-CH
2cH
2.
In the embodiment of another compound representated by formula (I), (III), (IV), (VII) or (XIII), R
13-C (R
7) (R
8)-.
At another by formula (II), (V), (VI), (VIII), or in the embodiment of compound representated by (IX),
R
1with R
2it is all phenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all phenyl; R
3with R
4it is all ethyl; R
7with R
8all-H;
R
1with R
2it is all 4-cyano-phenyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 4-p-methoxy-phenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all phenyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all phenyl; R
3with R
4it is all ethyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 4-cyano-phenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,5-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,5-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 3-cyano-phenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 3-fluorophenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 4-chloro-phenyl-; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 2-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 3-p-methoxy-phenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,3-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,3-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 2,5-difluorophenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,5-difluorophenyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 2,5-dichlorophenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,5-3,5-dimethylphenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,5-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all phenyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2,5-Dimethoxyphenyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all ethyl; R
7with R
8all-H;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all methyl; R
7it is methyl; R
8-H;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl; R
7methyl and R
8-H;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl; R
7ethyl and R
8-H;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl; R
7n-propyl and R
8-H;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl; R
7with R
8it is all methyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all ethyl; R
7with R
8all-H;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3methyl, and R
4it is ethyl; R
7with R
8all-H;
R
1with R
2it is all 2-methylcyclopropyl groups; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 2-phenycyclopropyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all 1-phenycyclopropyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all cyclobutyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all cyclopentyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all cyclohexyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all cyclohexyl; R
3with R
4it is all phenyl; R
7with R
8all-H;
R
1with R
2it is all methyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is all methyl; R
3with R
4it is all the tertiary butyl; R
7with R
8all-H;
R
1with R
2it is all methyl; R
3with R
4it is all phenyl; R
7with R
8all-H;
R
1with R
2it is all the tertiary butyl; R
3with R
4it is all methyl; R
7with R
8all-H;
R
1with R
2it is ethyl; R
3with R
4it is all methyl; R
7with R
8all-H; Or
R
1with R
2it is all n-propyl; R
3with R
4it is all methyl; R
7with R
8all-H.
In the embodiment of another compound representated by formula (III) or (IV), Z
1with Z
2all O.
In the embodiment of another compound representated by formula (III) or (IV), Z
1with Z
2all S.
In the embodiment of another compound representated by formula (III) or (IV), Z
3with Z
4all O.
In the embodiment of another compound representated by formula (III) or (IV), Z
3with Z
4all S.
In the embodiment of another compound representated by formula (III) or (IV), R
9, R
10, and R
11the alkyl being-H independently of one another or being optionally substituted.
In the embodiment of another compound representated by formula (III), X
3with X
4be all
In the embodiment of another compound representated by formula (IV), X
1with X
2be all
In the embodiment of another compound representated by formula (V), X
3with X
4be all
more specifically, R
9it is the alkyl be optionally substituted.Even more specifically, R
9it is methyl.
In the embodiment of another compound representated by formula (VII), X
5-S (O)
2oS (O)
2-,-S (O)
2sS (O)
2-,-S (O)
2n (R
5) S (O)
2, P (O) (OR
12) OP (O) (OR
12)-,-P (O) (OR
12) SP (O) (OR
12)-or-P (O) (OR
12) N (R
5) P (O) (OR
12)-.
In the embodiment of another compound representated by formula (VII), (X), (XII), (XIV), (XV) or (XVI), two Z groups are all S.
In the embodiment of another compound representated by formula (VII), (X), (XII), (XIV), (XV) or (XVI), two Z groups are all O.
In the embodiment of another compound representated by formula (VII), X
5be-S (O)-,-S (O)
2-or-P (O) (OR
12)-.On the one hand, X
5-S (O)
2-.On the one hand, X
5-P (O) (OR
12)-.
In the embodiment of another compound representated by formula (VII), X
5-S (O)
2r
13s (O)
2-or-P (O) (OR
12) R
13p (O) (OR
12)-.On the one hand, X
5-S (O)
2r
13s (O)
2-.On the one hand, X
5-P (O) (OR
12) R
13p (O) (OR
12)-.
In the embodiment of another compound representated by formula (X), (XI) or (XII), X
6-O-or-N (R
5)-.On the one hand, X
6-O-or-NH-.On the one hand, X
6-O-.On the one hand, X
6-NH-.
In the embodiment of another compound representated by formula (X), (XI) or (XII), X
6-S-.
In the embodiment of another compound representated by formula (X), (XI) or (XII), X
6-C (R
5)
2-.
In the embodiment of another compound representated by formula (X) or (XI), X
9with X
10all-CH-.
In the embodiment of another compound representated by formula (X) or (XI), X
9with X
10-CH-,-C (CH independently
3)-or-C (CH
2cH
3)-.
In the embodiment of another compound representated by formula (X), (XI) or (XII),
R
1with R
2it is all phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all phenyl; R
3with R
4it is all ethyl;
R
1with R
2it is all 4-cyano-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 4-p-methoxy-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 4-cyano-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-Dimethoxyphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 3-cyano-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 3-fluorophenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 4-chloro-phenyl-; R
3with R
4it is all methyl;
R
1with R
2it is all 2-Dimethoxyphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 3-p-methoxy-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,3-Dimethoxyphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-difluorophenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-dichlorophenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-3,5-dimethylphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all ethyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all ethyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3methyl, and R
4it is ethyl;
R
1with R
2it is all 2-methylcyclopropyl groups; R
3with R
4it is all methyl;
R
1with R
2it is all 2-phenycyclopropyl; R
3with R
4it is all methyl;
R
1with R
2it is all 1-phenycyclopropyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclobutyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclopentyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclohexyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclohexyl; R
3with R
4it is all phenyl;
R
1with R
2it is all methyl; R
3with R
4it is all methyl;
R
1with R
2it is all methyl; R
3with R
4it is all the tertiary butyl;
R
1with R
2it is all methyl; R
3with R
4it is all phenyl;
R
1with R
2it is all the tertiary butyl; R
3with R
4it is all methyl;
R
1with R
2it is ethyl; R
3with R
4it is all methyl; Or
R
1with R
2it is all n-propyl; R
3with R
4it is all methyl.
In the embodiment of another compound representated by formula (XI) or (XII), X
7with X
8all-O-or-N (R
5)-.On the one hand, X
7with X
8be all-N (H)-.On the one hand, X
7with X
8all-O-.
In the embodiment of another compound representated by formula (XI) or (XII), X
7with X
8all-S-.
In the embodiment of another compound representated by formula (XI) or (XII), X
7with X
8all-C (R
5)
2-.
In the embodiment of another compound representated by formula (XI) or (XII), X
11with X
12all N.
In the embodiment of another compound representated by formula (XIII), this compound is representated by formula (XIIIA):
In the embodiment of another compound representated by formula (XIII), this compound is representated by formula (XIIIB):
More specifically, R
13it is C1-C6 alkylen group that is that be substituted or that be unsubstituted.Even more specifically, R
13-CH
2-.
In the embodiment of another compound representated by formula (XIII), this compound is representated by formula (XIIIC):
More specifically, R
26be optionally be substituted (such as, with lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30, with-OC (O) R
30) phenyl group or be optionally substituted (such as, with lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30-with OC (O) R
30) C1-C6 alkyl group.
In the embodiment of another compound representated by formula (XIII), this compound is representated by formula (XIIID):
More specifically, R
27-H.
In the embodiment of another compound representated by formula (XIII), this compound is representated by formula (XIIIE):
More specifically, R
12be optionally be substituted (such as, with lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30, with-OC (O) R
30) alkyl group or be optionally substituted (such as, with lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30with-OC (O) R
30) phenyl group.Even more specifically, R
12it is phenyl group.
In the embodiment of another compound representated by formula (XIII), (XIIIA), (XIIIB), (XIIIC), (XIIID) or (XIIIE), R
1with R
2each be optionally substituted naturally (such as, with lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30with-OC (O) R
30) aromatic yl group, and R
3with R
4each be optionally substituted naturally (such as, with lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30with-OC (O) R
30) alkyl group.More specifically, R
1with R
2each phenyl be optionally substituted naturally; And R
3with R
4each methyl or ethyl naturally.Even more specifically, for formula (XIII), (XIIIA), (XIIIB), (XIIIC), (XIIID), R
5with R
6all-H.
In the embodiment of another compound representated by formula (XIII), (XIIIA), (XIIIB), (XIIIC), (XIIID) or (XIIIE),
R
1with R
2it is all phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all phenyl; R
3with R
4it is all ethyl;
R
1with R
2it is all 4-cyano-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 4-p-methoxy-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 4-cyano-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-Dimethoxyphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 3-cyano-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 3-fluorophenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 4-chloro-phenyl-; R
3with R
4it is all methyl;
R
1with R
2it is all 2-Dimethoxyphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 3-p-methoxy-phenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,3-Dimethoxyphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-difluorophenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-dichlorophenyl; R
3with R
4it is all methyl;
R
1with R
2it is all 2,5-3,5-dimethylphenyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclopropyl; R
3with R
4it is all ethyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all methyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3with R
4it is all ethyl;
R
1with R
2it is all 1-methylcyclopropyl groups; R
3methyl, and R
4it is ethyl;
R
1with R
2it is all 2-methylcyclopropyl groups; R
3with R
4it is all methyl;
R
1with R
2it is all 2-phenycyclopropyl; R
3with R
4it is all methyl;
R
1with R
2it is all 1-phenycyclopropyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclobutyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclopentyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclohexyl; R
3with R
4it is all methyl;
R
1with R
2it is all cyclohexyl; R
3with R
4it is all phenyl;
R
1with R
2it is all methyl; R
3with R
4it is all methyl;
R
1with R
2it is all methyl; R
3with R
4it is all the tertiary butyl;
R
1with R
2it is all methyl; R
3with R
4it is all phenyl;
R
1with R
2it is all the tertiary butyl; R
3with R
4it is all methyl;
R
1with R
2it is ethyl; R
3with R
4it is all methyl; Or
R
1with R
2it is all n-propyl; R
3with R
4it is all methyl.More specifically, for formula (XIII), (XIIIA), (XIIIB), (XIIIC) or (XIIID), R
5with R
6all-H.
In the embodiment of another compound representated by formula (XIV), (XV) or (XVI), X
14be-C (O)-.
In the embodiment of another compound representated by formula (XIV), (XV) or (XVI), X
14be-S (O)-.
In the embodiment of another compound representated by formula (XIV), (XV) or (XVI), X
14-S (O)
2-.
In the embodiment of another compound representated by formula (XIV), (XV) or (XVI), X
14-P (O) (OR
12)-.
In the embodiment of another compound representated by formula (XV) or (XVI), R
24with R
25each alkyl group naturally.On the one hand, R
24with R
25each methyl or ethyl naturally.
In the embodiment of another compound representated by formula (XV) or (XVI), R
24with R
25each-H naturally.
Exemplary compounds of the present invention (comprising its tautomer, pharmacy acceptable salt, solvate, inclusion compound, hydrate, polymorph or prodrug) is in describing with following table 1.
Table 1:
In one embodiment, compound of the present invention does not comprise the compound that the Patent Case of listing in table 2 and patent application case disclose.
Table 2
| Patent Case or patent application case numbering | Open numbering | The applying date | Publication date |
| U.S.6,800,660 | U.S.2005/0009920 | On July 10th, 2002 | On June 26th, 2003 |
| U.S.7,037,940 | U.S.2003/0119914 | On May 14th, 2004 | On January 13rd, 2005 |
| U.S.11/244,324 | U.S.2006/0122183 | On October 5th, 2005 | On June 8th, 2006 |
| U.S.6,762,204 | U.S.2003/0045518 | On July 10th, 2002 | On March 6th, 2003 |
| U.S.6,924,312 | U.S.2003/0195258 | On January 15th, 2003 | On October 16th, 2003 |
| U.S.7,001,923 | U.S.2004/0235909 | On March 18th, 2004 | On November 25th, 2004 |
| U.S.11/244,427 | U.S.2006/0116374 | On October 5th, 2005 | On June 1st, 2006 |
| U.S.6,825,235 | U.S.2003/0069225 | On July 10th, 2002 | On April 10th, 2003 |
| U.S.7,074,952 | U.S.2004/0229952 | On March 24th, 2004 | On November 18th, 2004 |
| U.S.11/440,429 | Not yet open | On May 24th, 2006 | Not yet open |
| U.S.11/157,213 | U.S.2006/0135595 | On June 20th, 2005 | On June 22nd, 2006 |
| U.S.11/432,307 | Not yet open | On May 11st, 2006 | Not yet open |
For herein, term " alkyl " means a kind of alicyclic hydrocarbons of saturated straight or branched, and it has 1 to 10 carbon atom.Representative saturated straight chained alkyl comprise methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, with positive decyl, and saturated branched-chain alkyl comprises sec.-propyl, sec-butyl, isobutyl-, the tertiary butyl, isopentyl, 2-methyl butyl, 3-methyl butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethyl amyl group, 2,2-dimethylhexanyl, 3,3-dimethyl amyl group, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethyl pentyl group, 3-ethyl pentyl group, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, 2-methyl-4-ethyl pentyl group, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethyl amyl group, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl, and fellow.Term " (C
1-C
6) alkyl " meaning the alicyclic hydrocarbons of saturated straight or branched, it has 1 to 6 carbon atom.Representative (C
1-C
6) alkyl group is as implied above and has those groups of 1 to 6 carbon atom.The alkyl group be included in compound of the present invention can optionally replace with one or more substituting group.
For herein, term " thiazolinyl " means a kind of alicyclic hydrocarbons of saturated straight or branched, and it has 2 to 10 carbon atoms and has at least one carbon-to-carbon double bond.(the C of representative straight chain and side chain
2-C
10) thiazolinyl comprises vinyl, propenyl, 1-butylene base, crotyl, isobutenyl, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-crotyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonene base, 2-nonene base, 3-nonene base, 1-decene base, 2-decene base, 3-decene base and fellow.Alkenyl group can optionally replace with one or more substituting group.
For herein, term " alkynyl " means a kind of alicyclic hydrocarbons of saturated straight or branched, and it has 2 to 10 carbon atoms and has at least one carbon-to-carbon triple bond.The alkynyl of representative straight chain and side chain comprises ethynyl, proyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl, 4-pentynyl, 1-hexin base, 2-hexin base, 5-hexin base, 1-heptyne base, 2-heptyne base, 6-heptyne base, 1-octyne base, 2-octyne base, 7-octyne base, 1-n-heptylacetylene base, 2-n-heptylacetylene base, 8-n-heptylacetylene base, 1-decynyl, 2-decynyl, 9-decynyl and fellow.Alkynyl group can optionally replace with one or more substituting group.
For herein, term " cycloalkyl " mean a kind of saturated, single-or multi-ring alkyl, it has 3 to 20 carbon atoms.Representative cycloalkyl comprises cyclopropyl, 1-methylcyclopropyl groups, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl ,-ring decyl, octahydro-pentalen base (octahydro-pentalenyl) and fellow.Group of naphthene base can optionally replace with one or more substituting group.In some embodiments, cycloalkyl comprises 3 to 10 carbon atoms.In some embodiments, cycloalkyl comprises 3 to 8 carbon atoms.In some embodiments, cycloalkyl comprises 3 to 8 carbon atoms.
For herein, term " cycloalkenyl group " means the alkyl of list-or many-ring-type non-fragrance, and it has at least one carbon-to-carbon double bond and 3 to 20 carbon atoms in loop systems.Representative cycloalkenyl group comprises cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, cycloheptatriene base, cyclooctene base, cyclooctadiene base, cyclo-octatriene base, cyclooctatetraenyl, cyclonoene base, cyclonoadiene base, cyclodecene base, cyclodecadiene base, 1,2,3,4,5,8-hexahydro naphthalene base and fellow.Cycloalkenyl groups can optionally replace with one or more substituting group.In some embodiments, cycloalkenyl group comprises 3 to 10 carbon atoms.In some embodiments, cycloalkenyl group comprises 3 to 8 carbon atoms.In some embodiments, cycloalkenyl group comprises 3 to 6 carbon atoms.
For herein, term " alkylhalide group " means a kind of alkyl group, and wherein one or more (comprising all) hydrogen bases are replaced by halogen group, wherein each halogen group be independently be selected from-F ,-Cl ,-Br, with-I.Term " halogen methyl " means a kind of methyl, and wherein one to three hydrogen base is replaced by halogen group.Representative haloalkyl group comprises trifluoromethyl, brooethyl, 1,2-Dichloroethyl, 4-iodine butyl, 2-fluorine amyl group and fellow.
For herein, " alkoxyl group " is a kind of alkyl group, and it is connected to another part (moiety) by an oxygen connexon.
For herein, " halogen alkoxyl group " is a kind of haloalkyl group, and it is connected to another part by an oxygen connexon.
For herein, term " aromatic nucleus " or " aryl " mean a kind of hydrocarbon polymer monocycle or many cyclic groups, and wherein at least one ring is fragrant.The example of the aromatic yl group be applicable to comprises (but being not limited to) phenyl, tolyl, anthryl, fluorenyl, indenyl, Azulene base (azulenyl) and naphthyl, and benzo-fused isocyclic part, such as 5,6,7,8-tetralyls.Aromatic yl group can optionally replace with one or more substituting group.In one embodiment, aromatic yl group is 6-14 person's ring.In one embodiment, aromatic yl group is monocycle, and wherein this ring comprises 6 carbon atoms, is called " (C herein
6) aryl ".
For herein, term " aralkyl " means a kind of aromatic yl group, and it is by (C
1-C
6) alkylen group is connected to another group.Representative aromatic alkyl group comprises phenmethyl, 2-phenyl-ethyl group, naphthalene-3-base-methyl and fellow.Aromatic alkyl group can optionally replace with one or more substituting group.
For herein, term " alkylene " means a kind of alkyl group, and it has two points connected.Term " (C
1-C
6) alkylene " meaning a kind of alkylen group, it has one to six carbon atom.Straight chain (C
1-C
6) alkylen group is preferably.The non-limiting examples of alkylen group comprises methylene radical (-CH
2-), ethylidene (-CH
2cH
2-), positive propylidene (-CH
2cH
2cH
2-), isopropylidene (-CH
2cH (CH
3)-) and fellow.Alkylen group can optionally replace with one or more substituting group.
For herein, term " heterocyclic radical " means monocycle (typically having 3-to 10-member) or many rings (typically having 7-to 20-member) heteroaryl ring system, and it is saturated ring or undersaturated non-aromatic nucleus.3-to 10-element heterocycle can contain 5 heteroatomss at the most; And 7-to 20-element heterocycle can contain 7 heteroatomss at the most.Typically, heterocycle has at least one carboatomic ring member.Each heteroatoms is be selected from nitrogen independently, (such as, N (O)) that but it be oxidized or level Four; Oxygen; With sulphur, comprise sulfoxide and sulfone.Heterocycle can connect by any heteroatoms or carbon atom.Representative heterocycle comprises morpholinyl, thio-morpholinyl, pyrrolidone-base, pyrrolidyl, piperidyl, piperazinyl, glycolylurea base (hydantoinyl), Valerolactim base (valerolactamyl), epoxy ethyl, oxa-fourth cyclic group (oxetanyl), tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydrochysene thiophenyl, tetrahydrochysene thiopyranyl and fellow.Heteroatoms can have the protectiveness group replacement usually knowing that the knowledgeable is known in technical field, and such as, the hydrogen on nitrogen can use tert-butoxycarbonyl group to replace.In addition, heterocyclic radical can optionally replace with one or more substituting group.The stable isomer of the heterocyclic group be so substituted only is considered in this definition.In some embodiments, heterocyclic radical comprises 3 to 10 annular atomses and 1-3 heteroatoms (being selected from N, O or S).In some embodiments, heterocyclic radical comprises 3 to 8 annular atomses and 1-3 heteroatoms (being selected from N, O or S).In some embodiments, heterocyclic radical comprises 3 to 6 annular atomses and 1-3 heteroatoms (being selected from N, O or S).
For herein, term " assorted fragrance ", " heteroaryl " or similar term mean monocycle or many rings and to mix aromatic nucleus, and it comprises carboatomic ring member and one or more heteroatom ring members.Each heteroatoms is be selected from nitrogen independently, and it can be (such as, the N (O)) of oxidation or level Four; Oxygen; With sulphur, comprise sulfoxide and sulfone.Representative heteroaryl groups comprises pyridyl, 1-ketone group-pyridyl, furyl, benzo [1, 3] di azoly (benzo [1, 3] dioxolyl), benzo [1, 4] alkyl dioxin (benzo [1, 4] dioxinyl), thienyl, pyrryl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl group, isoquinolyl, indazolyl, benzoxazolyl, benzofuryl, indyl (indolizinyl), imidazopyridyl, tetrazyl, benzimidazolyl-, benzothiazolyl, diazosulfide base, Ben Bing oxadiazolyl, indyl, tetrahydro indole base, azaindolyl, imidazopyridyl, quinazolyl, purine radicals, pyrrolo-[2, 3] pyrimidyl, pyrazolo [3, 4] pyrimidyl, imidazo [1, 2-a] pyridyl, with benzothienyl.In one embodiment, assorted aromatic nucleus is selected from 5-8 person's bicyclic heteroaryl ring.Assorted fragrance or heteroaryl ring is connected to the assorted fragrance of point of another group or the carbon atom of heteroaryl ring or heteroatoms.Heteroaryl groups can optionally replace with one or more substituting group.
For herein, term " (C
5) heteroaryl " mean the aromatic nucleus of a kind of 5 Yuans, wherein in ring, at least one atom is heteroatoms, such as (such as) oxygen, sulphur or nitrogen.Representative (C
5) heteroaryl comprises furyl, thienyl, pyrryl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl group and fellow.
For herein, term " (C
6) heteroaryl " mean the aromatic nucleus of a kind of 6 Yuans, wherein in ring, at least one atom is heteroatoms, such as (such as) oxygen, sulphur or nitrogen.Representative (C
6) heteroaryl comprises pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazine base (tetrazinyl) and fellow.
For herein, term " heteroaralkyl " means heteroaryl groups, and it is by (C
1-C
6) alkylene is connected to another group.Representative heteroaralkyl comprises 2-(pyridin-4-yl)-propyl group, 2-(thiene-3-yl-)-ethyl, imidazol-4 yl-methyl and fellow.Heteroaralkyl group can optionally replace with one or more substituting group.
For herein, term " halogen " or " halogen " mean-F ,-Cl ,-Br or-I.
To alkyl, alkylene, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl and heteroaralkyl group be applicable to substituting group be that those can form the group of stable compound of the present invention.To alkyl, alkylene, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl, and the substituent example of heteroarylalkyl comprises the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, the aralkyl be optionally substituted, the heteroaralkyl be optionally substituted, alkylhalide group,-C (O) NR
28r
29,-C (S) NR
28r
29,-C (NR
32) NR
28r
29,-NR
30c (O) R
31,-NR
30c (S) R
31,-NR
30c (NR
32) R
31, halogen ,-OR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-C (S) R
30,-C (NR
32) R
30,-NR
28r
29,-C (O) OR
30,-C (S) OR
30,-C (NR
32) OR
30,-OC (O) R
30,-OC (S) R
30,-OC (NR
32) R
30,-NR
30c (O) NR
28r
29,-NR
30c (S) NR
28r
29,-NR
30c (NR
32) NR
28r
29,-OC (O) NR
28r
29,-OC (S) NR
28r
29,-OC (NR
32) NR
28r
29,-NR
30c (O) OR
31,-NR
30c (S) OR
31,-NR
30c (NR
32) OR
31,-S (O)
hr
30,-OS (O)
pr
30,-NR
30s (O)
pr
30,-S (O)
pnR
28r
29,-OS (O)
pnR
28r
29, or-NR
30s (O)
pnR
28r
29.
In some embodiments, to alkyl, alkylene, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl, aralkyl, heteroaryl, and the substituent example of heteroarylalkyl comprises alkyl and (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), heteroaryl, aralkyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), heteroaralkyl, alkylhalide group,-C (O) NR
28r
29,-C (S) NR
28r
29,-C (NR
32) NR
28r
29,-NR
30c (O) R
31,-NR
30c (S) R
31,-NR
30c (NR
32) R
31, halogen ,-OR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-C (S) R
30,-C (NR
32) R
30,-NR
28r
29,-C (O) OR
30,-C (S) OR
30,-C (NR
32) OR
30,-OC (O) R
30,-OC (S) R
30,-OC (NR
32) R
30,-NR
30c (O) NR
28r
29,-NR
30c (S) NR
28r
29,-NR
30c (NR
32) NR
28r
29,-OC (O) NR
28r
29,-OC (S) NR
28r
29,-OC (NR
32) NR
28r
29,-NR
30c (O) OR
31,-NR
30c (S) OR
31,-NR
30c (NR
32) OR
31,-S (O)
hr
30,-OS (O)
pr
30,-NR
30s (O)
pr
30,-S (O)
pnR
28r
29,-OS (O)
pnR
28r
29, or-NR
30s (O)
pnR
28r
29.
Selectively, exemplary substituting group comprises lower alkyl groups and (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-8 element heterocycle base, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), 5-6 person's heteroaryl, (such as phenmethyl, is optionally selected from by lower alkyl groups with one or more low carbon number aralkyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number heteroaralkyl, low carbon number alkylhalide group,-C (O) NR
33r
29,-C (S) NR
33r
29,-C (NR
32) NR
33r
29,-NR
30c (O) R
31,-NR
30c (S) R
31,-NR
30c (NR
32) R
31, halogen ,-OR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-C (S) R
30,-C (NR
32) R
30,-NR
33r
29,-C (O) OR
30,-C (S) OR
30,-C (NR
32) OR
30,-OC (O) R
30,-OC (S) R
30,-OC (NR
32) R
30,-NR
30c (O) NR
33r
29,-NR
30c (S) NR
33r
29,-NR
30c (NR
32) NR
33r
29,-OC (O) NR
33r
29,-OC (S) NR
33r
29,-OC (NR
32) NR
33r
29,-NR
30c (O) OR
31,-NR
30c (S) OR
31,-NR
30c (NR
32) OR
31,-S (O)
hr
30,-OS (O)
pr
30,-NR
30s (O)
pr
30,-S (O)
pnR
33r
29,-OS (O)
pnR
33r
29, and-NR
30s (O)
pnR
33r
29.Selectively, exemplary substituting group comprises lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-8 element heterocycle base, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), 5-6 person's heteroaryl, low carbon number aralkyl (such as phenmethyl, and be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number heteroaralkyl, low carbon number alkylhalide group,-C (O) NR
33r
29,-C (S) NR
28r
29,-NR
30c (O) R
31,-NR
30c (S) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-C (S) R
30,-NR
28r
29,-C (O) OR
30,-C (S) OR
30,-OC (O) R
30,-OC (S) R
30,-OC (NR
32) R
30with-NR
30c (O) NR
28r
29.Selectively, exemplary substituting group comprises lower alkyl groups, low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, the substituting group of the group that low carbon number halogen alkoxyl group and-OH form replaces), low carbon number alkylhalide group,-C (O) NR
28r
29,-NR
30c (O) R
31, halogen ,-OR
30,-SR
30, cyano group, nitro, halogen alkoxyl group ,-C (O) R
30,-NR
28r
29,-C (O) OR
30with-OC (O) R
30.
Wherein R
28with R
29, each occur (independently) be H, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, the aralkyl be optionally substituted or the heteroaralkyl that is optionally substituted; Or R
28with R
29the heterocyclic radical be optionally substituted or the heteroaryl be optionally substituted is formed together with the nitrogen that they connect;
R
30with R
31each appearance (independently) is H, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, the aralkyl be optionally substituted or the heteroaralkyl that is optionally substituted; And
R
32, each appearance (independently) is H, the alkyl be optionally substituted, the thiazolinyl be optionally substituted, the alkynyl be optionally substituted, the cycloalkyl be optionally substituted, the cycloalkenyl group be optionally substituted, the heterocyclic radical be optionally substituted, the aryl be optionally substituted, the heteroaryl be optionally substituted, the aralkyl be optionally substituted, the heteroaralkyl be optionally substituted ,-C (O) R
30,-C (O) NR
28r
29,-S (O)
pr
30, or-S (O)
pnR
28r
29;
P is 1 or 2; And
H is 0,1 or 2.
In some embodiments, R
28with R
29, each appearance (independently) is H, alkyl (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), thiazolinyl, alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-8 element heterocycle base, C6-C14 aryl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), 5-14 person's heteroaryl, aralkyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or heteroaralkyl, or R
28with R
293-8 element heterocycle base or 5-6 person's heteroaryl is formed together with the nitrogen that they connect, R
30with R
31each appearance (independently) is H, alkyl (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), thiazolinyl, alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-8 element heterocycle base, C6-C14 aryl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), 5-14 person's heteroaryl, aralkyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or heteroaralkyl, and R
32, each appearance (independently) is H, alkyl (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), thiazolinyl, alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-8 element heterocycle base, C6-C14 aryl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), 5-14 person's heteroaryl, aralkyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or heteroaralkyl,-C (O) R
30,-C (O) NR
28r
29,-S (O)
pr
30, or-S (O)
pnR
28r
29.
In some embodiments, R
28with R
29, each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-6 element heterocycle base, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), 5-6 person's heteroaryl, low carbon number aralkyl (such as phenmethyl, and be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or low carbon number heteroaralkyl, or R
28with R
293-6 element heterocycle base or 5-6 person's heteroaryl is formed together with the nitrogen that they connect, R
30with R
31each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-6 element heterocycle base, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), 5-6 person's heteroaryl, low carbon number aralkyl (such as phenmethyl, and (be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or low carbon number heteroaralkyl, and R
32, each appearance (independently) is H, lower alkyl groups (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl group, 3-6 element heterocycle base, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), 5-6 person's heteroaryl, low carbon number aralkyl (such as phenmethyl, and be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or low carbon number heteroaralkyl,-C (O) R
30,-C (O) NR
28r
29,-S (O)
pr
30, or-S (O)
pnR
28r
29.
In some embodiments, R
28with R
29, each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or low carbon number aralkyl (such as phenmethyl, and be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or R
28with R
295-6 element heterocycle base or 5-6 person's heteroaryl is formed together with the nitrogen that they connect, R
30with R
31each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or low carbon number aralkyl (such as phenmethyl, and be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), and R
32, each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl group, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number aralkyl (such as phenmethyl, and be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces),-C (O) R
30,-C (O) NR
28r
29,-S (O)
pr
30, or-S (O)
pnR
28r
29.
In some embodiments, R
28with R
29, each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces) or phenmethyl (be optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or R
28with R
295-6 element heterocycle base or 5-6 person's heteroaryl is formed together with the nitrogen that they connect, R
30with R
31each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), and R
32, each appearance (independently) is H, lower alkyl groups (optionally selects free phenyl with one or more, phenmethyl, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), low carbon number thiazolinyl, low carbon number alkynyl, phenyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces), or phenmethyl (is optionally selected from by lower alkyl groups with one or more, halogen, cyano group, nitro, amido, single (lower alkyl groups) amido, two (lower alkyl groups) amido, low carbon number alkoxyl group, low carbon number halogen alkoxyl group, the substituting group of the group formed with-OH replaces),-C (O) R
30,-C (O) NR
28r
29,-S (O)
pr
30, or-S (O)
pnR
28r
29.
In some embodiments, R
28with R
29, each appearance (independently) is H, lower alkyl groups, low carbon number alkylhalide group, low carbon number thiazolinyl, low carbon number alkynyl, phenyl or benzyl; Or R
28with R
295-6 element heterocycle base or 5-6 person's heteroaryl is formed together with the nitrogen that they connect; R
30with R
31each appearance (independently) is H, lower alkyl groups, low carbon number alkylhalide group, low carbon number thiazolinyl, low carbon number alkynyl, phenyl or phenmethyl; And R
32, each appearance (independently) is H, lower alkyl groups, low carbon number alkylhalide group, low carbon number thiazolinyl, low carbon number alkynyl, phenyl or phenmethyl ,-C (O) R
30,-C (O) NR
28r
29,-S (O)
pr
30, or-S (O)
pnR
28r
29.
In addition, alkyl, cycloalkyl, alkylene, heterocyclic radical, with any thiazolinyl, cycloalkenyl group, alkynyl, aralkyl, with the saturated part of heteroaralkyl group, also can by=O ,=S ,=N-R
32replace.
When heterocyclic radical, heteroaryl or heteroaralkyl group contain nitrogen-atoms, its can be substituted or be unsubstituted.When there is substituting group at the fragrant ring nitrogen of heteroaryl groups, but this nitrogen level Four nitrogen.
For herein, term " individuality ", " patient ", and " mammal " be use interchangeably.Term " individuality " and " patient " mean an animal (such as, birds, such as chicken, quail or turkey or mammal), it is preferably mammal, comprise non-primate (such as, ox, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog and mouse) and primate (such as, monkey, chimpanzee and the mankind), and be more preferably the mankind.In one embodiment, individuality is non-human animal, such as farm-animals (such as, horse, ox, pig or sheep) or pet (such as, dog, cat, guinea pig or rabbit).In one preferably embodiment, individuality is the mankind.
For herein, term " low carbon number " means a kind of group having four carbon atom at the most.Such as, " lower alkyl groups " means a kind of alkyl with 1 to 4 carbon atom, and " low carbon number alkoxyl group " means "-O-(C
1-C
4) alkyl and " low carbon number thiazolinyl " or " low carbon number alkynyl " means a kind of alkenyl or alkynyl with 2 to 4 carbon atoms separately." low carbon number aralkyl " means a kind of aromatic yl group, and it is by (a C
1-C
4) alkylene is connected to another group." low carbon number heteroaralkyl " means a kind of heteroaryl groups, and it is by (a C
1-C
4) alkylene is connected to another group.
Point out unless separately added, the compound of the present invention containing reactive functional group (such as (but being not limited to) carboxyl, hydroxyl, sulfenyl and amine moieties) also comprises its derivative through protecting." derivative through protection " is the compound blockaded by one or more protectiveness group in those wherein one or more reactive positions.Example for the protectiveness group be applicable to of oh group comprises phenmethyl, methoxymethyl, propenyl, TMS, t-butyldimethylsilyi, acetoxy group and fellow.The example of amine protectiveness group be applicable to comprise benzene methoxycarbonyl, tertbutyloxycarbonyl, the tertiary butyl, phenmethyl, with fluorenes methoxy-carbonyl (Fmoc).The example of the sulfenyl protectiveness group be applicable to comprises phenmethyl, the tertiary butyl, ethanoyl, methoxymethyl and fellow.Other protectiveness groups be applicable to have in those technical fields usually know known by the knowledgeable and comprise those at T.W.Greene; Protecting Groups inOrganic Synthesis; John Wiley & Sons, can find in Inc.1981.
For herein; term " compound of the present invention " and similar term mean compound or its pharmacy acceptable salt, solvate, inclusion compound, hydrate, polymorph or the prodrug of formula (I) to (XVI) and table 1, and also comprise it through protection derivative.
Compound of the present invention can containing one or more chiral centre and/or double bond and (therefore) exist with the form of steric isomer, such as double bond isomer (that is, geometrical isomer), enantiomer or non-corresponding isomer.According to the present invention, the chemical structure described herein comprises (comprising compound of the present invention) enantiomer of the compound of all correspondences, diastereomer and geometrical isomer, namely, the pure form of stereochemistry (such as, geometrically pure, enantiomer ground pure or diastereo-isomerism ground pure) with isomerism mixture (such as, enantiomer, diastereomer, with geometric isomerism mixture) both.In some instances, a kind of enantiomer, diastereomer or geometrical isomer can have toxicity or the kinetic curve of higher activity or improvement compared to other isomer.In those examples, the enantiomer like this of compound of the present invention, diastereomer, be preferably with geometrical isomer.
For herein, term " polymorph " means the solid crystallization way of the compounds of this invention or its complex compound (complex).The different polymorphs of same compound can represent characteristic that is different physics, chemical and/or spectroscopy.Different physical characteristics comprises, but be not limited to stability (such as, to heat or light), compressibility and density (allocating and being important in product manufacture) and dissolution rate (it can have an impact to bioavailability).Difference in stability can be derived from change in chemical reactivity (such as, the oxidation of difference, fade when dose form is comparatively made up of another kind of polymorph when being made up of a kind of polymorph faster) or mechanicalness feature is (such as, tablet is pulverized because the polymorph of kinetics preference is transformed into polymorph more stable on thermodynamics in storage) or both (such as, a kind of polytypic tablet is in high humidity easy disintegratings).Polytypic different physical property can have an impact to their processing.Such as, a kind of polymorph more can may form solvate or can more difficult filtering or wash away impurity compared to another polymorph, and it is external form due to (such as) its particle or distribution of sizes.
For herein, term " hydrate " means compound or its salt of the present invention, and it comprises the water of the stoichiometric or stoichiometric amount of non-that power by between non-covalent molecule combines further.
For herein, term " inclusion compound " means compound or its salt of the present invention, and it is in such as, containing the form having guest molecule (guest molecule, solvent or water) and fall into the lattice in space (such as, passage) in the inner.
For herein and unless otherwise directed, term " prodrug " means the derivative of compound, its can hydrolysis under biotic condition (in vitro or in vivo), oxidation or otherwise reaction to provide compound of the present invention.Prodrug can become active in like this reaction under biotic condition, or they can have activity in their non-reacted form.The example of prodrug desired in the present invention include, but is not limited to formula (I) to (XVI) and the compound of table 1 comprise biohydrolyzable moieties (the hydrolyzable acid amides of biological example, biological hydrolyzable ester, biological hydrolyzable amine manthanoate, biological hydrolyzable carbonic ether, biological hydrolyzable urea (ureide), with the hydrolyzable phosphoric acid ester analogue of biology) analogue or derivative.Other examples of prodrug comprise formula (I) to (XVI), comprise-NO ,-NO with the compound of table 1
2,-ONO or-ONO
2the derivative of part.Prodrug typically can use the method preparation known, and such as those are by 1BURGER ' S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178,949-982 (Manfred E.Wolff ed., 5
thed) institute narrator.
For herein and unless otherwise directed, term " biological hydrolyzable acid amides ", " biological hydrolyzable ester ", " biological hydrolyzable amine manthanoate ", " biological hydrolyzable carbonic ether ", " biological hydrolyzable urea ", a kind of acid amides is meant separately with " biological hydrolyzable phosphoric acid ester analogue ", ester, amine manthanoate, carbonic ether, urea, or phosphoric acid ester analogue, its: the biological activity of compound 1) can not be destroyed and give this compound in vivo useful characteristic, that such as improves is water-soluble, the circulation half life improved in blood (such as, because the metabolism of the attenuating of this prodrug), the picked-up improved, between the action period of improving, or the effect improved starts, or 2) itself be biological not active but be in vivo transformed into bioactive compound.The example of biological hydrolyzable acid amides comprise (but being not limited to) lower alkyl groups acid amides, alpha-amino acid amides, alkoxyacyl amides, with alkyl amine group alkyl-carbonyl acid amides.The example of biological hydrolyzable ester comprises (but being not limited to) lower alkyl groups ester, alkoxy-cyloxy esters, alkyl acyl aminoalkyl ester and cholinesterase.The example of biological hydrolyzable amine manthanoate comprises (but being not limited to) lower alkyl groups amine, the quadrol be substituted, amino acid, hydroxyalkyl amine, heterocycle and assorted aromatic amine and polyetheramine.
For herein, " Hsp70 " comprises each member of the family of the heat shock protein(HSP) of the molecular weight with about 70-kilodalton, comprise such as constitutive character, homology, cell-specificity, glucose-modulability, inducibility, etc. form.The example of special Hsp70 albumen comprises hsp70, hsp70hom; Hsc70; Grp78/BiP; Mt-Hsp70/Grp75 and fellow.Typically, the method disclosed increases the performance of inducibility Hsp70.Function Shangdi, 70-kDa HSP (HSP70) family be a group tenuigenin, Mitochondria, with endoplasmic reticulum in assist the folding of protein, transport, chaperonins (chaperon) with assembling.In the mankind, membrane-binding Hsp70, Hsp70 family comprises at least 11 genes, the protein of its coding a group height correlation.See people such as (such as) Tavaria, Cell Stress Chaperones, 1996; 1 (1): 23-28; The people such as Todryk, Immunology.2003,110 (1): 1-9; And Georgopoulos and Welch, Annu Rev Cell Biol.1993; 9:601-634; The entire teachings of these documents includes in herein with way of reference.
For herein, " Hsp70-replys disorder " is a kind of medical conditions, and the cell be wherein stressed can be treated by the Hsp70 performance increased.Disease like this can be caused by the extensive various cellular stress factor, and it includes, but are not limited to Alzheimer's disease; Huntington chorea; Parkinson's disease; Spinal cord/bulbar muscular atrophy (such as, sweet is Di Shi disease (Kennedy ' s disease)), myeloid cerebral atrophy (spinocerebellar ataxic disease) and other neuromuscular atrophys; Familial amyotrophic inclined side sclerosis; Local asphyxia; Outbreak (seizure); Hypothermy; Hyperpyrexia; Burn; Atherosclerosis; Radioactive exposure; Glaucoma; Toxin exposure; Mechanicalness injures; Inflammation; Autologous disease; Infect (bacterium, virus, fungi or parasite); And fellow.
In some embodiments, Hsp70-replys disorder is neurodegenerative disorders.For herein, neurodegenerative disorders comprise neurone (such as cerebellum, spinal cord, with the neurone of surrounding (such as, in neuromuscular cynapse) degraded, be more typically brain with the degraded of spinal neuron, or in preferably embodiment, be the neuronic degraded of brain.Neurodegenerative disorders can comprise Alzheimer's disease; Huntington chorea; Parkinson's disease; Spinal cord/bulbar muscular atrophy and other neuromuscular atrophys; And Familial amyotrophic inclined side sclerosis or to suddenly change relevant other diseases to superoxide-dismutase (SOD).Neurodegenerative disorders also can comprise the neuronic degraded caused by local asphyxia, outbreak, thermal pressure, radiation, toxin exposure, infection, injury and fellow.
In some embodiments, Hsp70-replys the disease that disorder is protein aggregation/mistake folding, such as Alzheimer's disease; Huntington chorea; Parkinson's disease; Spongiform encephalopathy (spongiformencelphalopathies); And fellow.
In another embodiment, Hsp70 replys disorder is cause the process or or illness that maybe may cause nervous lesion.For the compound of method of the present invention can be used to following in individuality with lower or prevention (suppress its) nervous lesion (namely; neuroprotective is provided) i) by causing the illness institute that maybe may cause nervous lesion bitter, or ii) accept to cause the treatment that maybe may cause nervous lesion.On the one hand, cause and the treatment of nervous lesion maybe may be caused to be radiation therapy.On the other hand, treatment is chemotherapy.On the one hand, chemotherapy comprises and gives antimitotic agent (such as vincristine(VCR), the auspicious treasured in Changchun, Paclitaxel (paclitaxel) or Paclitaxel analogue).On the one hand, chemotherapy comprises and gives Paclitaxel.On the other hand, chemotherapy comprises and gives platinum derivatives (such as Platinol (Cisplatin), carboplatin (carboplatin) or oxaliplatin (oxaliplatin)).In some embodiments, the compound for method of the present invention maybe can may cause the treatment of nervous lesion to be combined treatment and give simultaneously with causing.In other embodiments, for method of the present invention compound can cause maybe may cause the treatment of nervous lesion before or after give.In some embodiments, the compound for method of the present invention can give with 12 little times, 1 hour and 6 little times causing maybe may cause for before or after the treatment of nervous lesion 30 minutes.
Nervous lesion can be caused by several treatments, includes, but is not limited to radiation therapy, chemotherapy, such as Platinol, carboplatin, oxaliplatin, vincristine(VCR) (vincristine), vincaleucoblastine (vinblastine), Vinorelbine (vinorelbine), vindesine (vindesine), ifosfamide (ifosfamide), methotrexate (methotrexate), carat monarch's treasured (cladribine), altretamine (altretamine), fludarabine (fludarabine), Procarbazine (procarbazine), Tespamin (thiotepa), teniposide (teniposide), ARSENIC TRI OXIDE 98, alemtuzumab, capecitabine (capecitabine), NSC-45388 (dacarbazine), denileukin diftitox, interferon alpha, liposomal daunorubicin (daunorubicin), tretinoin (tretinoin), Etoposide (etoposide)/VP-16, cytosine arabinoside (cytarabine), hexamethyl melamine (hexamethylmelamine), Suramine (suramin), Paclitaxel, Docetaxel (docetaxel), gemcitabine (gemcitibine), Thalidomide (thalidomide), with Velcade (bortezomib), heart or vascular pressure medicine, such as amiodarone (amiodarone), hydralazine (hydralazine), digoxin (digoxin), with perhexiline (perhxiline), to anti-infective medicine, such as metronidazole (metronidazole), furadantin (nitrofurantoin), Thalidomide (thalidomide) and INH, the medicine for the treatment of skin disorder, such as dapsone (dapsone), anticonvulsant drug, such as 5,5-Diphenyl-2,4-imidazolidinedione (phenytoin), anti-alcohol medicine, such as Tosse) (disulfiram), HIV medicine, such as zidovudine (zidovudine), didanosine (didanonsine), Stavudine (stavudine), zalcitabine (zalcitabine), ritonavir (ritonavir), d4T, ddC, ddl, with amprenavir (amprenavir), cholesterol drugs, such as lovastatin (lovastatin), Pravastatin (pravastatin), indapamide (indapamid), Simvastatin (simvastatin), fluvastatin (fluvastatin), atorvastatin (atorvastatin), Xue Li cut down Shi Dading (cerivastatin), with gemfibrozil (gemfibrozil), antirheumatic thing, such as chloroquine (chloroquine), colchicine (cholchicine), You Jijin, with Trolovol (penicillamine), Nitrous Oxide, lithium, and ergot class (ergots).
In some embodiments, Hsp70-replys disorder is local asphyxia.Local asphyxia can pass through multiple pathways (comprise oxygen depletion, glucose exhausts, in the oxidative stress of Reperfu-sion and/or glutamate toxicity and fellow) damaging tissue.Injury (such as, at the Reperfu-sion pressure of transplant organ) and fellow that local asphyxia can be derived from endogenous illness (such as, apoplexy, heart attack and fellow), be derived from the injury of accident mechanicalness, is derived from operation.Selectively, the tissue that may damage because of local asphyxia comprises neurone, cardiac muscle, liver organization, skeletal muscle, renal tissue, the tissue of lung, the tissue of pancreas and fellow.In one preferably embodiment, it is brain or spinal cord local asphyxia that Hsp70-replys disorder.In another preferably embodiment, Hsp70-replys the local asphyxia that disorder is heart.
In various embodiments, it is outbreak that Hsp70-replys disorder, such as epileptic seizures, injury-inducibility outbreak, chemically-inducibility outbreak and fellow.
In some embodiments, Hsp70-replys disorder is due to thermal pressure.Thermal pressure comprises hyperpyrexia (such as, being derived from fever, heatstroke, burn and fellow) and hypothermy.In one preferably embodiment, disease is hyperpyrexia.In another preferably embodiment, it is burn that Hsp70-replys disorder.
In preferably embodiment, it is atherosclerosis that Hsp70-replys disorder.
In various embodiments, it is radiation damage that Hsp70-replys disorder, such as, because visible ray, UV-light, microwave, Millikan's rays, α radiation, β radiation, the radiation of character used in proper names and in rendering some foreign names horse, X-ray and fellow caused.Such as, the radiation damage of infringement to the non-cancerous tissue in the individuality by radiation therapy Therapeutic cancer.In one preferably embodiment, it is the radiation damage being derived from visible ray or UV-light that Hsp70-replys disorder.
In various embodiments, it is mechanicalness injury that Hsp70-replys disorder, such as, be derived from the wound of operation, accident, some disease states (pressures compromises such as, in glaucoma) and fellow.In one preferably embodiment, it is brain or spinal cord injuries receptor that Hsp70-replys disorder.In another preferably embodiment, it is glaucoma (causing amphiblestroid ganglionic pressures compromises) that Hsp70-replys disorder.
In various embodiments, Hsp70-replys the exposure that disorder is contratoxin.In preferably embodiment, it is exposure to being selected from following neurotoxin that Hsp70-replys disorder: methamphetamine; The HIV therapy (such as, nucleoside reverse transcriptase inhibitors) of anti-retroviral; Heavy metal (such as, mercury, lead, arsenic, cadmium, its compound and fellow), amino acid analogue, chemical oxidizing agent, ethanol, L-glutamic acid, metabolic inhibitor, microbiotic and fellow.
Some compound of the present invention also increases NK cell (NK) cytoactive.For herein, " NK cell-response disorder " be a kind of medical conditions, it can improve by the increase in NK cytoactive.Such as, the individuality having NK cell-response disorderly may need immunity system to expand, because infect or its possibility.In some embodiments, individuality like this can have infection (or being exposed to the infectious environment (such as in hospital) of pathogeny body existence), and its sign can alleviate by method disclosed herein.Such as, need the individuality for the treatment of can have infections (bacterium, viral, fungi or parasitic, protozoic), and treatment be can be for the method for the activated NK that it discloses.
In some embodiments, have NK cell-response disorderly individuality there is immunological incompetence.Individuality like this (such as, to infect have incomplete, impaired or otherwise (compromised) that get involved defence or meet with the individuality of infectious environment or fellow) need maybe can benefit from prophylactic treatment.Such as, individuality can be in infectious environment, and this place exists pathogeny body (such as within the hospital); Open wound or burn can be had; Congenital or Acquired immunity complete (such as, complete or " bubble boy (bubble the boy) " syndrome of serious combined immunological, variability immunological incompetence disease group, Acquired immunity insufficiency disorder wait group (AIDS) or fellow) can be had; Repressed immunity system can be had due to physical disorder, age, toxin exposure, effect of drugs (immunosuppressor, such as, in transplanting recipient) or side effect (such as, due to carcinostatic agent); Or fellow.
In some embodiments, can in the individuality of that there is minimizing or infull NK cytoactive, in illness (such as chronic fatigue syndrome (chronic fatigue immune dysfunction syndrome) or Epstein-Barr virus infection, post-viral fatigue syndrome, syndrome (particularly allotransplantation) or host-transplant disease after transplanting, be exposed to medicine, such as carcinostatic agents or nitric oxide synthase inhibitors, weather aging, with various immunological incompetence illness, such as serious combined immunological is incomplete, variability immunological incompetence disease group, and fellow) middle increase NK cytoactive.
In some embodiments, there is the disorderly individual need of NK cell-response for bacteremic treatment.Microbemia is the illness of bacterial infection in blood flow.Septic shock comprises serious localization or the infection of bacterium courage and uprightness of adjoint systemic inflammation, has in other words and has the very few and hypotensive septicemia of the blood perfusion of resistance to liquid undergoing treatment.Septicemia (or systemic inflammation reaction syndrome) comprises the various serious conditions causing acute inflammation, such as infection, pancreatitis, burn, wound.Septic shock is relevant to the infection caused by gram negative organism, staphylococcus (staphylococcus) or meningococcus (meningococcus) typically.The feature of septic shock is acute circulatory sexual exhaustion, typically have hypopiesia, with multiple organ's exhaustion.
Temporary microbemia can by perform the operation or traumatic wounds cause.Gram-negative bacteraemia is intermittent and opportunistic; Although it can without impact on the people of health, its have make it weak disease, after chemotherapy, with the immune affected persons in malnourished setting in can be seriously important.Infecting typically can at lung, in urogenital (GU) or stomach and intestine (GI) road or at soft tissue, such as have bedsore patient skin, have the mouth ulceration of the patient of mouth ulceration danger, with have valvular heart disease, heart valve artifucial limb (prosthetic heart valve) or other transplant the patient of artifucial limb.
Typically, appear in the patient that Gram-negative bacteraemia can be got involved in chronic disease and immunity.In patient like this, bloodstream infection also can by aerobism bacillus, Anaerobic Bacteria, cause with fungi.Bacteroides (Bacteroides) can cause belly with the infection complication of pelvis, particularly female.Temporary or persistence microbemia typically can cause the transitivity of meninx or serous cavity (serous cavities) to infect, such as pericardium or larger joint.Faecalis (Enterococcus), staphylococcus or fungi can cause endocarditis, but then more uncommon to Gram-negative bacteraemia.Staphylococcic microbemia is typical to IV drug use person, and typical case can be the endocarditic origin cause of formation of Gram-positive bacterial.
The incidence of systemic mycosis sexuality dye significantly increases, special in the mankind, it is in part because have the increase of individual amount of the immunity system (such as old man, AIDS patient, the patient carrying out chemotherapy, fire victim, have the patient of diabetic ketone acid disease (ketoacidosis) and use the transplant patient of immunosuppressive drug) of getting involved.Research finds that about 40% death of infection obtained from the while in hospital is due to mycosis; See people such as Sternberg, Science, Vol.266, (1994), pp.1632-1634, its entire teachings includes in herein with way of reference.
In various embodiments, have NK cell-response disorderly individuality can need for fungal infection (such as pathogenic dermatophytes, pathogenic filamentous fungus and/or pathogenic non-filamentous fungus (such as yeast) or fellow) treatment.Pathogenic dermatophytes can comprise the species of genus of (such as) Trichophyton (Trichophyton), tinea (Tinea), little gemma Pseudomonas (Microsporum), Epidermophyton (Epidermophyton) or fellow.Pathogenic filamentous fungus can comprise the species of (such as) the such as genus of aspergillus (Aspergillus), tissue milk Pseudomonas (histoplasma), genera cryptococcus (Cryptococcus), little gemma Pseudomonas or fellow.Pathogenic non-filamentous fungus (such as yeast) can comprise the species of genus of (such as) Candida (Candida), Malassezia (Malassezia), hair bacillus sp (Trichosporon), Rhodotorula (Rhodotorula), torulopsis (Torulopsis), genera cryptococcus (Blastomyces), the mould Pseudomonas of secondary ball (Paracoccidioides), the mould Pseudomonas of ball (Coccidioides) or fellow.In various embodiments, can be individual for the fungal infection treatment of the species of the genus from aspergillus or Trichophyton.The species of Trichophyton can comprise (such as) trichophyton mentagrophytes (Trichophyton mentagrophytes), trichophyton purpureatum, trichophyton schonenleini (Trichophyton schoenleinii), oerbiss Trichophyton (Trichophyton tonsurans), trichophyton verrucosum (Trichophyton verrucosum), with trichophyton violaceum (Trichophyton violaceum).The species of aspergillus can comprise (such as) fumigation look aspergillus (Aspergillus fumigatus), yellow aspergillus (Aspergillus flavus), black aspergillus (Aspergillus niger), Amsterdam aspergillus (Aspergillus amstelodami), brilliant white aspergillus (Aspergillus candidus), yellowish pink aspergillus (Aspergillus carneus), little nido aspergillus (Aspergillus nidulans), rice aspergillus (A oryzae), limitation aspergillus (Aspergillus restrictus), poly-many aspergillus (Aspergillus sydowi), golden native aspergillus (Aspergillus terreus), aspergillus ustus (Aspergillus ustus), variegated aspergillus (Aspergillusversicolor), light blue grey aspergillus (Aspergillus caesiellus), bar-shaped aspergillus (Aspergillusclavatus), oat shape aspergillus (Aspergillus avenaceus), with elbow aspergillus (Aspergillusdeflectus).In some embodiments, can be individual for the fungal infection treatment from following person: pathogenic dermatophytes, such as Trichophyton (such as, trichophyton purpureatum), tinea, little gemma Pseudomonas or Epidermophyton; Or genera cryptococcus (such as, Cryptococcus neoformans), Candida (such as Candida albicans), the mould Pseudomonas of secondary ball (such as, Brazilian secondary ball mould) or the mould Pseudomonas of ball (such as, thick ball mould).In special embodiment, can be individual for the fungal infection treatment from trichophyton purpureatum, Cryptococcus neoformans, Candida albicans, Brazilian secondary ball mould or thick ball mould.
Therefore, in various embodiments, individuality can have by being selected from the infection caused with the fungi of subordinate: Trichophyton, tinea, little gemma Pseudomonas, Epidermophyton, aspergillus, tissue milk Pseudomonas, genera cryptococcus, little gemma Pseudomonas, Candida, Malassezia, hair bacillus sp, Rhodotorula, torulopsis, genera cryptococcus, the mould Pseudomonas of secondary ball, with the mould Pseudomonas of ball.In some embodiments, individuality can have and causes infection by the fungi of the genus being selected from following person: Trichophyton, tinea, little gemma Pseudomonas, Epidermophyton, genera cryptococcus, Candida, the mould Pseudomonas of secondary ball, with the mould Pseudomonas of ball.In some embodiments, individuality can have the infection caused by the fungi being selected from following person: trichophyton purpureatum, Cryptococcus neoformans, Candida albicans, Brazilian secondary ball mould, with thick ball mould.
In various embodiments, there is the treatment that the disorderly individuality of NK cell-response can need for being selected from the bacterial infection caused with the bacterium of subordinate by (such as): Allochromatium, motionless Pseudomonas (Acinetobacter), Bacillaceae, curved bar Pseudomonas (Campylobacter), coating Pseudomonas (Chlamydia), (Chlamydophila) is belonged to addicted to clothing body, fusobacterium (Clostridium), Citrobacter (Citrobacter), Colibacter (Escherichia), Bacillaceae (Enterobacter) in intestines, enterococcus spp, Francisella (Francisella), hemophilus (Haemophilus), screw rod Pseudomonas (Helicobacter), gram stay Bordetella (Klebsiella), Lee Bordetella (Listeria), mora Bordetella (Moraxella), Mycobacterium (Mycobacterium), micrococcus sp (Micrococcus), neisseria (Neisseria), proteus (Proteus), Rhodopseudomonas (Pseudomonas), salmonella spp (Salmonella), saw rod Pseudomonas (Serratia), bacillus dysenteriae belongs to (Shigella), oligotrophy unit cell mattress belongs to (Stenotrophomonas), Staphylococcus, streptococcus (Streptococcus), synechococcus belongs to (Synechococcus), Vibrio (Vibrio), with Ye Shi Bacillaceae (Yersina), or the genus of anaerobic bacterium, such as Peptostreptococcus (Peptostreptococci), Porphyromonas Pseudomonas (Porphyromonas), actinomyces (Actinomyces), fusobacterium, Bacteroides, prevotella (Prevotella), Anaerobiospirillum (Anaerobiospirillum), thin fusobacterium (Fusobacterium) and Bilophila.In some embodiments, have NK cell-response disorderly individuality can need for the bacterial infection from following person treatment: Allochromatiumvinosum, acinetobacter calcoaceticus (Acinetobacter baumanii), anthrax bacillus (Bacillus anthracis), jejunum curved bar bacterium (Campylobacter jejuni), trachoma Chlamydia (Chlamydia trachomatis), pneumonia Chlamydia (Chlamydia pneumoniae), Clostridial species, citric acid bacillus species, intestinal bacteria (Escherichia coli), Bacillaceae species in intestines, enterococcus faecalis (Enterococcus faecalis), faecium (Enterococcus faecium), soil draws Wen bacillus (Francisella tularensis), hemophilus influenzae (Haemophilus influenzae), helicobacter pylorus revolves bacterium (Helicobacter pylori), gram stay Bordetella species, increasing property of monocyte Lee Salmonella, cattamolars bacteria (Moraxella catarrhalis), mycobacterium tuberculosis, meningococcus (Neisseria meningitidis), gonorrhea diplococcus (Neisseriagonorrhoeae), Proteus mirabilis (Proteus mirabilis), common variation bacillus (Proteusvulgaris), embroider look pseudomonas (Pseudomonas aeruginosa), Salmonella species, saw rod ella species, bacillus dysenteriae species, addicted to Fructus Hordei Germinatus oligotrophy unit cell mattress (Stenotrophomonasmaltophilia), streptococcus aureus (Staphyloccocus aureus), S.epidermidi ball (Staphyloccocus epidermidis), streptococcus pneumoniae (Streptococcus pneumoniae), streptococcus pyogenes (Streptococcus pyogenes), streptococcus agalactiae (Streptococcus agalactiae), plague Ye Shi bacillus (Yersina pestis), with small intestine colitis Ye Shi bacillus (Yersinaenterocolitica), or fellow, or peptostreptococcus asaccharolyticus (Peptostreptococciasaccharolyticus), peptostreptococcus magnus (Peptostreptococci magnus), peptostreptococcus micros (Peptostreptococci micros), peptostreptococcus prevotii (Peptostreptococci prevotii), do not understand sugared Detection of Porphyromonas (Porphyromonas asaccharolytica), Porphyromonas canoris, porphyromonas gingivalis (Porphyromonas gingivalis), Porphyromonas macaccae, Yi Siruo actinomycetes (Actinomyces israelii), actinomyces dentocariosus (Actinomyces odontolyticus), clostridium innocuum (Clostridium innocuum), fusiformis fusiformis (Clostridium clostridioforme), refractory clostridium (Clostridium difficile), Bacteroides tectum, Bacteroides urolyticus (Bacteroides urealyticus), very thin bacterioide (Bacteroides gracilis, very thin curved bar bacterium (Campylobactergracilis)), Prevotella (Prevotella intermedia), separate heparin melaninogenicus (Prevotella heparinolytica), mouth-cheek melaninogenicus (Prevotella oris-buccae), two road melaninogenicus (Prevotella bivia), produce black melaninogenicus (Prevotella melaninogenica), Fusobacterium naviforme, the thin clostridium (Fusobacterium necrophorum) of gangrene heat, can be attenuated clostridium (Fusobacterium varium), the thin clostridium of ulcer (Fusobacterium ulcerans), Fusobacterium russii, Bilophila wadsworthia, Du Shi influenzae (Haemophilusducreyi), Calymmatobacterium granulomatis or fellow.
It is believed that compound of the present invention has the individuality being used for the treatment of and having intracellular infection especially.Generally believe in technical field that NK cell is effective in antagonism intracellular infection especially.Intracellular infection be infectious pathogeny bodies of those wherein parts be present in sufferer cell in person.
Such as, intracellular infection is caused by one or more bacteriums being selected from following person: Ai Lixi body belongs to (Ehrlichia) (such as, necessary, in lymphocyte and neutrophil(e) cell, present the Intracellular bacterial of minicell matter inclusion body, such as glandular fever Ai Lixi body (Ehrlichia sennetsu), dog Ai Lixi body (Ehrlichia canis), Cha Feiailixi body (Ehrlichia chaffeensis), addicted to phagocytic cell Ai Lixi body (Ehrlichia phagocytophilia) or fellow); Lee Bordetella (such as, increasing property of monocyte Lee Salmonella); Veteran Pseudomonas (Legionella, such as, veteran is addicted to tuberculosis bacterium (Legionellapneumophila)); Rickettsiae (Rickettsiae, such as, Rickettsia prowazeki (Rickettsiaeprowazekii), rickettsia exanthematotyphi (Rickettsiae typhi, rickettsia mooseri (Rickettsiaemooseri)), rickettsia rickettsii (Rickettsiae rickettsii), dermacetor orientalis (Rickettsiaetsutsugamushi), dermacetor sibericus (Rickettsiae sibirica); Dermacetor australis (Rickettsiae australis); Rickettsia conorii (Rickettsiae conorii); Dermacetor akari (Rickettsiae akari); Bai Shi rickettsia (Rickettsiae burnetii)); Coating Pseudomonas (such as, psittacosis Chlamydia (Chlamydia psittaci); Pneumonia Chlamydia; Sand holes Chlamydia (Chlamydiatrachomatis) or fellow); Mycobacterium (mycobacterium tuberculosis; Mycobacterium marinum (Mycobacterium marinum); Mycobacterium avium (Mycobacterium AviumComplex); Mycobacterium bovis (Mycobacterium bovis); Mycobacterium scrofulaceum (Mycobacteriumscrofulaceum); Mycobacterium buruli (Mycobacterium ulcerans); The crazy mycobacterium of Ma (Mycobacterium leprae) (Ma is crazy, HansenShi bacillus)); Brucella (Brucella, such as, Mediterranean fruit fly Brucella (Brucella melitensis); Alcaligenes abortus (Brucellaabortus); Pig Brucella (Brucella suis); Bang's bacillus belongs to (Brucella canis)); Coxiella (Coxiella, such as, rickettsia burneti (Coxiella burnetii)); Or fellow.Therefore, in some embodiments, individuality can have by being selected from genus Ai Lixi body genus; Lee Bordetella; Veteran Pseudomonas; Rickettsia; Coating Pseudomonas; Mycobacterium; Brucella; And the intracellular bacterial that the bacterium of the genus of Coxiella is caused infects.
In various embodiments, there is the treatment that the disorderly individuality of NK cell-response can need the bacterial infection from one or more upper respiratory tract bacteriums.The example of upper respiratory tract bacterium comprises those genus persons belonging to such as veteran Pseudomonas, Rhodopseudomonas and fellow.In some embodiments, bacterium embroiders look pseudomonas.At special embodiment, but bacterium veteran addicted to tuberculosis bacterium (such as, comprise serotype 1, 2, 3, 4, 5, 6, 7, 8, and fellow), Du Mofu veteran bacterium (Legionella dumoffli), long beach veteran bacterium (Legionella longbeacheae), Mick wears moral veteran bacterium (Legionella micdadei), Legionella oakridgensis, Legionellafeelei, Legionella anisa, Legionella sainthelensi, Bo Ziman veteran bacterium (Legionellabozemanii), dagger-axe Germania veteran bacterium (Legionella gormanii), Hua Wozisi veteran bacterium (Legionella wadsworthii), Jordan veteran bacterium (Legionella jordanis), or Ge Erman veteran bacterium.
In some embodiments, there is the disorderly individuality of NK cell-response can need the acute bacterial of chronic bronchitis can be caused for coming to worsen the treatment of the bacterial infection of (acute bacterial exacerbationof chronic bronchitis, ABECB) person in comfortable sufferer.Typically, ABECB can be caused by streptococcus pneumoniae, hemophilus influenzae, haemophilus parainfluenzae (Haemophilus parainfluenzae) or cattamolars bacteria.
In some embodiments, the individuality with NK cell-response disorder can need the treatment for causing in comfortable sufferer the bacterial infection of Acute Community acquired pneumonia (community acquired pneumonia, CAP) person.Typically, CAP can be starched mould (Mycoplasma pneumoniae), pneumonia Chlamydia or pneumonia gram and be stayed Salmonella (Klebsiella pneumoniae) to cause by streptococcus pneumoniae, hemophilus influenzae, cattamolars bacteria, pneumonia.In a special embodiment, CAP can be caused by anti-medicine tolerant bacteria (the multiple drug resistance strain of such as streptococcus pneumoniae).
In various embodiments, there is the disorderly individuality of NK cell-response can need for staying Salmonella, streptococcus aureus, streptococcus pyogenes, Lu Shi amotile bacterium (Acinetobacter lwoffi) from streptococcus pneumoniae, hemophilus influenzae, haemophilus parainfluenzae, cattamolars bacteria, pneumonia slurry mould, pneumonia Chlamydia, pneumonia gram, produce acid gram and stay Salmonella (Klebsiella oxytoca), veteran addicted to the treatment of the bacterial infection of tuberculosis bacterium or common variation bacillus.
In various embodiments, there is the treatment that the disorderly individuality of NK cell-response can need for the bacterial infection bacterium from highmore antrum pathogenic bacteria.For herein, highmore antrum pathogenic bacteria is separated from the bacterium strain of acute or chronic highmore antrum inflammation, or the highmore antrum strain isolated of (such as) following person: the anaerobism strain of streptococcus aureus, streptococcus pneumoniae, Haemophilus species, cattamolars bacteria, non-fermentable gram negative bacillus, meningococcus or β-melt courageous and upright suis (β-Haemolytic Streptococcus).In various embodiments, highmore antrum pathogenic bacteria can comprise the bacterium strain be separated from acute or chronic highmore antrum inflammation, streptococcus aureus, streptococcus pneumoniae, Haemophilus species, cattamolars bacteria, the anaerobism strain of non-fermentable gram negative bacillus, meningococcus, β-melt courageous and upright suis, hemophilus influenzae, enterobacteriaceae (Enterobacteriaceae), non-fermentable gram negative bacillus, streptococcus pneumoniae, streptococcus pyogenes, anti-methicillin Staphylococcus species, veteran is addicted to tuberculosis bacterium, slurry Streptomyces species, with Chlamydia species, hemophilus influenzae, haemophilus parainfluenzae, Peptostreptococcus (Peptostreptococcus), Bacteroides spp, with the highmore antrum strain isolated of Bacteroides urolyticus.
In various embodiments, there is the treatment that the disorderly individuality of NK cell-response can need cause in individuality for meeting the bacterial infection of urinary tract infection (UTI).The example of UTI comprises urethritis, urocystitis, prostatitis, pyelonephritis (acute, chronic, with Xanthogranulomatous (xantho is granulomatous)) and hematopoietic UTI (such as, from the microbemia person with hypertoxicity bacillus (such as salmonella spp, streptococcus aureus and fellow)).Typically, UTI can be caused by following person: Gram-negative aerobism bacterium, such as Colibacter (such as intestinal bacteria), gram to stay Bacillaceae in Bordetella, proteus, intestines, Rhodopseudomonas, with saw rod Pseudomonas; Gram-negative Anaerobic Bacteria; Gram positive bacterium, such as enterococcus spp (such as, enterococcus faecalis) and Staphylococcus species (such as, Staphylococcus saprophyticus (Staphylococcus saprophyticus), streptococcus aureus and fellow); Mycobacterium tuberculosis; And property infective bacterial sexuality dye (such as, sand holes Chlamydia, gonorrhea diplococcus and fellow).
In some embodiments, having the disorderly individuality of NK cell-response can need for the next treatment that will cause the infection of the microorganism of such as following sexually transmitted disease: treponema pallidum; Vagina flagellum trichomonad (Trichomonas vaginalis); Candida (Candida albicans); Gonorrhea diplococcus; Sand holes Chlamydia; Reproductive tract mycoplasm hyopneumoniae (Mycoplasma genitalium), molten mould of urinating (Ureaplasmaurealyticum); Haemophilus ducreyi (Haemophilus ducreyi); Calymmatobacterium granulomatis (Calymmatobacterium granulomatis) (being before called donovan organism (Donovania granulomatis)); Hsv (HSV-1 or HSV-2); Human papillomavirus (HPV); Human Immunodeficiency virus (HIV); Various bacillary (bacillus dysenteriae genus, curved bar Pseudomonas or salmonella spp), viral (A type hepatitis) or parasitic (Giardia (Giardia) or Amoeba (amoeba), such as Di Pasi inner amoeba (Entamoeba dispar is called entamoeba tetragena (Entamoeba histolytica) before); Or fellow.
Therefore, in various embodiments, there is the disorderly individuality of NK cell-response and can need the treatment for the infection causing following person: the acute bacterial of upper respiratory tract bacterial infection, chronic bronchitis worsens; Acute Community acquired pneumonia, highmore antrum pathogenic bacteria; Urinary tract infection; Or property infects infection.
It is believed that method of the present invention can be effective in the individuality that treatment has viral infection especially.Therefore, in various embodiments, the individuality having NK cell-response disorderly can need for the treatment from the such as infection of the virus of following person: pico+ribonucleic acid+virus (Picornavirus) (such as, poliomyelitis virus, rhinovirus, and some according to coe virus (echovirus) and Ke Shaqi virus (coxsackievirus)); Small virus section (Parvoviridae) (mankind's small virus B19); Hepatitis, such as liver DNA (desoxyribose nucleic acid) virus (Hepadnavirus) (viral hepatitis type b); Papovavirus (Papovavirus) (JC virus); Adenovirus (human adenovirus); Simplexvirus (such as, the huge virus of cell (Cytomegalo), Chinese mugwort Epstein-Ba Er Er Shi virus (Epstein Barr virus) (monocyte increase disease), class monocyte increase disease syndrome, roserash (Roseola Infantum), varicella zoster virus (chicken pox), zoster (zoster (Shingles)), hsv (oral area bleb, genital herpes)), poxvirus (smallpox); Ka Lixi virus (Calicivirus) (Norwalk virus (Norwalkvirus)), arthropods Portability virus (Arbovirus) (such as Togavirus (Togavirus) (german measles virus, dengue fever virus), flavivirus (Flavivirus) (yellow fever virus), bunyavirus (Bunyavirus) (California encephalitis), reovirus (Reovirus) (rotavirus (Rotavirus)); Coronavirus (Coronavirus) (coronavirus); Retrovirus (the 1st type Human Immunodeficiency virus, the 2nd type Human Immunodeficiency virus); Rhabdovirus (Rhabdovirus) (rabies virus), inovirus (Filovirus) (diseases of Marburg virus (Marburgvirus), Ebola virus, other hemorrhagic virals); Paramyxovirus (Paramyxovirus) (Measles virus, mumps virus); Positive myxovirus (Orthomyxovirus) (influenza virus); Sand shape virus (Arenavirus) (lassa fever); I and II type Human T-cell is addicted to lymphoma virus (HTLV-I, HTLV II); Human papillomavirus (HPV); Or fellow.Therefore, in various embodiments, individuality can have by the infection being selected from following virus and causing: pico+ribonucleic acid+virus; Small virus section; Hepatitis virus; Papovavirus; Adenovirus; Simplexvirus, poxvirus; Ka Lixi virus; Arthropods Portability virus; Coronavirus; Retrovirus; Rhabdovirus; Paramyxovirus; Positive myxovirus; Sand shape virus; Human T-cell is addicted to lymphoma virus; Human papillomavirus; And Human Immunodeficiency virus.
In some embodiments, have NK cell-response disorderly individuality can need for such as, from the infection of virus or its treatment infected, Human Immunodeficiency virus-1, Human Immunodeficiency virus-2, the huge virus of cell, Chinese mugwort Epstein-Ba Er Er Shi virus, class monocyte increase disease syndrome, rose fever, varicella zoster virus, zoster, hsv or hepatitis.
It is believed that method of the present invention can be effective in the individuality that treatment has parasitic infection especially.Therefore, in various embodiments, there is the treatment that the disorderly individuality of NK cell-response can need for the infection from following person: plasmodium (Plasmodium) (such as, plasmodium falciparum (Plasmodiafalciparum), Plasmodium vivax (Plasmodia vivax), Plasmodium ovale (Plasmodia ovale), with malariae (Plasmodia malariae), typically by malarial mosquito propagate), leishmaniasis (Leishmania) (is propagated by chaff mosquito and is caused by protobiont in the cell of such as necessity of following person: Leishmania donovani (Leishmania donovani), leishmania infantum (Leishmaniainfantum), summer Coriolis leishmania (Leishmania chagasi), leishmania mexicana (Leishmania mexicana), Leishmania amazonensis (Leishmania amazonensis), Venezuela leishmania (Leishmania venezuelensis), crithidia cunninghami (Leishmaniatropica), leishmania major (Leishmania major), according to a rope sub-leishmania (Leishmania aethiopica), and subgenus Viannia, leishmania brasiliensis (LeishmaniaViannia braziliensis), Guyana leishmania (Leishmania Viannia guyanensis), Panamanian leishmania (Leishmania Viannia panamensis) and leishmania peruviana (Leishmania Viannia peruviana)), vertebra Eimeria (Trypanosoma) (such as, by Bu Shi castellanella gambiense (Trypanosoma brucei gambiense), the nona that causes with Bu Shi Trypanosoma rhodesiense (Trypanosoma brucei rhodesiense)), the Amoeba of the genus of Nai Geli Amoeba (Naegleria) or sour jujube Amoeba (Acanthamoeba), the pathogeny body of the genus of inner amoeba (Entamoeba) (entamoeba tetragena and Di Pasi inner amoeba), Giardia lamblia (Giardia lamblia), hidden sporozoite Eimeria (Cryptosporidium), isospora belongs to (Isospora), Cyclospora belongs to (cyclospora), microsporidium (Microsporidia), roundworm (Ascarislumbricoides), there is bilharzia and belong to (Schistosoma) (such as, Egyptian bilharzia (S.haematobium), graceful Sen Shi bilharzia (S.mansoni), schistosoma japonicum (S.japonicum), the public bilharzia (S.mekongi) of river bank, interleave bilharzia (S.intercalatum)) the infection of blood fluke, bow parasitosis (such as, bending worm (Toxoplasma gondii)), treponema pallidum, vagina flagellum trichomonad, or fellow.
In some embodiments, the individuality having NK cell-response disorderly can have the infection caused by the protobiont being selected from following person: bow worm, Bu Shi castellanella gambiense, Bu Shi Trypanosoma rhodesiense, Leishmania donovani, leishmania infantum, the summer Coriolis leishmania, leishmania mexicana, Leishmania amazonensis, Venezuela leishmania, crithidia cunninghami; Leishmania major; According to a rope sub-leishmania; And subgenus Viannia, leishmania brasiliensis, Guyana leishmania, Panamanian leishmania, leishmania peruviana, plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and malariae.
In a upper century, developed the many microbiotic causing mortality ratio obviously to reduce.Unfortunate, widely use the generation that microbiotic has caused antibiotic-resistant bacteria, such as Methicillin Resistive Staphylococcus Aureus (MRSA), Vancomycin resistant faecalis (VRE), with penicillin-resistant S suis (PRSP).The antibiosis of some bacteriums to a certain scope have resistance, such as, to isoniazid, Rifampin (rifampin), Tibutol (ethambutol), Streptomycin sulphate, ethionamide (ethionamide), health mycin, have the mycobacterium tuberculosis strain of resistance with Mycobutin (rifabutin).Except resistance, the region of relatively unknown bacterium self-isolation is disseminated to new group by whole world travelling.In addition, these bacteriums are had to be used as the threat of biological weapon.These bacteriums possibly cannot use existing antibiotic therapy easily.
It is believed that compound of the present invention can effective especially in for individual treatment drug-resistance pathogeny body (such as drug-resistant bacterial) or to its without medicine can pathogeny body (such as much virus).Be not intended to be limited to theory, it is believed that because compound of the present invention can be had an effect by increase NK cytoactive, and therefore NK cell can kill infective micro-organisms or infected cell (except compound to pathogeny body or infected cell any direct acting except).Therefore, it is believed that compound of the present invention can have at least one and typical anti-infection property medicine (such as typically can directly to the microbiotic that bacterium itself is had an effect) distinguishing binding mode.
Drug resistance pathogeny body and can typically be various and has resistance at least one, such as drug-resistant bacterial can have resistance to the microbiotic of a kind of such as following person or the antibiosis typically being at least two kinds of such as following persons: penicillin, methicillin, second generation cephalosporin (such as, cefuroxime (cefuroxime) and fellow), huge cyclic lactone, tsiklomitsin, trimethoprim/first oxazole (trimethoprim/methoxazole), vancomycin or fellow.Such as, in some embodiments, can be the bacterium that individual treatment is selected from following strain: multiple drug resistance streptococcus pneumoniae (MDRSP, front be called Penicillin Resistant S suis, PRSP), Vancomycin resistant faecalis, Methicillin Resistive Staphylococcus Aureus, Penicillin Resistant S Diplococcus (Pneumococcus), antibiotics resistance salmonella spp, resistance and multiple resistance gonorrhea diplococcus are (such as, to tsiklomitsin, penicillin, fluoro quinolinone, cynnematin, ceftriaxone (ceftriaxone) (Rocephin), Cefixime Micronized (Cefixime) (Suprax), azithromycin (Azithromycin), or the one of fellow, two kinds, or multiplely have resistance), and resistance and multiple-resistance tuberculosis (such as, vazadrine (isoniazid), Rifampin, Tibutol, Zinamide, aminoglycoside, capromycin (Capreomycin), Ciprofloxacin (Ciprofloxacin), Ofloxacine USP 23 (Ofloxacin), gemifloxacin (gemifloxacin), seromycin, ethionamide, the one of para-aminosalicylic acid or fellow, two kinds, or multiplely have resistance).
In some embodiments, NK cytoactive can be increased in the individuality with immunological incompetence.In various embodiments, this can have its source in that reduce or defective NK cytoactive.In some embodiments, immunological incompetence is any known immunological incompetence, even those directly do not produce Dasher to NK cell.Be not intended to be limited to theory, it is believed that the short NK cytoactive that rises can improve immunologic function with in " supplying (make-up) " at least part of immunological incompetence, except the aspect that those are directly involved in NK cytoactive in many immunological incompetence illnesss.
In various embodiments, immunological incompetence disease can comprise have increase to the disease of susceptibility infected, be such as one or morely selected from following disease: cyclicity and systemic disease (anemia sickle cell disease, diabetes, ephrosis, varix, congenital heart defects); Occlusive disease (Eustachische Roehre of ureter or urethrostenosis, bronchial asthma, bronchiectasis, allergic rhinitis, obstruction); The defect (eczema, burn, fracture of the skull, center line Dou Shu (midline sinus tracts), cilium are abnormal) of skin; Primary immunodeficiency (X-cognation Hypogammaglobulinemia (agammaglobinemia), DiGeorge abnormal (DiGeorge anomaly), chronic granulomatous disease, C3 deficiency); Secondary property immune deficiency (nutritional trouble, precocity, lymphoma, splenectomy, uremia, immunosuppressant therapy, protein-forfeiture property enteropathy change, chronic viral diseases); The non-usual microbes factor (microbiotic hypertrophy, have resistant organisms chronic infection, infect again continuously (water supply of pollution, infectious contact, the Inhalation in Treating equipment that pollutes)); Foreign body, wound (ventricular shunt (ventricular shunt), central vein catheter, artificial heart do the foreign body of film, catheter, sucking-off) allotransplantation, transplanting-to anti-host disease, uterine dysfunction (such as, endometriosis) or fellow.
In various embodiments, immunological incompetence disease can comprise (such as) infantile temporary Hypogammaglobulinemia, selective IgA deficiency, X-cognation Hypogammaglobulinemia (BrutonShi Hypogammaglobulinemia, congenital Hypogammaglobulinemia), common variability immunological incompetence (common variable immunodeficiency) (the Hypogammaglobulinemia day after tomorrow), height-IgM (hyper-IgM) immunological incompetence, IgG type flaw, chronic mucocutaneous candidiasis (Candidiasis), associativity immunological incompetence, Wiskott-Aldrich syndrome, ataxia-telangiectasis disease, X-cognation lymphoproliferative syndrome, height-IgE (hyper-IgE) syndrome (Job-Buckley syndrome), chronic granulomatous disease, white cell adhesion defect (MAC-1/LFA-1/CR3 defect), or fellow.
In various embodiments, immunological incompetence disease can comprise primary immunological incompetence disease, such as: B-cell (antibody) defect (X-cognation Hypogammaglobulinemia, there is the Ig defect (XL) of height-IgM, IgA defect), IgG type flaw, there is antibody deficiency, the immunological incompetence with thymoma, common variability immunological incompetence, the infantile temporary Hypogammaglobulinemia of Ig that is normal or that improve), (significance T-cell defect: DiGeorge is abnormal for T-cell (cellularity) defect, chronic mucocutaneous candidiasis, there is the associativity immunological incompetence (Nezelof syndrome) of Ig, nucleosides phosphinylidyne enzyme defect (AR), natural killer cell defect, idiopathic CD4 lymphopenia, associativity T-and B-Cell binding: serious combined immunological incomplete (AR or XL), adenosine deaminase defect (AR), reticular dysgenesis (Reticular dysgenesis), bare lymphocyte syndrome (bare lymphocytesyndrome), ataxia-telangiectasis disease (AR), Wiskott-Aldrich syndrome (XL), short-limb dwarfism disease, XL lymphoproliferative syndrome), phagocytic cell disease (defect of cell movement: the defect of hyperimmunoglobulinemia E syndrome, the 1st type white cell adhesion defect (AR), microbiocidal activity: chronic granulomatous disease (XL or AR), neutrophil(e) cell G6PD defect, myeloperoxidase deficiency (AR), Xie Diyake-Dong Er Shi syndrome (Chediak-Higashi syndrome) (AR)), complement disease (defect of complement integrant: the defect of C1q defect, control albumen: C1 suppresses sub-defect (D1), factor I (C3b inactivation) defect (ACD), factor H defect (ACD), factor D defect (ACD), properdin (Properdin) defect (XL)), or fellow.
In various embodiments, immunological incompetence disease can comprise time sends out property immunological incompetence disease, and such as one or more are selected from following illness: premature labor and ewborn infant (lead because of in immune jejune physiological immunological incompetence); Heredity and metabolic disease are (chromosome abnormalty (such as, Down syndrome), uremia, diabetes (namely, from the complication of diabetes, such as relevant to surrounding loop and abnormality of nerve function gangrene), nutritional trouble, VITAMIN and mineral deficiency, protein-forfeiture property enteropathy become, nephrotic syndrome, myotonia atrophica, anemia sickle cell disease); Immunosuppressor (radiation, immunosuppressive drug, reflunomide, antilymphocyte or antithymocyte globulin, anti-T-cell monoclonal antibody); Infectious diseases (congenital wind is examined, the disease of viral erythema (exanthema) (such as, measles, varicella), the huge virus infection of HIV, cell, infectious monocyte increase disease, acute bacterial, serious mycobacteria or the disease of fungi); Perviousness and blood disease (tissue ball increases, sarcoidosis, HodgkinShi sick with lymphoma, leukemia, myelomatosis, graininess ball deficiency disease, with meromorphosis anaemia); Operation with wound (burn, splenectomy, anesthesia, wound); And its other (SLE, chronic active hepatitis, alcoholic cirrhosis, aging, anticonvulsant drug, transplanting-to anti-host disease); Or fellow.
In some embodiments, there is the treatment that the disorderly individuality of NK cell-response can need for burn or wound.Typically, wound like this or burn are the grievous injuries immune defense of individuality being caused to significantly burden.Such as, in some embodiments, be for individual treatment cover the surface-area of individual health at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, or more secondary or three grades of burns.In addition, in some embodiments, be the one or more wound of individual treatment or wound, such as at least about 1cm
2, 2cm
2, 5cm
2, 10cm
2, 20cm
2, 50cm
2or larger, or 1% of the surface-area of individual health, 2%, 3%, 4%, 5%, 10%, 15%, or more open wound; Or the otch of one or more transdermal total length at least 1cm, 2cm, 3cm, 4cm, 5cm, 7cm, 10cm, 20cm, 25cm, 50cm; Amputation; And fellow.
In various embodiments, the individuality having NK cell-response disorderly can have the infection caused by antibiotic-resistant bacteria.In some embodiments, individuality can have the infection caused by the bacterium being selected from following person: multiple drug resistance streptococcus pneumoniae, Vancomycin resistant faecalis, Methicillin Resistive Staphylococcus Aureus, Penicillin Resistant S Diplococcus, antibiotics resistance salmonella spp, resistance/multiple-resistance gonorrhea diplococcus, with resistance/multiple-resistance tuberculosis.In some embodiments, individuality can have the bacterial infection that the antibiosis being selected from following person at least one have resistance: penicillin, methicillin, second generation cephalosporin, huge cyclic lactone, tsiklomitsin, trimethoprim/first oxazole, vancomycin, tsiklomitsin, fluoro quinolinone, ceftriaxone, Cefixime Micronized, azithromycin, vazadrine, Rifampin, Tibutol, Zinamide, aminoglycoside, capromycin, Ciprofloxacin, Ofloxacine USP 23, gemifloxacin, seromycin, ethionamide and para-aminosalicylic acid.
Therefore, various embodiment, the individuality with the disorder of NK cell response can have immunological incompetence disease.In some embodiments, individuality can have primary immunological incompetence disease.In some embodiments, individuality can have time property sent out immunological incompetence disease.
In some embodiments, immunological incompetence disease can comprise uremia, diabetes (its infection complication, nutritional trouble, VITAMIN and mineral deficiency, the protein property lost enteropathy become, nephrotic syndrome, myotonia atrophica, anemia sickle cell disease; Or fellow.
In some embodiments, immunological incompetence disease can be all or part of by immunosuppressor (such as radiation, immunosuppressive drug, reflunomide, antilymphocyte or antithymocyte globulin, anti-T-cell monoclonal antibody; Or fellow) cause.
In some embodiments, immunological incompetence disease can all or part of by operation and wound (such as burn, splenectomy, anesthesia, wound, the medical apparatus transplanted; Or fellow) cause.
In some embodiments, immunological incompetence disease can comprise chronic fatigue syndrome (chronic fatigue immune dysfunction syndrome); Epstein-Barr virus infection, post-viral fatigue syndrome, transplant after syndrome (host-transplant disease), be exposed to that nitric oxide synthase inhibitors, aging, serious combined immunological are complete, variability immunological incompetence disease group and fellow.
Increasing NK cytoactive can be also useful to treating the individuality with the disease including but not limited to neurodegenerative disorders.For herein, neurodegenerative disorders comprises the degraded of neurone (such as cerebellum, spinal cord, neurone (such as, being positioned at neuromuscular juncture) with surrounding), that be more typically brain with degraded that is spinal neuron.Neurodegenerative disorders can comprise Alzheimer's disease; Huntington chorea; Parkinson's disease; Spinal cord/bulbar muscular atrophy (such as, sweet is Di Shi sick), myeloid cerebral atrophy, with other neuromuscular atrophys; Familial amyotrophic inclined side sclerosis; Local asphyxia; Outbreak; Hypothermy; Hyperpyrexia; Burn; Atherosclerosis; Radioactive exposure; Glaucoma; Toxin exposure; Mechanicalness injures; Inflammation; Epileptic fits, injury-inducibility outbreak, chemically-inducibility outbreak or other relevant diseases of suddenling change to superoxide-dismutase (SOD); And fellow.Neurodegenerative disorders also can comprise the neuronic degraded caused by local asphyxia, outbreak, thermal pressure, radiation, toxin exposure, infection, injury and fellow.Local asphyxia can pass through multiple pathways (comprise oxygen depletion, glucose exhaust, Reperfu-sion time oxidative stress and/or glutamate toxicity and fellow) damaging tissue.Injury (the Reperfu-sion pressure such as, on transplant organ) and fellow that local asphyxia can be derived from endogenous illness (such as, apoplexy, heart attack and fellow), be derived from the injury of accident mechanicalness, is derived from operation.Selectively, neurone, cardiac muscle, liver organization, skeletal muscle, renal tissue, the tissue of lung, the tissue of pancreas and fellow can be comprised by the tissue of Ischemic lesions.
Other wherein increase NK cytoactive can be the disease that useful disease comprises due to following person: thermal pressure (thermal pressure comprises hyperpyrexia (such as, from fever, heatstroke, burn and fellow) and hypothermy); Radiation damage, such as due to visible ray, UV-light, microwave, Millikan's rays, α radiation, β radiation, the radiation of character used in proper names and in rendering some foreign names horse, X-ray and fellow person's (such as, the radiation damage of infringement to the non-cancerous tissue in the individuality by radiation therapy Therapeutic cancer); Mechanicalness injures, such as, from the wound of operation, unexpected, some disease states (pressures compromises such as, in glaucoma) and fellow; Be exposed to toxin, be such as exposed to the neurotoxin being selected from methamphetamine; HIV therapy (such as, the nucleoside reverse transcriptase inhibitors of anti-retroviral; Heavy metal (such as, mercury, lead, arsenic, cadmium, its compound and fellow), amino acid analogue, chemical oxidizing agent, ethanol, L-glutamic acid, metabolic inhibitor, microbiotic and fellow.
Another embodiment of the invention is a kind of method that treatment has the individuality of cancer.Optionally, method of the present invention can be used for multi-drug resistance cancer, as will be outlined below.The method comprises the formula (I) to (XVI) or the compound of table 1 or the step of its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug that give significant quantity.Preferably, one or more extra cancer therapy drug be total to-gives with compound of the present invention.The example of cancer therapy drug describes in following.Preferably, the cancer therapy drug that is total to-gives be can the agent of stabilization microtubule, such as eliminate cancer victory
or taxanes derivative.
Specified by above, an embodiment of the invention are the individualities about treatment with cancer." treatment has the individuality of cancer " comprises (partly or essence Shangdi) reaches one or more following person: prevent the growth of cancer or distribution, reduction cancer degree (such as, reduce the size of tumour or reduce the number of influenced position), suppress the growth rate of cancer, with improve or improve sign relevant with cancer clinically or index (such as organizing or serum integrant).
In another embodiment, compound of the present invention can be used as assisting therapy to the recurrence giving preventing cancer.Such as, II phase and III phase melanoma typically with operative treatment to shift out melanoma, then the treatment of chemotherapy is with the recurrence of preventing cancer.In one embodiment, one or more extra cancer therapy drug be total to-gives as assisting therapy with compound of the present invention.The example of cancer therapy drug describes in following.In one embodiment, the cancer therapy drug that is total to-gives be can the agent of stabilization microtubule, such as eliminate cancer victory
or taxanes derivative.In another embodiment, the cancer therapy drug that is total to-gives be immunotherapeutical carcinostatic agent.
Human sarcoma and cancer can be included, but are not limited to, such as fibrosarcoma by the cancer of method treatment of the present invention or prevention, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, EwingShi tumour, leiomyosarcoma, rhabdosarcoma, the rectum cancer, carcinoma of the colon and rectum, anus cancer, esophagus cancer, cancer of the stomach (gastric cancer), hepatocellular carcinoma, bladder cancer, carcinoma of endometrium, cancer of pancreas, breast cancer, ovarian cancer, prostate cancer, cancer of the stomach (stomach cancer), atrial myxoma, squamous cell carcinoma knurl, rodent cancer, gland cancer, syringocarcinoma, sebaceous carcinoma, Tiroidina and Parathyroid true tumor (neoplasm), papillary carcinoma, papillary carcinoma, cystadenocarcinoma, medullary substance cancer, the former cancer of tracheae, kidney cell cancer, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, spermocytoma, tire cancer, WilmsShi knurl, cervical cancer, the tumour of testis, lung cancer, small cell lung cancer, nonsmall-cell lung cancer, bladder cancer, epithelial cancer, neuroglia knurl, pituitary gland true tumor, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic tumor, schwannoma, few dendron glioma, meningioma, spinal cord knurl, melanoma, spongioblastoma, pheochromocytoma, 1-3 type incretory gland true tumor is formed, retinoblastoma, leukemia, such as, acute lymphoblastic leukemia and acute myelogenous leukemia (bone marrow blasts, progranulocyte, bone marrow mononuclear cell, monocarpotic cellularity, erythroleukemia), chronic leukemia (chronic myeloid (granular cell) leukemia and chronic lymphocytic leukemia), and true property erythrocytosis, lymphoma (the sick and non-HodgkinShi of HodgkinShi is sick), multiple myeloma, WaldenstrobmShi macroglobulinemia and heavy chain disease.
Other examples leukemic comprise acute and/or chronic leukemia, such as, Lymphocytic leukemia (such as, as p388 (muroid) cell be as illustrated in person), large granular lymphocyte leukemia and lymphoblastic leukemia; T-chronic myeloid leukemia, such as, T-chronic myeloid leukemia (such as, as CEM, Jurkat, with HSB-2 (acute), YAC-1 (muroid) cell be as illustrated in person), T-Lymphocytic leukemia, with T-lymphoblastic leukemia; B cell leukemia (such as, as SB (acute) cell be as illustrated in person), with B-Lymphocytic leukemia; Cell mixing leukemia, such as, B and T cell leukemia and B and T Lymphocytic leukemia; Myelomatosis, such as, granulosa cell leukemia, myelocytic leukemia (such as, as HL-60 (primitive marrow cell) cell be as illustrated in person), with haematogonium leukemia (such as, as K562 (chronic) cell be as illustrated in person); Neutrophils leukemia; Addicted to eosin white cell leukemia; Monocytic leukemia (such as, as THP-1 (acute) cell be as illustrated in person); Myelomonocyte leukemia; Naegeli type shape myeloid leukemia; With non-lymphocytic leukemia.Other leukemic examples are described in The Chemotherapy Sourcebook, Michael C.Perry Ed., Williams & Williams (1992) the 60th chapter and Holland Frie Cancer Medicine the 5th edition, the people Eds. such as Bast, B.C.Decker Inc. (2000) Section 36.The entire teachings of aforementioned cited literature 2 includes in herein with way of reference.
Oral cavity and pharynx cancer can be included, but are not limited to by the extra cancer of method of the present invention treatment or prevention, comprise tongue, mouth, pharynx, and other mouth cancers; Cancer in digestive system, comprise oesophagus, small intestine, rectum, anus, anus road, anal orifice and rectal intestine, liver and stones in intrahepatic bile duct, gall-bladder relevant with other courages, pancreas and other digestion organs; Respiratory system cancer, comprises larynx and segmental bronchus; B&J cancer; Soft tissue (comprising heart) cancer; Reproductive system cancers, comprises uterine cervix, body of uterus, ovary, vaginal orifice, vagina is relevant to other reproductive organ, female, testis, other reproductive organ of penis and other are relevant, male; Urinary system cancer, comprises kidney and renal plevis and ureter and other urinary organs; Eye and eyeball cancer; Leukemia, comprises acute myelogenous leukemia and chronic lymphocytic leukemia.
In one embodiment, the method disclosed is considered to be effective in the individuality that treatment has non-solid tumors (such as multiple myeloma) especially.In another embodiment, the method disclosed is considered to T-leukemia (such as, illustrated person by Jurkat and cem cell), B-leukemia (such as, illustrated person by SB cell), progranulocyte (promyelocyte, such as, illustrated person by HL-60 cell), sarcoma of uterus (such as, illustrated person by MES-SA cell), monocytic leukemia (such as, illustrated person by THP-1 (acute) cell) and lymphoma (such as, be illustrated person by U937 cell) be especially effective.
In another embodiment, the method disclosed is considered to be effective in the individuality that treatment has Immune Sensibility cancer especially.Immune Sensibility cancer is the cancer to using the treatment of immunotherapy to respond.Immunotherapy more describes in detail in following.The cancer that immunotherapy is responded comprise kidney cell cancer, melanoma (comprise surface distribution melanoma, nodular melanoma, acra mole sample melanoma (acral lentiginous melanoma), freckle malignant melanoma (lentigo malignamelanoma), it is also referred to as HutchinsonShi spot), multiple myeloma, myelomatosis, lymphoma, non-little-cell lung cancer, squamous cell knurl, rodent cancer, fibrosarcoma and malignant brain tumor.
In another embodiment, the method disclosed is considered to be effective in treatment especially and has melanomatous individuality.
In another embodiment, the method disclosed is considered to be effective in the individuality that treatment has kidney cell cancer especially.
The method disclosed is effective in the individuality that its cancer for the treatment of becomes " multiple drug resistance " especially.When a kind of cancer therapy drug no longer valid in treat there is cancer individual time, this cancer can reacted this cancer therapy drug at first becomes has resistance to this cancer therapy drug.Such as, many tumours play first meeting and separate slow mode to the therapeutic response using cancer therapy drug, to develop the resistance to this medicine to make size reduce or even to become.The feature of drug-resistant tumors be seem to transfer to separate slow after recover again their growth again and/or occur again, even if this anticancer medicine giving to increase dosage is also like this.Develop and the cancer of the resistance of two or more cancer therapy drug has been called " multiple drug resistance ".Such as, be transformed into and have resistance to be common to cancer for three kinds or multiple carcinostatic agent, it is planted carcinostatic agents to five kinds or more often and has resistance, and sometimes plants carcinostatic agents to ten kinds or more and have resistance.
Numerous non-Cancerous disease comprises superfluous or hyperproliferative cell growth, is called hyperplasia.For herein, term " proliferative disease ", " hyperproliferative disease ", be the disease that grows of the pathology being used interchangeably to mean to comprise cell or medical conditions with " cell proliferative diseases ".Disease like this comprises cancer.
The carcinous proliferative disease of non-comprises smooth muscle cell proliferation, Systemic sclerosis, the sclerosis of liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, such as diabetic retinopathy or other retinopathys, cardiac hyperplasia, reproductive system are diseases related, such as benign prostate hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, choristoma, Lymphangiomatosis, sarcoidosis, fibroma durum and fellow.
Smooth muscle cell proliferation comprises proliferative vascular disease, such as, intimal smooth muscle cells hyperplasia, restenosis and vascular occlusion, that particularly follows after the blood vessel injury of biological or physical property mediation is narrow, such as, relevant to blood vessel prosthesis blood vessel injury or angiostenosis.In addition, intimal smooth muscle cells hyperplasia can be included in the hyperplasia of the outer unstriated muscle that blood vessel is, such as, closes at bile duct, is having the segmental bronchus air flue of the lung of the patient of asthma, having the kidney of patient and the hyperplasia of fellow of kidney region fibrosis.
The carcinous proliferative disease of non-is also included in the cell hyperplasia of skin, such as psoriasis with it various clinical form, ReiterShi syndrome, pityriasis rubra red pityriasis, with hyperproliferative variants's (such as, actinic keratoses, senile keratosis) of keratinization disease, scleroderma (scleroderma) and fellow.
Other anti-proliferate or anticancer therapy can be combined with compound of the present invention, to treat proliferative disease and cancer.The other treatment that can be combined with invention carcinostatic agent of the present invention or carcinostatic agent comprise operation, radiation cure (comprises, but be not limited to, γ-radiation, neutron beam radiation cure, electron beam evaporation line is treated, proton therapeutic, close to treatment, with general radioactive isotope), endocrine therapy, biological respinse amendment (comprises, but be not limited to, Interferon, rabbit, interleukin, with tumour necrosis factor (TNF)), pyroprocessing (hyperthermia), with cold therapy, weaken the agent of any deleterious effects (such as, antiemetic), the chemotherapeutics of permitting with other.
Preventative or the therapeutic agent of combined treatment of the present invention can give in order or side by side.
For herein, term " pyroprocessing ", " pyroprocessing treatment ", " heat cure (thermaltherapy) ", with " heat cure (thermotherapy) " be use interchangeably, to mean the treatment that wherein bodily tissue is exposed to high temperature (to as many as 113 °F).For herein, this term comprises the pyroprocessing of form of ownership, comprise local, (regional) at position, with whole body.Various forms of energy can be used for sending heat such as, to desired region, microwave, radiation frequency, laser and ultrasound.Treatment temperature changes with the approach used according to the position of tumour.
In the pyroprocessing of local, heat is administered to zonule (such as tumour).Method for localized hyperthermia's process changes according to knub position.Outside approach be used for the treatment of in skin or be next to skin under tumour.In this method, medicator places near tumour or is placed in tumor vicinity, and direct delivery of energy is to tumour.In chamber or body intracavitary route use probe with in delivery of energy to body cavity or near the tumour of body cavity.Chromic fibrous approach is used for the treatment of the tumour (such as cerebral tumor) being positioned at body deeply, and it is by under anaesthesia probe or pin being inserted into tumour.
In the pyroprocessing at position, heat is the tissue (such as body cavity, organ or limbs) being applied to large regions.Deep tissue approach is the cancer (such as neck or bladder cancer) for the treatment of in body, and it is by using outside medicator.The perfusion approach at position is the cancer (such as melanoma, liver or lung cancer) for the treatment of in limbs or organ.In this approach, some blood are moved out of and heat, and then blowback limbs or organ.Cancer therapy drug can administration in the process.Continuous high temperature process peritoneal perfusion (CHPPContinuous hyperthermic peritoneal perfusion) is in order to the cancer (the middle rind gall of such as peritonaeum or cancer of the stomach) for the treatment of in abdominal cavity.In this approach, the cancer therapy drug through heating passes through aspiration of abdominal cavity.
Whole-body hyperthermia process is used for the treatment of metastatic cancer.In this approach, whole body is heated to 107-108 °F by the various technology of use (such as hot cell (heat chamber) or hot water blanket).
Pyroprocessing condition has notified the synthesis bringing out Hsp70.
" significant quantity " is the amount of the compound that wherein can reach useful clinical effectiveness when compound is given individuality.Such as, when compound of the present invention be given there is cancer individual time, " useful clinical effectiveness " is included in individuality (compared to lacking this treatment) in the minimizing of tumor quality, minimizing in transfer, the minimizing in the seriousness of the sign relevant to cancer and/or the increase in the life-span.When compound of the present invention be given there is the disorderly or NK cell-response of Hsp70-response disorderly individual time, " useful clinical effectiveness " is included in individuality (compared to this treatment of shortage) in the seriousness of the sign with disease-related or the minimizing of number, the eliminating of infection or the increase in life-span.Give the accurate amount of individual compound, can according to the type of disease or illness and seriousness, and according to the feature of individuality, such as general health, the age, sex, body weight, with the patience to medicine.It also can according to the degree of cancer, seriousness and type.Be familiar with this operator and can determine suitable dosage according to these and other factor.The significant quantity of the compound disclosed typically falls between about 1mg/mm
2every day and about 10 grams/mm
2the scope of every day, and preferably between 10mg/mm
2every day and about 5 grams/mm
2.When with another carcinostatic agent altogether-to when giving Therapeutic cancer, " significant quantity " of the second carcinostatic agent can determine according to the type of used medicine.The dosage be applicable to of approved carcinostatic agent is known, and can by being familiar with the illness of this operator according to individuality, the type for the cancer for the treatment of, and the compound of the present invention that uses and adjusting.
Another embodiment of the invention is pharmaceutical composition, and it comprises compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug) and pharmaceutically acceptable supporting agent or thinner.
The pharmaceutically acceptable supporting agent be applicable to can comprise can not the bioactive inert fraction of exceedingly Inhibitor.Pharmaceutically acceptable supporting agent should be bio-compatible, that is, atoxic, non-inflammatory, non-immunogenicity, and not to have the reaction of other not wishs when giving individuality.The pharmaceutical formulation technology of standard can be used, such as they in Remington ' s Pharmaceutical Sciences, MackPublishing Company, person described in Easton, PA.The pharmaceutical carrier be applicable to given for parenteral comprises (such as) sterilized water, normal saline solution, antibacterial salt solution (comprising the salt solution of about 0.9%mg/ml benzyl alcohol), phosphate buffer saline, HankShi solution, RingerShi lactic acid salt and fellow.The method of (such as in the coating of glutoid or ring dextran) is the known (people such as Baker in technical field for being enclosed by constituent in capsule, " Controlled Release of Biological ActiveAgents ", John Wiley and Sons, 1986).
Compound of the present invention can give by any applicable approach, and it is oral in capsule, suspension or tablet or give by parenteral that it comprises (such as).Parenteral gives to comprise (such as) general and gives, such as, by intramuscular, intravenous, subcutaneous or endoperitoneal injection.Compound of the present invention also can orally (such as, diet ground), give partly, by suction (such as, in segmental bronchus, in nose, oral area sucks or intranasal drops) or rectum ground, it is according to the type of the cancer for treating.Oral area and parenteral preferably give pattern.
Many novel drugs are had to can be the tumour scholar patient for treatment with cancer used at present.Often, when cancer therapy drug be combination give time, tumour comparatively more responds to treatment when identical medicine is indivedual and sequentially gives.The advantage of this method be carcinostatic agent often for act on synergistically because tumour cell is simultaneously to have the various effect of various modes.Therefore, give these medicines by combination and often may reach minimizing in tumor size more fast.Another advantage in conjunction with chemotherapy is that tumour more may be eradicated entirely and the more impossible resistance developed the cancer therapy drug being used for the treatment of patient.
Optionally, compound of the present invention (or its tautomer, pharmacy acceptable salt, solvate, inclusion compound or prodrug) can with other carcinostatic agents of such as following person altogether-to the patient giving treatment and have proliferative disease (such as cancer), or to prevent the recurrence of proliferative disease (such as cancer): A Deli mycin (Adriamycin), gengshengmeisu (Dactinomycin), bleomycin (Bleomycin), vincaleucoblastine, Platinol, U 42126 (acivicin); Aclacnomycin A (aclarubicin); Hydrochloric acid acodazole (acodazole hydrochloride); Acronine (acronine); U 73975 (adozelesin); RIL-2 (aldesleukin); Altretamine; Duazomycin C (ambomycin); Acetic acid ametantrone (ametantrone acetate); Aminoglutethimide (aminoglutethimide); Amsacrine (amsacrine); Anastrozole (anastrozole); Anthramycin (anthramycin); L-asparagine; Asperline (asperlin); Azacitidine (azacitidine); Ah letter's TEPA (azetepa); Azotomycin (azotomycin); Cling to terraced horse Stuart (batimastat); Benzodepa (benzodepa); Than card Rumi (bicalutamide); Bisantrene hydrochloride (bisantrene hydrochloride); Two methylsulfonic acid Bisnafides (bisnafide dimesylate); U 77779 (bizelesin); Bleomycin sulfate; Brequinar sodium (brequinar sodium); Bropirimine (bropirimine); Busulfan (busulfan); Sanarnycin (cactinomycin); U-22550 (calusterone); Caracemide (caracemide); Carbetimer (carbetimer); Carboplatin; Carmustine (carmustine); Hydrochloric acid carminomycin I (carubicinhydrochloride); U 80244 (carzelesin); Cedefingol (cedefingol); Chlorambucil (chlorambucil); U 12241 (cirolemycin); Carat monarch is precious; Methylsulfonic acid Ku Lisinietuo (crisnatol mesylate); Endoxan; Cytosine arabinoside; NSC-45388; Daunorubicin hydrochloride; Decitabine (decitabine); U 78938 (dexormaplatin); Guanine (dezaguanine) is pricked on ground; Guanine is pricked on methylsulfonic acid ground; Diaziquone (diaziquone); Zorubicin (doxorubicin); Doxorubicin hydrochloride; Droloxifene (droloxifene); K-21060E; Propionic acid is bent him and is tieed up ketone (dromostanolone propionate); Duazomycin (duazomycin); Edatrexate (edatrexate); Vaniqa (eflornithine hydrochloride); Elsamitrucin (elsamitrucin); Enloplatin (enloplatin); Enpromate (enpromate); Epipropidine (epipropidine); Epirubicin hydrochloride (epirubicin hydrochloride); R 55104 (Erbulozole); Esorubicin hydrochloride (esorubicin hydrochloride); Estramustine (estramustine); Estramustine phosphate sodium; Etanidazole (etanidazole); Etoposide; Etoposide phosphate; Rely on and send (etoprine); CGS-16949A (fadrozole hydrochloride); Fazarabine (fazarabine); Fenretinide (fenretinide); Floxuridine (floxuridine); Fludarabine phosphate; Fluracil; Flurocitabine (flurocitabine); Fosquidone (fosquidone); Phosphotrienin sodium (fostriecin sodium); Gemcitabine; Gemcitabine hydrochloride; Hydroxyurea; Idarubicin hydrochloride (idarubicin hydrochloride); Ifosfamide; Thio ALP (ilmofosine); Interleukin I I (comprising recombinant interleukin II or rIL2), Intederon Alpha-2a; Interferon Alpha-2b; Interferon alfa-n1; Alferon N; Interferon beta-I a; Interferon, rabbit Jia Ma-I b; Iproplatin (iproplatin); U 101440E (irinotecan hydrochloride); Lanreotide acetate (lanreotide acetate); Hold in the palm azoles (letrozole); Bright third Reed of acetic acid (leuprolide acetate); Liarozole hydrochloride (liarozole hydrochloride); Lometrexol sodium (lometrexol sodium); Lomustine (lomusitne); Losoxantrone hydrochloride (losoxantrone hydrochloride); Masoprocol (masoprocol); Maytenin (maytansine); Mustine hydrochlcride (mechlorethamine hydrochloride); Magace (megestrol acetate); Melengestrol acetate (melengestrol acetate); Melphalan (melphalan); Menogaril (menogaril); Purinethol; Methotrexate; Methotrexate sodium; Beautiful Trotskyite (metoprine); Meturedepa (meturedepa); Mitindomide (mitindomide); meter Tuo Kaxin (mitocarcin); Rice holder Crow bright (mitocromin); Mitogillin (mitogillin); Mitomalcin (mitomalcin); Mitomycin (mitomycin); Mitosper (mitosper); Mitotane (mitotane); Mitoxantrone hydrochloride (mitoxantrone hydrochloride); Mycophenolic Acid (mycophenolic acid); R 17934 (nocodazole); Nogalamycin (nogalamycin); Ormaplatin (ormaplatin); Oxisuran (oxisuran); Accompany a winter enzyme (pegaspargase); Peliomycin (peliomycin); Neptamustine (pentamustine); Sulfuric acid nogalamycin (peplomycinsulfate); Perfosfamide; Pipobroman (pipobroman); Piposulfan (piposulfan); Hydrochloric acid piroxantrone (piroxantrone hydrochloride); Plicamycin (plicamycin); Plomestane (plomestane); Porfimer sodium (porfimer sodium); Porfiromycin (porfiromycin); PM (prednimustine); Procarbazine hydrochloride; Puromycin (puromycin); Puromycin hydrochloride; Pyrazofurin (pyrazofurin); Riboprine (riboprine); Rogletimide (rogletimide); Safingol (safingol); Hydrochloric acid Safingol (safingol hydrochloride); Semustine (semustine); Simtrazene (simtrazene); This Paphos acid sodium (sparfosate sodium); Sparsomycin (sparsomycin); Hydrochloric acid germanium spiral shell ammonium (spirogermanium hydrochloride); Spiromustine (spiromustine); Spiroplatin (spiroplatin); Rufochromomycin (streptonigrin); Streptozocin (streptozocin); Sulofenur (sulofenur); Talisomycin (talisomycin); Iron can gallon sodium (tecogalan sodium); Tegafur (tegafur); Teloxandrone hydrochloride (teloxantroneHydrochloride); Temoporfin (temoporfin); Teniposide; Teroxirone (teroxirone); Testolactone; ITG (thiamiprine); Tioguanine; Tespamin (thiotepa); Tiazofurine (tiazofurin); Win-59075 (tirapazamine); FC-1157a (toremifene citrate); Acetic acid trestolone (trestolone acetate); Phosphoric acid triciribine (triciribine phosphate); Trimetrexate (trimetrexate); Glucuronic acid trimetrexate; Triptorelin (triptorelin); Tubulozole hydrochloride (tubulozole Hydrochloride); Uracil mustard (uracil mustard); Urethimine (uredepa); Vapreotide (vapreotide); Visudyne (verteporfin); Vinblastine Sulfate; Vincristine sulphate; Vindesine; Vindesine sulfate; Sulfuric acid vinepidine (vinepidine sulfate); Sulfuric acid vinglycinate (vinglycinate sulfate); Sulfuric acid vinleurosine (vinleurosinesulfate); Vinorelbine tartrate; Sulfuric acid vinrosidine (vinrosidine sulfate); Sulfuric acid vinzolidine (vinzolidine sulfate); Vorozole (vorozole); Outstanding Buddhist nun's platinum (zeniplatin); Zinostatin (zinostatin); Zorubicin hydrochloride (zorubicin hydrochloride).
Other can with compound of the present invention be combined to treat there is proliferative disease (for example cancer) patient or with the medicine of recurrence of prevention proliferative disease (for example cancer), include, but is not limited to: 20-shows-1,25 dihydroxy vitamin d3s; 5-ethinyluracil; Abiraterone (abiraterone); Aclacnomycin A (aclarubicin); Acyl group fulvene (acylfulvene); A Disaipunuo (adecypenol); Adozelesin (adozelesin); Aldesleukin (aldesleukin); ALL-TK antagonist; Hemel; Ambamustine (ambamustine); A meter Da Kesi (amidox); Amifostine (amifostine); Amido levulic acid (aminolevulinic acid); Amrubicin (amrubicin); Amsacrine (amsacrine); Anagrelide (anagrelide); Anastrozole (anastrozole); Andrographolide (andrographolide); AI; Antagonist D; Antagonist G; An Talei makes every effort to overcome department (antarelix); Anti-dorsal part morphogenetic proteins-1; Antiandrogen, prostate cancer; Antiestrogenic; Antitumor same ketone (antineoplaston); ASON; Gly propylhomoserin aphidicolin ester (aphidicolin glycinate); Apoptosis gene conditioning agent; Apoptosis regulation agent; Apurinic nucleic acid; Arabinose-CDP-DL-PTBA; Spermine acid propylhomoserin deaminase; A Suleke indigo plant (asulacrine); Atamestane (atamestane); Atrimustine (atrimustine); Acsine Na Sitading 1 (alaxinastatin 1); Acsine Na Sitading 2; Acsine Na Sitading 3; Azasetron (azasetron); Azo toxin (azatoxin); Azo Tyrosine propylhomoserin (azatyrosine); Ba Kading III (baccatin III) derivative; Ba Lanuo (balanol); Cling to terraced horse Stuart (batimastat); BCR/ABL antagonist; Benzo Crow woods (beznochlorins); Benzoyl staurosporin (benzoylstaurosporine); Beta-lactam derivative; β-philharmonic pungent (beta-alethine); The β gram of pungent B of company (beta-clamycin B); Birch acid; BFGF inhibitor; Than card Rumi (bicalutamide); Bisantrene (bisantrene); Two aziridinyl spermine (bisaziridinylspermine); Bisnafide (bisnafide); Than the vertical booth A (bistratene A) of department;Bizelesin (bizelesin); Mine-laying husband thunder (breflate); Bropirimine (bropirimine); Budotitane (budotitane); S-butyl homocysteine propylhomoserin sulphoxide imine (buthionine sulfoximine); Its salts (calcipotriol); Ka Fosiding C (calphostin C); Camptothecin derivative; Canary pox IL-2 (canarypox IL-2); Capecitabine (capecitabine); Carboxylic acid amides-amido-triazole (carboxamide-amino-triazole); Carboxyamidotraiazol (carboxyamidotriazole); CaRest M3; CARN 700; The derivative inhibitor of cartilage; Carzelesin (carzelesin); Casein kinase 2 enzyme inhibitor (ICOS); Chestnut seed beans alkali; Cecropin B (cecropin B); Cetrorelix (cetrorelix); Crow woods (chlorlns); Chloroquinoline sulfonamide (chloroquinoxaline sulfonamide); Cicaprost (cicaprost); Cis-sclererythrin (cis-porphyrin); Carat monarch's treasured (cladribine); Clomifene (clomifene) analog; Clotrimazole (clotrimazole); The mycin A of Kou Li department (collismycin A); The mycin B of Kou Li department; Kan Leisitading A4 (combretastatin A4); Kan Leisitading analog; Bandit Nei Jining (conagenin); Kan Bixiding 816 (crambescidin 816); Ku Lisinietuo (crisnatol); Hidden algae element 8 (cryptophycin 8); Hidden algae element A derivative; Plain A (curacin A) is drawn in storehouse; Encircle penta anthraquinone; Cycloplatin (cycloplatam); Match general mycin (cypemycin); Cytarabine Losec phosphate (cytarabineocfosfate); The cytolysis factor; Cell Si Tading (cytostatin); Dacliximab (dacliximab); Decitabine (decitabine); Dehydrogenation tunica peptide B (dehydrodidemnin B); Deslorelin (deslorelin); Dexamethasone (dexamethasone); Right ifosfamide (dexifosfamide); Dexrazoxane (dexrazoxane); Dexverapamil (dexverapamil); Diaziquone (diaziquone); Tunica peptide B (didemnin B); Dai Dukesi (didox); Spermin (diethylnorspermine) falls in diethyl;Dihydro-5-nitrogen cytosine nucleosides; 9-ambomycin (9-dioxamycin); Diphenyl spiromustine (diphenylspiromustine); Tadenan; Dolasetron (dolasetron); Doxifluridine; Droloxifene (droloxifene); Dronabinol (dronabinol); Road Ka-7038Ⅶ (duocarmycin) SA; Ebselen (ebselen); Ecomustine (ecomustine); Edelfosine (edelfosine); Edrecolomab (edrecolomab); According to fluorine bird amino acid propylhomoserin (eflornithine); Elemene (elemene); According to rice furan (emitefur); Epirubicin (epirubicin); Yi Pusite (epristeride); Estramustine analog; Estrogen agonist; Estrogen antagonist; Etanidazole (etanidazole); Etoposide phosphate (etoposide phosphate); Exemestane (exemestane); Fadrozole (fadrozole); Fazarabine (fazarabine); Fragrant dimension A (fenretinide) amine; Filgrastim (filgrastim); Finasteride (finasteride); Fu Lafo benefit (flavopiridol); Fu Leizhalasiding (flezelastine); Fu Lasitelong (fluasterone); Fludarabine (fludarabine); Hydrochloric acid fluorine daunorubicin; Forfenimex (forfenimex); Formestane (formestane); Fostriecin (fostriecin); Fotemustine (fotemustine); Moral porphyrin gadolinium (gadolinium texaphyrin); Gallium nitrate; Galocitabine (galocitabine); Ganirelix (ganirelix); Gelatinase inhibitor; Gemcitabine (gemcitabine); Glutathione inhibitor; He Pusha divides (hepsulfam); He Lei guilt woods (heregulin); Vitro By Hexamethylene Bisacetamide; Hypericin (hypericin); According to class's phosphonic acids (ibandronic acid); Idarubicin (idarubicin); Idoxifene (idoxifene); Idramantone (idramantone); Ilmofosine (ilmofosine); Ilomastat (ilomastat); Imidazo acridone; Miaow quinoline is (imiquimod) not; Immunostimulating peptide; IGF-1 acceptor inhibitor; Interferon activator; Interferon; Interleukin; MIBG (iobenguane); Iododoxorubicin (iododoxorubicin); Sweet potato alcohol (ipomeanol),4-; Iroplact (iroplact); Irsogladine (irsogladine); Different adds azoles (isobengazole); The black power bandit of foreign peoples fourth B (isohomohalicondrin B); Itasetron (itasetron); Add in department Jino, pula (jasplakinolide); F (kahalalide F) in card Harrar; Triacetic acid sheet spiral shell element-N (lamellarin-Ntriacetate); Lanreotide (lanreotide); Connect that mycin (leinamycin); Lenograstim (lenograstim); Sulfuric acid mushroom polysaccharide (lentinan sulfate); Carry out Tuo Sitading (leptolstatin); Hold in the palm azoles (letrozole); LIF ELISA; White blood cell IFN-α; Bright the third Reed (leuprolide)+estrogen+progesterone; Leuprorelin (leuprorelin); Levamisol (levamisole); Liarozole (liarozole); Linear polyamine analogs; Lipophilicity disaccharide peptide; Lipophilicity platinum compounds; Acid amides 7 (lissoclinamide 7) in sharp gram; Lobaplatin (lobaplatin); Earthworm propylhomoserin (lombricine); Lometrexol (lometrexol); Lonidamine (lonidamine); Losoxantrone (losoxantrone); Lovastatin (lovastatin); Loxoribine (loxoribine); Lurtotecan (lurtotecan); Moral porphyrin gold-plating (lutetium texaphyrin); Carry out Suo Feilin (lysofylline); Dissolve peptide; Maitansine (maitansine); His fourth A (mannostatin A) of sweet dew department; Horse Lima department he (marimastat); Masoprocol (masoprocol); Ma Siping (maspin); Stromelisines (matrilysin) inhibitor; NMPI; Menogaril (menogaril); Mai Erbalong (merbarone); meter Te Rayleigh (meterelin); MET propylhomoserin enzyme; Metoclopramide (metoclopramide); MIF inhibitor; Mifepristone (mifepristone); Miltefosine (miltefosine); Mirimostim (mirimostim); Mispairing AMPLIGEN; Mitoguazone (mitoguazone); Dibromoducitol (mitolactol); Mitomycin analogs; meter Tuo Naifade (mitonafide); Rice holder toxin (mitotoxin) fibroblast growth factor-saporin; Mitoxantrone (mitoxantrone);Mofarotene (mofarotene); Molgramostim (molgramostim); Monoclonal antibody, hCG; Monophosphoryl lipid A+side chain bacilli-cell wall sk; Mopidamol (mopidamol); Multiple drug resistance gene inhibitor; Based on the cure of multiple tumor inhibitor 1; Mustargen anticancer; Indian Ocean sponge B (mycaperoxide B); Side chain bacilli-cell wall essence is got thing; meter Li Ya is dragon (myriaporone) quite; N-acetyl group dinaline (N-acetyldinaline); The benzamide that N-is substituted; Nafarelin (nafarelin); Na Gelisi ground (nagrestip); His azoles of that Lip river ketone (naloxone)+Pan new (pentazocine); Na Paping (napavin); Na Teping (naphterpin); Nartograstim (nartograstim); Nedaplatin (nedaplatin); Nemorubicin (nemorubicin); Neridronic Acid (neridronic acid); Native peptides restriction endonuclease; Nilutamide (nilutamide); Silt mycin (nisamycin); Nitrogen oxide conditioning agent; Nitrogen oxide antioxidant; How native woods (nitrullyn); O6-BG; Octreotide (octreotide); Very agriculture of Ou Ji (okicenone); Oligonucleotides; Ou Nalisi ketone (onapristone); Ondansetron (ondansetron); Ondansetron; Euler pungent (oracin); Oral cytokine inducing agent; Ormaplatin (ormaplatin); Husky ketopregnene difficult to understand (osaterone); Oxaliplatin (oxaliplatin); A promise mycin (oxaunomycin) difficult to understand; Palau amine (palauamine); Palmityl agile new (palmitoylrhizoxin); The acid of handkerchief rice; Panaxatriol (panaxytriol); Panomifene (panomifene); Parabacteria element (parabactin); Pazelliptine (pazelliptine); Accompany a winter enzyme (pegaspargase); Pei Erdexin (peldesine); Pentosan Polysulfate Sodium (pentosan polysulfatesodium); Pentostatin (pentostatin); Spray tall and erect azoles (pentrozole); 17 fluorine bromooctanes (perflubron); Perfosfamide; Perilla alcohol (perillyl alcohol); Fei Najinuo mycin (phenazinomycin); Phenylacetic acid; Inhibitors of phosphatases; Pi Xi Barney (picibanil); Hydrochloric acid Pilocarpus jaborandi (pilocarpine hydrochloride); THP (pirarubicin);Piritrexim (piritrexim); The booth A of Prey department (placetin A); The booth B of Prey department; Plasminogen activator inhibitor; Platinum complex; Platinum compounds; Platinum-tri-amine complex; Porfimer Sodium (porfimer sodium); Porfiromycin (porfiromycin); Metacortandracin (prednisone); Propyl group is two-acridone; Prostaglandin J2; Proteasome inhibitor; Based on the immunomodulator of a-protein; Protein kinase C inhibitor; Protein kinase C inhibitor, micro-algae property; Protein Tyrosine propylhomoserin inhibitors of phosphatases; Purine nucleoside phosphorylase inhibitor; Alizarinopurpurin (purpurin); Pyrazolo acridine (pyrazoloacridine); Trembling of pyrrole Hemoglobin Polyoxyethylene conjugate; Raf antagonist; Raltitrexed (raltitrexed); Ramosetron (ramosetron); Ras farnesyl protein transferase inhibitors; Ras inhibitor; Ras-GAP inhibitor; The ferreous booth of demethylation thunder (retelliptine demethylated); Etidronic acid rhenium Re 186; Agile new (rhizoxin); Ribozyme; RII looks yellow acid amides; Rogletimide (rogletimide); Luo Xituji (rohitukine); Romurtide (romurtide); Roquinimex (roquinimex); Rupee base agriculture B1 (rubiginone B1); Lu Bake Xi Er (ruboxyl); Safingol (safingol); Sheng Tuoping (saintopin); SarCNU; The husky non-top A of bandit (sarcophytol A); Sargramostim (sargramostim); Sdi 1 analogies; Semustine (semustine); Old and feeble derivative inhibitor 1; Meaning oligonucleotides; Signal transduction inhibitor; Signal transduction conditioning agent; Single chain antigen binding proteins matter; Sizofiran (sizofiran); Sobuzoxane (sobuzoxane); Boron sodium caprate; Sodium; Suo Weilong (solverol); Long-living plain medium (somatomedin) conjugated protein; Sonermin (sonermin); This Paphos acid (sparfosic acid); The pick up mycin D of department (spicamycin D); Spiromustine (spiromustine); Spleen Pan Ting (splenopentin); His fourth 1 (spongistatin 1) of sponge department; Squalamine (squalamine); Stem cell inhibitors; Stem cell division inhibitor; Skin acid amides (stipiamide) is carried by department; Stromelysin inhibitors (stromelysin); Sulphur promise pungent (sulfinosine); Superactivity vasoactive peptide antagonists; Ursula Di Sita (suradista); Suramin (suramin);Spherosin (swainsonine); Synthesis type glycosaminoglycan; Tallimustine (tallimustine); TAM (tamoxifen) methiodide; Tauromustine (tauromustine); He is Zha Luoting (tazarotene); Iron can gallon sodium (tecogalan sodium); Tegafur (tegafur); Iron land La Pili (tellurapyrylium); Telomerase inhibitor; Temoporfin (temoporfin); Temozolomide (temozolomide); Teniposide (teniposide); Tetrachloro ten alkoxide; Four nitrogen amine (tetrazomine); Sha Li step La Siding (thaliblastine); Thiophene bandit draws woods (thiocoraline); TPO; Thrombopoietin mimetics; Thymalfasin (thymalfasin); Thymopoietin receptor stimulating agent; Thymotrinan (thymotrinan); Thyroid-stimulating hormone; Ethyl etioporphyrin (ETIO) tin (tin ethyletiopurpurin); Tirapazamine (tirapazamine); Titanocene dichloride (titanocenebichloride); Torsen booth (topsentin); Toremifene toremifene; Totipotency stem cell factor; TI; Tretinoin (tretinoin); Triacetyl uridine; Triciribine (triciribine); Trimetrexate (trimetrexate); Triptorelin (triptorelin); Tropisetron (tropisetron); Turosteride (turosteride); Tyrosine histidine kinase inhibitor; Tyrosine propylhomoserin phosphorylation inhibitor (tyrphostin); UBC inhibitor; Ubenimex (ubenimex); The derivative growth inhibition sex factor of urogenital sinus; Urokinase receptor antagonist; Vapreotide (vapreotide); Cut down Leo woods B (variolinB); Carrier system, red blood cell gene therapy; Velaresol (velaresol); Veratramine (veramine); Dimension fourth (verdins); Verteporfin (verteporfin); Vinorelbine (vinorelbine); Wen Shating (vinxaltine); Wei Takexin (vitaxin); Vorozole (vorozole); Zanoterone (zanoterone); Outstanding Buddhist nun's platinum (zeniplatin); Ya Benzyl ties up (zilascorb); And Zinostatin department is for beautiful (Zinostatinstimalamer).Preferably extra anticancer medicine is 5 FU 5 fluorouracil and formyl tetrahydrofolic acid (leucovorin)
Can be combined with compound of the present invention treat proliferative disease (such as cancer) or include, but is not limited to the example of the therapeutic antibodies preventing the recurrence of proliferative disease (such as cancer): Herceptin
(HERCEPTIN
herceptin (Trastuzumab)) (Genentech, CA), it is the anti-HER2 monoclonal antibody of the peopleization being used for the treatment of the patient with transitivity breast cancer; REOPRO
(ReoPro (abciximab)) (Centocor), it is the sugar-protein IIb/IIIa receptor antibody resisted in the little version of blood for preventing clot to be formed; ZENAPAX
(Dacliximab (daclizumab)) (Roche Pharmaceuticals, Switzerland), it is the anti-CD25 monoclonal antibody of inhibitive ability of immunity for preventing acute renal allograft rejection, peopleization; PANOREX
tM, it is muroid anti-17-IA cell-surface antigens IgG2a antibody (Glaxo Wellcome/Centocor); BEC2, it is rodent antibody genotype (GD3 epitope) IgG antibody (ImClone System); IMC-C225, it is the anti-EGFR IgG antibody of mosaic type (ImClone System); VITAXIN
tM, it is the whole even protein antibodies (Applied Molecular Evolution/MedImune) of anti alpha V β 3 of peopleization; Campath 1H/LDP-03, it is the anti-CD52IgG1 antibody (Leukosite) of peopleization; Smart M195, it is the anti-CD 33 IgG antibody (Protein Design Lab/Kanebo) of peopleization; RITUXAN
tM, it is mosaic type anti-CD20 IgG1 antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOCIDE
tMit is the anti-CD22 IgG antibody (Immunomedics) of peopleization; LYMPHOCIDE
tMy-90 (Immunomedics); Lymphoscan (demarcates through Tc-99m; Radiophotography; Immunomedics); Nuvion is (for CD3; Protein Design Labs); CM3 is the anti-ICAM3 antibody (ICOS Pharm) of peopleization; IDEC-114 is primatized Anti-CD80 McAb (IDECPharm/ Mitsubishi); ZEVALIN
tMit is the muroid anti-CD20 antibodies (IDEC/ScheringAG) that radiation is demarcated; IDEC-131 is the anti-CD40L antibodies (IDEC/Eisai) of peopleization; IDEC-151 is primatized anti-CD 4 antibodies (IDEC); IDEC-152 is primatized anti-CD23 antibody (IDEC/Seikagaku); SMART AntiCD3 McAb is the AntiCD3 McAb IgG (Protein DesignLab) of peopleization; 5G1.1 is anticomplement factor 5 (C5) antibody (Alexion Pharm) of peopleization; D2E7 is the anti-TNF-α antibody (CAT/BASF) of peopleization; CDP870 is the anti-tnf-alpha Fab fragment (Celltech) of peopleization; IDEC-151 is primatized anti-CD4 IgG1 antibody (IDECPharm/SmithKline Beecham); MDX-CD4 is the anti-CD4 IgG antibody (Medarex/Eisai/Genmab) of the mankind; CD20-chain enzyme antibiotin (+vitamin H-Y90; NeoRx); CDP571 is the anti-tnf-alpha IgG4 antibody (Celltech) of peopleization; LDP-02 is anti alpha 4 β 7 antibody (LeukoSite/Genentech) of peopleization; OrthoClone OKT4A is the anti-CD4 IgG antibody (Ortho Biotech) of peopleization; ANTOVA
tMit is the anti-CD 40 L IgG antibody (Biogen) of peopleization; ANTEGREN
tMit is the anti-VLA-4 IgG antibody (Elan) of peopleization; And CAT-152 is mankind's anti-TGF-beta 2 antibody (Cambridge Ab Tech).
Can be combined to treat the patient with proliferative disease (such as cancer) with compound of the present invention or include but not limited to alkylating agent, metabolic antagonist, natural product or hormone with the chemotherapeutic agent of the recurrence preventing proliferative disease (such as cancer).In method of the present invention and constituent, have and be used for the treatment of or prevent the example of the alkylating agent of T-cell malignancies to include, but is not limited to mustargen (nitrogen mustard, such as, two (chloroethyl) methylamine (mechloroethamine), endoxan, Chlorambucil, etc.), alkyl sulfonic ester (such as, busulfan), nitrosourea (such as, carmustine, lomustine etc.) or triazene (Dacarbazine (decarbazine), etc.).Have in method of the present invention and constituent, the example of the metabolic antagonist for the treatment of or prevention T-cell malignancies includes but not limited to that folacin (such as, methotrexate) or pyrimidine analogue is (such as, cytosine arabinoside), purine analogue (such as, purinethol, Tioguanine, pentostatin).Have in method of the present invention and constituent, the example of the natural product for the treatment of or prevention T-cell malignancies includes but not limited to that vinca alkaloids (such as, vincaleucoblastine, vincristine(VCR)), podophyllotoxin (epipodophyllotoxin) (such as, Etoposide), microbiotic (such as, daunorubicin, Zorubicin, bleomycin), ferment (such as, L-ASP) or biological response modifier (such as, interferon alpha).
Have for treating in method of the present invention and compound or preventing the example of the alkylating agent of proliferative disease (such as cancer) to include but not limited to, mustargen (such as, two (chloroethyl) methylamine, endoxan, Chlorambucil, melphalan, etc.), ethyleneimine and methylmelamine (such as, altretamine, Tespamin), alkyl sulfonic ester (such as, busulfan), nitrosourea (such as, carmustine, lomustine, semustine, streptozocin, etc.) or triazene (Dacarbazine, etc.).Have in method of the present invention and constituent, the example of the metabolic antagonist for the treatment of or preventing cancer includes but not limited to that folacin (such as, methotrexate) or pyrimidine analogue is (such as, Fluracil, fluodeoxyuridine, cytosine arabinoside), purine analogue (such as, purinethol, Tioguanine, pentostatin).Have in method of the present invention and constituent, the example of the natural product for the treatment of or preventing cancer includes but not limited to that vinca alkaloids (such as, vincaleucoblastine, vincristine(VCR)), podophyllotoxin (such as, Etoposide, teniposide), microbiotic (such as, radiating streptozotocin D, daunorubicin, Zorubicin, bleomycin, Plicamycin, mitomycin), ferment (such as, altheine) or biological response modifier (such as, interferon alpha).Have in method of the present invention and constituent, treatment or the hormone of preventing cancer and the example of antagonist include but not limited to that adrenocortical steroid (such as, prednisone), progesterone (such as, hydroxyprogesterone caproate, Magace, medroxyprogesterone acetate (medroxyprogesterone acetate)), oestrogenic hormon (such as, diethylstilbestrol (diethlystilbestrol), Ethinylestradiol (ethinyl estradiol)), estrogen antagonist (such as, tamoxifen), male sex hormone (such as, testosterone propionate, Fluoxymesterone (fluoxymesterone)), androgen antagonist (such as, his acid amides (flutamide) of fluorine), gonadotropin releasing hormone analogues (such as, bright third Reed).Other can have in method of the present invention and constituent, to be used for the treatment of or the agent of preventing cancer comprises platinum coordination complex (such as, Platinol, carboplatin), amerantrone (anthracenedione, such as, mitoxantrone), the urea that is substituted (such as, hydroxyurea), methyl hydrazine derivatives (such as, Procarbazine), adrenal cortex inhibitor (such as, mitotane, aminoglutethimide).
In one embodiment, compound of the present invention can be combined with immunotherapeutic agent, to treat proliferative disease (such as cancer) or to prevent the recurrence of proliferative disease (such as cancer).Immunotherapy (Immunotherapy, also referred to as the treatment of biological respinse amendment (biological responsemodifier therapy), biological treatment (biologic therapy), biotherapy (biotherapy), immunotherapy (immune therapy) or biologic treatment (biological therapy)) uses immune part with the treatment to anti-disease.The reaction that immunotherapy can help immunity system to recognize cancer cell or improve for cancer cell.Immunotherapy comprises initiatively and passive immunotherapy.Active immunity treatment stimulates the immunity system of health itself, and passive immunotherapy is generally used in the immunity system integrant that health manufactures outward.
The example of active immunity treatment comprises: cancer vaccine, tumour-cell vaccine (autologous or allochthonous), dendritic cell vaccine, antigen vaccine, anti-body idiotype vaccine, DNA vaccination, lymph medium-reactivity kill and wound (Lymphokine-Activated Killer, LAK) cell therapy or tumour-infiltrating lymphocytes (Tumor-perviousness Lymphocyte, TIL) vaccine add interleukin-2 (IL-2).Active immunity treatment be just used at present treatment or testing its effect being used for the treatment of various types of cancer, comprise melanoma, kidney (kidney) cancer, bladder cancer, prostate cancer, ovarian cancer, newborn disease, carcinoma of the colon and rectum, lung cancer, leukemia, prostate cancer, non-Hodgkin lymphomas, cancer of pancreas, lymphoma, multiple myeloma, head and neck cancer, liver cancer, malignant brain tumor, with later stage melanoma.
The example of passive immunotherapy comprises: monoclonal antibody and the qualitative treatment of target containing toxin.Monoclonal antibody comprise naked antibody with through binding antibody (also referred to as tagging, through demarcate or through loading antibody).Naked monoclonal antibody does not have medicine or radioactive materials connects on it, and through being be bonded to chemotherapeutics (chemistry load (chemolabeled)), radioactivity particle ((radioactivity is demarcated) that radiation is loaded) or toxin (immunotoxin) in conjunction with monoclonal antibody.Some naked monoclonal antibody medicines are used for the treatment of cancer by approval, comprising:
The appropriate Xidan of profit anti-(Rituximab, Rituxan), is a kind ofly used for the treatment of the lymphadenomatous antibody for CD20 antigen of B cell non-Hodgkin; Herceptin (Herceptin), a kind of antibody for HER2 protein being used for the treatment of later stage breast cancer; Alemtuzumab (Alemtuzumab, Campath), one is used for the treatment of the antibody for CD52 antigen of B cell lymphocytic leukemia (B-CLL); Cetuximab (Cetuximab, Erbitux), a kind of be combined with irinotecan to treat later stage carcinoma of the colon and rectum with to treat the antibody for EGFR protein of head and neck cancer; With rhuMAb-VEGF (Bevacizumab, cancer think stop (Avastin)), it is a kind of anti-angiogenic therapies, and it is antagonism vegf protein matter and acts on and be combined with chemotherapy to treat transitivity carcinoma of the colon and rectum.Some are through being used for the treatment of cancer by approval in conjunction with monoclonal antibody, comprise: antibody ibritumomab tiuxetan (the Ibritumomab tiuxetan that radioactivity is demarcated, Zevalin), it directly sends radioactivity to carcinous bone-marrow-derived lymphocyte, and is be used for the treatment of B cell non-Hodgkin lymphoma; The antibody tositumomab (Tositumomab, Bexxar) that radioactivity is demarcated, it is the non-Hodgkin lymphoma being used for the treatment of some type; And the lucky trastuzumab of immunotoxin azoles rice star (Gemtuzumab ozogamicin, Mylotarg) difficult to understand, it contains Calicheamicin (calicheamicin) and is be used for the treatment of acute one-tenth myelomatosis (AML).BL22 be a kind of testing at present its be used for the treatment of the leukemic effect of trichoblast through in conjunction with monoclonal antibody, and have several treatment leukemia, lymphoma, carry out with the immunotoxin clinical experiment of cerebral tumor.Also the antibody having the approved radioactivity for detecting cancer to demarcate, comprises the OncoScint for detecting rectum colon and ovarian cancer and the ProstaScint for detecting prostate cancer.The qualitative therapy of target containing toxin be linked to somatomedin toxin and not containing antibody.The example of the qualitative treatment containing toxin of approved target be denileukin diftitox (Ontak) its be the lymphoma cutis (cutaneous T cell lymphoma) being used for the treatment of a type.
The example of adjuvant immunotherapy comprises: cytokine, such as particulate cell-macrophage colony-pungency factor (GM-CSF), particulate cell-group's pungency factor (G-CSF), scavenger cell inflammatory albumen (MIP)-1-α, interleukin (comprising IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21 and IL-27), tumour necrosis factor (comprising TNF-α), with Interferon, rabbit (comprise IFN-α, IFN-β, with IFN-γ); Albumin oxyhydroxide (alum); Bacille Calmette-Guerin vaccine (Bacille Calmette-Gu é rin, BCG); Keyhole limpet hemocyanin (Keyhole limpethemocyanin, KLH); Incomplete FreundShi adjuvant (IFA); QS-21; DETOX; LEVAMISOLE HCL (Levamisole); And dinitrophenyl (DNP).Clinical study shows and can cause concerted reaction in conjunction with IL-2 and other cytokines (such as IFN-α).
The immunotherapy of several type is just being used to treat melanoma patients.IFN-α and IL-2 is used for the treatment of the people with metastasis melanin tumor by approval.At present just in effect that test b CG is combined with melanoma vaccines and other immunotherapies.In the first phase is clinical, tumour-infiltrating lymphocytes has been shown and melanoma tumor can be made to shrink.Mankind's monoclonal antibody for Sphingolipids,sialo antigen has been shown and the recurrent melanoma tumor of skin can be made to disappear.Some autologous with allogeneic tumor cell vaccine, antigen vaccine (comprising polyvalent antigen vaccine), virus vaccines, with dendritic cell vaccine also display can make actual shrinkage.The clinical study had these and other melanoma immunotherapy continued.The melanoma patients with height IgM reaction does not often cause or causes low IgM antibody person's survival rate good people such as (, 1992) Morton compared with those.In three tumour patterns mouse (B16F10 melanoma, Lewis lung (LL/2) cancer, with L1 sarcoma), compared to control group and the mouse using separately any one cytokine treat, in conjunction with the treatment of IL-12/TNF-alpha immunization shownly significantly can postpone tumor growth.IFN-α by approval be used for the treatment of malignant melanoma, chronic one-tenth myelomatosis (CML), trichoblast leukemia, with Kaposi sarcoma.
The immunotherapy of several type is just being used to treat the patient with renal cancer.IFN-α and IL-2 is used for the treatment of the patient with transitivity kidney (kidney) cancer by approval.Testing at present and using IL-2, Interferon, rabbit, treating effect of renal cancer with the combined treatment of chemotherapy.In some later stages renal cancer patient, the treatment of adjuvanticity BCG has been shown and can have made actual shrinkage to use tumour-cell vaccine to add.Also effect of renal cancer is just used for the treatment of at present at test dna vaccine and tumour-infiltrating lymphocytes.The two specificity G250/ AntiCD3 McAb monoclonal antibody of mosaic type has been shown can by the selected mankind CD8+T cell grown or the molten born of the same parents of cell being by IL-2 pungency peripheral blood cell mediated kidney cell cancer cells.
For herein, " microtubule stabilizing agent " means a kind of carcinostatic agent, and it acts on by preventing cell in the G2-M phase due to stabilization microtubule.Agent for microtubule stabilizing agent can be combined to treat the patient with proliferative disease (such as cancer) with compound of the present invention or to prevent the recurrence of proliferative disease (such as cancer).The example of microtubule stabilizing agent comprises to be eliminated cancer victory and eliminates cancer and win analogue.The example of other microtubule stabilizing agent includes but not limited to following marketed drugs and the medicine researched and developed: coil suberite lactide (Discodermolide, also referred to as NVP-XX-A-296); Ebormycine (Epothilone) (such as ebomycin A, epothilone B, epothilones C (also referred to as deoxidation ebomycin A or dEpoA); Epothilone D (also referred to as KOS-862, dEpoB or deoxidation epothilone B); Ebormycine E; Ebormycine F; The positive oxide compound of epothilone B; Ebomycin A N-oxide compound; 16-azepine (aza)-epothilone B; 21-aminoepothilone B (also referred to as BMS-310705); 21-hydroxyepothilone D (also referred to as deoxidation ebormycine F and dEpoF), 26-fluorine ebormycine); FR-182877 (Teng Ze (Fujisawa), also referred to as WS-9885B), BSF-223651 (BASF, also referred to as ILX-651 and LU-223651); AC-7739 (element (Ajinomoto) of taste, also referred to as AVE-8063A and CS-39.HCl); AC-7700 (element of taste, also referred to as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl and RPR-258062A); Fushan Mountain lactide (Fijianolide) B; Labour Malaysia (Laulimalide); Caribbean glycosides (Caribaeoside); Caribbean element (Caribaeolin); Taccalonolide (Taccalonolide); Eleutherobin (Eleutherobin); Picogram enemy's fourth (Sarcodictyin); Labour Malaysia; Di Tiousitading (Dictyostatin)-1; False white olive alkane ester (Jatrophane); And their analogue and derivative.
For herein, " Antitubulin " means a kind of carcinostatic agent, and it acts on by suppression microtubule polymerization or microtubule assembling.Agent for Antitubulin can be combined with compound of the present invention in treatment have proliferative disease (such as cancer) patient or to prevent the recurrence of proliferative disease (such as cancer).The example of Antitubulin includes but not limited to following marketed drugs and the medicine researched and developed: R 55104 (also referred to as R-55104); His fourth 10 (Dolastatin 10, also referred to as DLS-10 and NSC-376128) of Duola department; 2-isethionic acid meter Fo Bulin (Mivobulin isethionate, also referred to as CI-980); Vincristine(VCR); NSC-639829; ABT-751 (Abbot, also referred to as E-7010); A Ertuolaiding (Altorhyrtin, such as A Ertuolaiding A and A Ertuolaiding C); Sponge Si Tading (such as his fourth 1 of sponge department, his fourth 2 of sponge department, his fourth 3 of sponge department, his fourth 4 of sponge department, his fourth 5 of sponge department, his fourth 6 of sponge department, his fourth 7 of sponge department, his fourth 8 of sponge department and sponge department he fourth 9); Hydrochloric acid Cemadotin (Cemadotin hydrochloride, also referred to as LU-103793 and NSC-D-669356); Orlistat fourth PE (Auristatin PE, also referred to as NSC-654663); Rope cloth benefit fourth (Soblidotin, also referred to as TZT-1027), LS-4559-P (Pharmacia, also referred to as LS-4577); LS-4578 (Pharmacia, also referred to as LS-477-P); LS-4477 (Pharmacia), LS-4559 (Pharmacia); RPR-112378 (Aventis); Vincristine sulphate; DZ-3358 (Daiichi); GS-164 (military field (Takeda)); GS-198 (military field); KAR-2 (science institute of Hungary (Hungarian Academy of Sciences)); SAH-49960 (Lilly/Novartis); SDZ-268970 (Lilly/Novartis); AM-97 (Armad/ synergism fermentation (Kyowa Hakko)); AM-132 (Armad); AM-138 (fermentation of Armad/ synergism); IDN-5005 (Indena); Hidden algae element 52 (also referred to as LY-355703); Dimension carries mist acid amides (Vitilevuamide); Handwoven cloth carrys out pungent A (Tubulysin A); Ka Nadansuo (Canadensol); Vow four chrysanthemum elements (Centaureidin, also referred to as NSC-106969); T-138067 (Tularik, also referred to as T-67, TL-138067 and TI-138067); COBRA-1 (Parker Hughes Institute, also referred to as DDE-261 and WHI-261); H10 (Kansas State University (Kansas State University)); H16 (Kansas State University); Gancidin A1 (Oncocidin A1, also referred to as BTO-956 and DIME); DDE-313 (ParkerHughes Institute); SPA-2 (Parker Hughes Institute); SPA-1 (Parker HughesInstitute, also referred to as SPIKET-P); 3-IAABU (Cytoskeleton/ Xi Naishan medical science school (Mt. Sinai School of Medicine), also referred to as MF-569); Narcosine (Narcosine, also referred to as NSC-5366); Na Sikapai (Nascapine), D-24851 (Asta Medica), A-105972 (Abbott); Half A Sitelin (Hemiasterlin); 3-BAABU (Cytoskeleton/ Xi Naishan medical science school, also referred to as MF-191); TMPN (Ya Lisangna state university (Arizona StateUniversity)); Acetopyruvic acid Wa Naduoxin (Vanadocene acetylacetonate); T-138026 (Tularik); Cover Saudi Arabia sieve (Monsatrol); Yi Nanuoxin (Inanocine, also referred to as NSC-698666); 3-IAABE (Cytoskeleton/ Xi Naishan medical science school); A-204197 (Abbott); T-607 (Tularik, also referred to as T-900607); RPR-115781 (Aventis); Eleutherobin (such as demethyl eleutherobin, go acetyl eleutherobin, different eleutherobin A, with Z-eleutherobin); Harry Kang get Lin B (Halichondrin B); D-64131 (Asta Medica); D-68144 (Asta Medica); Diazoamines A Diazonamide A); A-293620 (Abbott); NPI-2350 (Nereus); TUB-245 (Aventis); A-259754 (Abbott); Dai Ousuo chalone (Diozostatin); (-)-phenylahistin ((-)-phenylahistin, also referred to as NSCL-96F037); D-68838 (AstaMedica); D-68836 (Asta Medica); Myostromin B (Myoseverin B); D-43411 (Zentaris, also referred to as D-81862); A-289099 (Abbott); A-318315 (Abbott); HTI-286 (also referred to as SPA-110, trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Profit department cuts down chalone sodium phosphate (Resverastatinphosphate sodium); BPR-0Y-007 (national health research institution (National Health ResearchInstitutes)); SSR-250411 (Sanofi); Combretastatin A-4 4 (Combretastatin A4); And their analogue and derivative.
Eliminate cancer victory
also referred to as " Paclitaxel ", be a kind of cancer therapy drug be widely known by the people, it is formed by increase and stabilization microtubule and acts on.Eliminate cancer victory
structure be show in Fig. 1.Many cancers of eliminating win
analogue be known, comprise gram cancer easy
(Taxotere
), its structure shows in Fig. 2.Gram cancer is easy
also referred to as " docetaxol ".Other eliminate cancer victory
the structure of analogue shows in Fig. 3-23.These compounds have basic taxanes skeleton as common constitutional features, and are also shown the ability having and to be prevented by cell due to the stabilization of microtubule in the G2-M phase.Therefore, from Fig. 3-23, significantly, extensive various substituting group can be modified taxanes skeleton and can not deleteriously have an impact to the activity of biology.Eliminating zero, one or two cyclohexane ring of cancer victory analogue, can have double bond in indicated position be also obvious.For the sake of clarity, basic taxanes skeleton shows in following structural formula (XXVI):
Double bond is ignored from the cyclohexane ring the taxanes skeleton showed by structural formula (XXVI).Basic taxanes skeleton can comprise zero or double bond at one or two cyclohexane ring, as pointed in Fig. 3-23 and following structural formula (XXVII) and (XXVIII).Some atoms have been ignored in self-structure formula (XXVI) to signify wherein eliminating the position that between cancer victory analogue, structural change occurs usually.Such as, the substituting group replacing symbol hydroxyl, acyl group, alkoxyl group or another band aerobic with Sauerstoffatom simply at taxanes skeleton finds in this position usually.Can manufacture these and other taxanes skeleton replacement and not with the forfeiture of ability, formed with stabilization microtubule to improve.Therefore, term " eliminates cancer victory
analogue " to be defined as in herein and to mean a kind of compound, it has basic taxanes skeleton and it promotes that microtubule is formed.Eliminate cancer victory
analogue can be formulated into nano-particle colloid constituent with improve infusion time and with eliminate with the needs of Cremophor (it causes anaphylaxis in some patients) delivering drugs.What be deployed into nano-particle colloid composite eliminates cancer victory
an example of analogue is Abraxane, and it is the nano-particle colloid constituent of the Paclitaxel (it reconstructs in salt solution) through protein stabilization.
Typically, win for cancer of eliminating herein
analogue is representated by structural formula (XXVII) or (XXVIII):
R
10lower alkyl groups group, the lower alkyl groups group that is substituted, phenyl group, the phenyl group ,-SR that are substituted
19,-NHR
19, or-OR
19.
R
11lower alkyl groups group, the lower alkyl groups group that is substituted, aromatic yl group or the aromatic yl group that is substituted.
R
12-H ,-OH, lower alkyl groups, the lower alkyl groups be substituted, low carbon number alkoxyl group, the low carbon number alkoxyl group be substituted ,-O-C (O)-(lower alkyl groups) ,-O-C (O)-(lower alkyl groups be substituted) ,-O-CH
2-O-(lower alkyl groups)-S-CH
2-O-(lower alkyl groups).
R
13-H ,-CH
3, or (with R
14-CH together)
2-.
R
14-H ,-OH, low carbon number alkoxyl group ,-O-C (O)-(lower alkyl groups), the low carbon number alkoxyl group be substituted ,-O-C (O)-(lower alkyl groups be substituted) ,-O-CH
2-O-P (O) (OH)
2,-O-CH
2-O-(lower alkyl groups) ,-O-CH
2-S-(lower alkyl groups) or (with R
20double bond together).
R
15-H, low carbon number acyl group, lower alkyl groups, the lower alkyl groups be substituted, alkoxy methyl, alkane thiomethyl (alkthiomethyl) ,-OC (O)-O (lower alkyl groups) ,-OC (O)-O (lower alkyl groups be substituted) ,-OC (O)-NH (lower alkyl groups) or-OC (O)-NH (lower alkyl groups be substituted).
R
16the phenyl being phenyl or being substituted.
R
17-H, low carbon number acyl group, the low carbon number acyl group be substituted, lower alkyl groups, be substituted, lower alkyl groups, (low carbon number alkoxyl group) methyl or (lower alkyl groups) sulphomethyl.
R
18-H ,-CH
3, or and R
17and R
17with R
18the carbon atom connected together, is the assorted cyclic rings of five or six Yuans non-fragrance.
R
19lower alkyl groups group, the lower alkyl groups group that is substituted, phenyl group, the phenyl group that is substituted.
R
20-H or halogen.
R
21-H, lower alkyl groups, the lower alkyl groups be substituted, low carbon number acyl group or the low carbon number acyl group that is substituted.
Preferably, the parameter in structural formula (XXVII) with (XXVIII) is as given a definition: R
10phenyl, tert.-butoxy ,-S-CH
2-CH-(CH
3)
2,-S-CH (CH
3)
3,-S-(CH
2)
3cH
3,-O-CH (CH
3)
3,-NH-CH (CH
3)
3,-CH=C (CH
3)
2, or p-chloro-phenyl-; R
11phenyl, (CH
3)
2cHCH
2-,-2-furyl, cyclopropyl or p-toluyl; R
12-H ,-OH, CH
3cO-or-(CH
2)
2-N-morpholinyl; R
13methyl or R
13with R
14-CH together
2-;
R
14-H ,-CH
2sCH
3, or-CH
2-O-P (O) (OH)
2; R
15cH
3cO-;
R
16it is phenyl; R
17-H or R
17with R
18-O-CO-O-together;
R
18-H; R
20-H or-F; And R
21-H ,-C (O)-CHBr-(CH
2)
13-CH
3, or-C (O)-(CH
2)
14-CH
3;-C (O)-CH
2-CH (OH)-COOH ,-C (O)-CH
2-O-C (O)-CH
2cH (NH
2)-CONH
2,-C (O)-CH
2-O-CH
2cH
2oCH
3or-C (O)-O-C (O)-CH
2cH
3.
Eliminate cancer victory
analogue also can be bonded to pharmaceutically acceptable polymkeric substance (such as polyacrylamide) or stretch out from it.An example of the polymkeric substance of this type shows in Figure 24.Term " eliminates cancer victory
analogue ", as it is for herein, comprise polymkeric substance like this.
In some embodiments, cancer victory is eliminated
analogue has the taxanes skeleton representated by structural formula XXIX, and wherein Z is O, S or NR.What have the taxanes skeleton shown by structural formula XXIX eliminates cancer victory
analogue can be connected on taxanes skeleton as display (such as Fig. 3-23) has various substituting group, and can have double bond at zero, one or two hexanaphthene.
Various cancer of eliminating wins
analogue with eliminate cancer and win
composite is in the people such as Hennenfent (2006) Annalsof Oncology 17:735-749; Gradishar (2006) Expert Opin.Pharmacother.7 (8): 1041-53; The people such as Attard (2006) Pathol Biol 54 (2): 72-84; The people such as Straubinger (2005) Methods Enzymol.391:97-117; Ten Tije etc. people (2003) Clin Pharmacokinet.42 (7): 665-85; And Nuijen etc. people (2001) Invest New Drugs.19 (2): 143-53 describes, their entire teachings includes in herein with way of reference.
In some embodiments, the invention provides the method occurred for treating or suppress blood vessel in the individuality needing treatment or suppress blood vessel to occur, it comprises the compound giving the representative by formula (I) to (XVI) of this individual effective dose or table 1.For herein, term " blood vessel generation " means a kind of elementary process producing neovascularity in tissue or organ.Blood vessel to be contained in numerous disease or illness or relevant to numerous disease or illness, includes but not limited to: cancer; The neovascular disorders of eye; Aging-Macular sexual involution (ag-related macular degeneration); Diabetic retinopathy, precocious retinopathy; Corneal graft rejection; Neovascular glaucoma; Terry's sign; Epidemic keratoconjunctivitis; Vitamin A deficiency; Contact lens transition is worn; Atopic keratitis (atopickeratitis); Top keratitis (limbic keratitis); Mist dry eyes keratitis (pterygium keratitissicca); Sjogrens; Acne rosacea (ache rosacea); Wart; Eczema; Phylectenulosis; Syphilis; Mycobacterial infections; Fat is degenerated; Chemical burn; Bacterial canker; Mycotic ulcer; Herpes simplex infection; Herpes zoster infection; Protozoal infections; Kaposi sarcoma; MoorenShi ulcer; TerrienShi edge degradation; Perforation dissolves (keratolysis); Rheumatoid arthritis; Systemic lupus; Polyarteritis; Wound; WegenerShi sarcoidosis; Scleritis; Stevens-Johnson disease; Pemphigus (pemphigoid); Radial keratotomy; Corneal graft rejection; Diabetic retinopathy; Muscle deterioration; Anemia sickle cell disease; Sarcoid; Syphilis; Pseudoxanthoma elasticum; PagetShi is sick; Venous occlusion; Arterial occlusion; Carotid artery blocking disease; Chronic uveitis/hyalitis (vitritis); Mycobacterial infections; LymeShi is sick; Systemic lupus erythematosus; Precocious retinopathy; EalesShi is sick; BehcetShi is sick; Cause the retinitis or uvaeformis infection; Presumption property ocular tissue slurry bacterium is sick; BestShi is sick; Myopia; Depending on recessed (optic pit); StargardtShi is sick; Uveal tract par inflammation (parsplanitis); Chronic retinal is separated; The excessive syndrome of viscosity; Bow worm disease; Wound and laser infectious-related complication; The disease (neovascularization of angle (angle)) relevant to measles; The disease caused by fibrovascular or fibrous tissue paraplasm, comprises the proliferative vitreous body retinopathy of form of ownership; Rheumatoid arthritis; Osteoarthritis; Ulcerative colitis; CrohnShi is sick; Bartonellosis; Atherosclerosis; Osler-Weber-Rendu disease; Hereditary hemorrhagic telangiectasia; Pulmonany angioma is sick; Before-faint from fear (pre-eclampsia); Endometriosis; The fibrosis of liver and kidney; Undergo an unusual development (organ generation); Skin depigmentation (discloloration) (such as, vascular tumor, flame mole (nevus flammeus) or simple mole (Nevus simplex)); Wound healing; Hypertrophic scar (that is, keloid (keloid); Wound roughening (wound granulation); Blood vessel is adhered; Cat scratch disease (cat scratch disease, Rocheleninalia quintosa); Ulcer (helicobacter pylorus revolves bacterium)); Keratoconjunctivitis; Gingivitis (gingivitis); Periodontopathy; Gingivitis (epulis); Hepatitis; Tonsillitis; Fat; Rhinitis; Laryngitis; Trachitis; Bronchitis; Bronchium; Pneumonia; The fibrosis of chromic fibrous lung; Pulmonary edema; Neurodermatitis; Thyroiditis; Thyromegaly; Endometriosis; Glomerulonephritis; Gastritis; Inflammatory skeleton and cartilage destruction; Thromboembolic disease; And BuergerShi is sick.Anti-angiogenic generation can by any know the known method of this operator (such as in herein example 9 and 10 the method that describes) show.
The anti-angiogenic agent that can be total to-give with compound of the present invention comprises DALT (Dalteparin), Suramine, ABT-510, Kan Leisitading A4 phosphoric acid salt, Revlimid (Lenalidomide), LY317615 (Enzastaurin), soybean isoflavones (Genistein, Soy protein isolates), Thalidomide, AMG-706, anti-VEGF antibodies (rhuMAb-VEGF, cancer is thought to stop
tM), AZD2171, Bay 43-9006 (Sorafenib tosylate), PI-88, PTK787/ZK 222584 (PTK787 (Vatalanib)), SU11248 (Sutent (Sunitinib) malate), VEGF-Trap, XL184, ZD6474, ATN-161, EMD 121974 (Cilenigtide), celecoxib (Celecoxib), angiostatin (Angiostatin), endostatin research (Endostatin), Regranex, Apligraf, Paclitaxel, tsiklomitsin, clarithromycin (clarithromycin), lasix, captopril (captopril), acetylsalicylic acid, vitamin D 3 analogs, retinoid, Imiquomod, Interferon a2a, U.S. promise tsiklomitsin (Minocycline), the cupric peptide topical application of drug (dressing), LucentisTM, ATG002, Macugen (Pegaptanib Sodium), tryptamines acyl group-tRNA synthetic enzyme, squalamine lactic acid salt, anecortave acetate (anecortave acetate), AdPEDF, AG-013958, JSM6427, TG100801, Veglin, xitix ether (and their analogue), with pamidronic acid (Pamidronate).
For herein, " prevention " means symptom or disease, and when using compounds for treating of the present invention, than not using, to recur possibility during compounds for treating of the present invention low (such as, possibility is low by least 10%, 20%, 30%, 40% or 50%), such as partial prophylaxis or suppress recurrence.Such as, the treatment disclosed can reduce the symptom of wish treatment or the possibility of disease palindromia.
Compound of the present invention can be prepared by according to following schema or by any method known known to this operator.
flow process I:
Formula A compound in flow process I can according to United States Patent (USP) case the 6th, 800, No. 660, United States Patent (USP) case the 6th, 762, No. 204 or United States Patent (USP) case the 6th, 825, No. 235 (their complete content includes in herein with way of reference), or prepare by the method that the personnel in technical field are known.
flow process II:
flow process III:
flow process IV:
flow process V:
flow process VI:
For flow process II-VI, thio-hydrazide (thiohydrazide), thioic acid sulfoacid muriate (thioacidchloride) or another carbonyl stand-in can be used for replacing hydrazides and sour muriate.Alkylation hydrazine and hydrazides can be used for replacing hydrazine or hydrazides.Carbonyl stand-in can replace carbonyl or thiocarbonyl group, and the hydrazine stand-in from a flow process can react with " close hydrazide group (hydrazidophile) " from another flow process.
flow process VII:
A.
flow process VIII:
flow process IX:
flow process X:
flow process XI:
See above flow process VIIA-C.
flow process XII.
The entire teachings of each of the document quoted in above flow process includes in herein with way of reference.
The present invention is illustrated by following examples, and it does not intend to be construed as limiting by any way.
Embodiment
Embodiment 1: compound of the present invention in vivo improves the antitumour activity of carcinostatic agent
A. the general procedure of in vivo antitumor research
The in vivo anticancer increase effect of compounds uses Tumor growth inhibition analysis and evaluation in the mouse of tumour.Tumour cell transplants by injecting tumor cell suspension hypodermically in mouse flank.Tumour uses the treatment of compound of the present invention and another carcinostatic agent (such as, Paclitaxel, it can start to use by way of example from here) to be that after tumour has been set up, (volume has been about 100mm
3) start.Then animal starts multiple injections planning chart, and wherein compound and Paclitaxel give administration by IV.Tumour measures twice weekly.During this analyzes, animal by every day supervise the sign of toxicity, comprise weight loss.
B. program
Prepare from following person through supplemental medium: the modified Eagle substratum of 50%DMEM/Dulbecco (the ied Eagle substratum of Dulbecco amendment) (high glucose), 50%RPMI 1640,10%FBS/ foetal calf serum are (through hybrid test; Through sterile filtration), 1%L-glutamine, 1% Pen .-Strep, 1%MEM Sodium.alpha.-ketopropionate, with 1%MEM non-must amino acid.FBS is that other compositions obtain from Invitrogen Life Science (Invitrogen Life Technologies, USA) from Sigma chemical company (Sigma Chemical Co.) acquisition.Be warmed to 37 DEG C through supplemental medium, and the substratum of 50mL is added to 175cm
2tissue culture flasks.
Cell for analyzing is the MDA-435 human breast cancer cells from U.S.'s Culture Collection.Shift out the MDA-435 cell of 1 bottle from liquid nitrogen frozen cell stock.Immediately the cryovial of cell inserted 37 DEG C of water-baths and leniently spin until melt.Freezing-bottle used 70% ethanol and immediately cell moved into containing the 175cm through supplemental medium with transfer pipet
2tissue culture flasks.Cell cultures is spent the night, and next day, substratum is shifted out and replace through supplemental medium with fresh.Culture flask is until flask becomes about 90% converges.This generally needs any time from 5-7 days.
Flask is cleaned with the room temperature phosphate buffer saline (PBS) that 10ml is aseptic.By cell by Tryptones-EDTA (Invitrogen) warm for 5ml being added in the flask of cell youngster with Tryptones process.Then cell is cultivated 2-3 minute until cell starts to be separated from the surface of flask in 37 DEG C.Equal volume added flask through supplemental medium (5ml).By all cell harvestings to 50ml test tube, and 20 DEG C in 1000RPM centrifugal totally 5 minutes.Sucking-off supernatant liquor and by cell pellet settling flux in 10ml through supplemental medium, and counting cells.1-3 1,000,000 cells/flask kind is entered 5-7 tissue culture flasks (175cm
2).Each flask should containing 50ml through supplemental medium.Culture flask is until about 90% converges.Repetitive cell goes down to posterity until obtain enough for the cell of tumour transplatation.
According to above for the program of Tryptones process and eccentric cell.Sucking-off supernatant liquor by cell pellet settling flux in the aseptic PBS of 10ml and counting cells.By cell centrifugation and then with the injection of the aseptic PBS settling flux of proper volume for the cell of the correct number needed for tumour transplatation.In the example of MDA-435,100,000,000 cells are suspended into ultimate density 5,000 ten thousand cell s/ml with the aseptic PBS of 2.0ml, with 0.1ml/ injected in mice 500 ten thousand cells.
Mouse (CD-1nu/nu) is available from laboratory, Charles river (Charles River Laboratories): name: Crl:CD-1-nuBR, age: 6-8 week is large.Before mouse is used to experimental arrangement, allow them to adapt to 1 week.
MDA-435 tumor cell suspension is generally the fat body (corpus adiposum) migrating to female CD-1 nu/nu mouse.This fatty body is the outside of belly abdominal organs being located at mouse.Tumour cell be migrate to hypodermically position right four points of hipbone (pelvis bone) and femur (femur) junction abdomen one fatty body.500 ten thousand MDA-435 cells in the aseptic PBS of 0.1ml are used the injection of 27G (1/2 inch) pin.MDA-435 tumour typically grows 2-3 week after transplanting.
Compound stock solution prepares by compound is dissolved in cell-cultivation-grade DMSO (methyl-sulphoxide) with desired concentration.This stock solution in DMSO is that sound shakes until all powder all dissolve in ultrasound water-bath.
Coordinating solvents is as following preparation: Cremophore RH40 (obtaining polyoxy 40 hydrogenated castor oil from BASF AG (BASF the corp.)) aqueous solution of 20% be by first by 100%Cremophore RH40 at 50-60 DEG C in heating in water bath until liquefaction and clarification and and prepare.The 100%Cremophore RH40 of 10ml is divided the conical centrifuge test tube (1: 5 dilution of Cremophore RH40) be filled to containing 40ml sterilized water.Reheat 20%Cremophore RH40 solution until it becomes clarification again, and mix by upset tube several times.This 20%Cremophore RH40 solution is stored in room temperature, and be saved to as many as 3 months.
For compound give to the preparation of drug solns: used by compound stock solution 20%Cremophore RH40 with 1: 10 dilution: 1) 10mg/ml of 2.0ml compound of the present invention is prepare by by the compound stock solution of 100mg/ml with the dilution of the 20%CremophoreRH40 aqueous solution of 1.8ml to drug solns; And 2) comprise the 1mg/ml Paclitaxel (obtaining from Sigma chemical company) of 2.0ml and the compound (1) of 5mg/ml be Paclitaxel DMSO stock solution (10mg/ml) by DMSO stock solution (50mg/ml) and the 0.1ml of the compounds of this invention mixing 0.1ml to drug solns and dilute with the 20%Cremophore RH40 aqueous solution of 1.8ml and obtain.For give the final composite of drug solns be 10%DMSO, 18%Cremophore RH40, with 72% water.
Mouse with MDA-435 human breast tumor will be injected to drug solns (administration volume: 0.01ml/ gram=10ml/kg) intravenously.Typical medication is shown with following table.
| Group | The compound of administration |
| 1 | Only supporting agent |
| 2 | Paclitaxel (5mg/kg) |
| 3 | Compound of the present invention (50mg/kg) |
| 4 | Paclitaxel (5mg/kg) and compound of the present invention (25mg/kg) |
| 5 | Paclitaxel (5mg/kg) and compound of the present invention (50mg/kg) |
Result
Compound of the present invention is anticipated and can be improved the anti-tumor activity of Paclitaxel significantly and can not increase toxicity.
Embodiment 2-6
Heat shock protein(HSP) (Hsp) is induced under various pressure condition and is bonded to other protein to prevent their sex change.Hsp can avoid apoptosis death by Cell protection.The agent that induction Hsp70 produces can have protectiveness activity to the attack of numerous species, and can have special effect in neurological disorder.The neuroprotective activity of bringing out property of Hsp70 compound of the present invention can be assessed in the disease pattern of various animal nerve.Especially, apoplexy, amyotrophic lateral sclerosis, Huntington chorea, Parkinson's disease, be the suitable setting for test efficacy with the zootype of Alzheimer's disease.The example of some zootypes is below provided.
Embodiment 2: the local asphyxia (apoplexy) of brain
The benefit of the use disclosed bringing out property of Hsp70 of the present invention compounds for treating can be assessed in the rodent pattern of apoplexy.Such as can utilize (the Longa such as the people that is described in Longa, E.Z., Weinstein, P.R., Carlson, S., with Cummins, R. (1989) Reversible middle cerebral artery occlusionwithout craniectomy in rats.Stroke 20:84-91) apoplexy pattern.
By rat Ke Taming (ketamine) to anaesthetize, and then by cranium outer vascular occlusion induction infraction.4-0 nylon chamber inner seam lines is inserted neck interior carotid artery and encephalic advance to blockade and flow to the blood of middle artery.Parallel blood flow lowers by interruption all branches of external carotid and all Lu Wai branches of internal carotid artery.Compound of the present invention can infraction bring out before or after administration immediately.10 to 100mg/kg body weight that administration can be (such as) gives once in a week, on every Wendesdays secondary or every day ground, it usual gives pattern by any, such as, oral area ground or intravenously ground.Can analyze neuroscience disappearance, mortality ratio, overall pathology (infraction size), with histochemical stain to assess effect of compound.Due to the pattern that this is very acute, and death is often observed in three days after infraction, and this pattern may be only made up of single medicine.
Embodiment 3: Familial amyotrophic inclined side sclerosis (ALS)
Compound of the present invention can use SODl gene to turn to grow mouse model simulation (Gurney in effect for the treatment of ALS, M.E., Pu, H., Chiu, A.Y., Dal Canto, M.C., Polchow, C.Y., Alexander, D.D., Caliendo, J., Hentati, A., Kwon, Y.W., with Deng, H.X. (1994) Motor neurondegeneration in mice that express a human CuZn superoxide dismutase mutation.Science 264:1772-1775).The sudden change of mankind CuZn superoxide-dismutase (SOD) finds having in familial ALS patients.In amino acid 93 containing glycine-to the showing that gene turns to grow in mouse and cause motor neurone disease of mankind's sod gene of the replacement of-L-Ala.Because motor neuron is lost from spinal cord, that mouse becomes paralysis and large in 5 to 6 months time dead.
In order to test effect of bringing out property of Hsp70 compound of the present invention, there is SOD1 sudden change (SOD1
g93A) gene turn that to grow mouse be with compounds for treating of the present invention, and supervise the effect to disease.Sign is obvious clinically these animals when 2.5 to 3 months large.Compound can in now starting administration.10 to 100mg/kg body weight that administration can be (such as) gives once in a week or secondary on every Wendesdays, by oral area or intravenous approach.Terminal (Endpoint) comprises the functional lesion of motor function and histological change.The latter's terminal is included in dynamoneure the brain of appearance and the histopathology of spinal cord of degeneration and the rich neurofilament inclusion body assessing motor neuron.If give for a long time, the impact of mouse survival can be assessed.
Embodiment 4: Huntington chorea (HD)
The gene having a kind of HD turns grows mouse model, it allows test bringing out property of Hsp70 compound of the present invention for effect (Mangiarini of this disease settings, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S.W., with Bates, G.P. (1996) Exon 1 of the HD gene with an expandedCAG repeat is sufficient to cause a progressive neurological phenotype intransgenic mice.Cell 87:493-506, Carter, R.J., Lione, L.A., Humby, T., Mangiarini, L., Mahal, A., Bates, G.P., Dunnett, S.B., with Morton, A.J. (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington ' s disease mutation.J.Neuroscience 19:3248-3257).HD is caused by CAG/ polyglutamine repetitive extension.These genes turn grows the 5 ' end that mouse (R6/2 gene turn grow) has the mankind HD gene containing (CAG) 115-(CAG) 150 repetitive extension.Mouse represents the gradual nervous pathology being similar to HD, comprises abnormal and involuntary motion, trembles and Epileptic fits.
These genes turn grow about 8 weeks of mouse large time show change on evident act.Morning, time large to 5 to 6 weeks, they appeared more small defect in acrobatics and tumblings.Bringing out property of Hsp70 compound of the present invention can start to give (such as, large in 5 to 6 weeks) in the various time to giving 10-100mg every kg body weight by intravenously or oral area.Compound can multiple different drug dosage schedule table (such as, once in a week relative to secondary on every Wendesdays) administration.Can carry out (such as treadmill (swimming tank), the walking of balance stalk (beam walking), roller machinery (rotarod apparatus), testing (see people such as Carter with footprint one or more rodent exercise test, 1999) carrying out), to assess the activity of compound in HD mouse prevention neuroscience afunction.
Embodiment 5: Parkinson's disease (PD)
Have the PD pattern that two kinds utilize widely, wherein disease is induced by chemotherapy.These are 6-OHDA (Zigmond, M.J. and Stricker, E.M. (1984) Parkinson ' s disease:studies with ananimal model.Life Sci.35:5-18, Sauer, H. with Oertel, W.H. (1994) Progressivedegeneration of nigrostriatal dopamine neurons following intrastriatal terminallesions with 6-Hydroxydopamine:a combined retrograde tracing andimmunocytochemical study in the rat.Neuroscience 59:401-415) and MPTP (Langston, J.W., Forno, L.S., Rebert, C.S., with Irwin, I. (1984) Selective nigraltoxicity after systemic administration of1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyrine (MPTP) in the squirrel monkey.Brain Res.292:390-4) pattern.Below describe the example that bringing out property of Hsp70 compound of the present invention uses the test of 6-OHDA.
Young Adult male rats is injected to the striatum of brain with fluoro-gold (FG) by stereoscopic localized (stereotactic) and injects, to promote the neural video picture in black substance (position of PD).Under anaesthesia, FG 4% solution of 0.2 μ l gives (before bregma 1mm, side 3mm, and from dura mater to two striatum outside of belly 4.5mm) by stereotaxical injection.After FG injects one week, rat accepts the stereotaxical injection of 6-OHDA, and (20 μ g, are dissolved in 4 μ l salt solutions; Sigma) to striatum in the side of brain, it is in the identical coordinate of FG injection.Bringing out property of Hsp70 compound of the present invention can give by intravenously or oral area to the dosage giving the every kg body weight of 10-100mg.Compound can (such as, 2-4 week) administration when 6-OHDA injection or after some times of 6-OHDA process.Rat be in 6-OHDA injection 8 and 16 weeks after sacrifice.The terminal of this pattern is 1) change in behavior, it supervises in several time by within all one's life, it is by the assessment of standing up (rotation) behavior using traditional neurologic reading (read-out), and 2) brain in sacrifice after shift out, cryostat is used to make thin section, and carry out immunohistochemistry, as in Zigmond and Stricker (1984) describe.Effect of bringing out property of Hsp70 compound of the present invention is the minimizing of the minimizing by circling behavior and the forfeiture at substantia nigra dopaminergic neuron and confirms.
Embodiment 6: Alzheimer's disease (AD)
There is the gene of several AD to turn and grow mouse model.These patterns one of them be widely used for testing drug effect person of AD be by the people such as Holcomb describe (Holcomb, L., Gordon, M.N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O ' Campo, K., Hardy, J., Prada, C.M., Eckman, C., Younkin, S., Hsiao, K., with Duff, K. (1998) Accelerated Alzheimer-typephenotype in transgenic mice carrying both mutant amyloid precursor protein andpresenilin 1 transgenes.Nature Medicine 4:97-100).This pattern contains two kinds of different genes relevant to AD.One is the sudden change at kind of starch albumen precursor protein (APP).It is that Tg2576, promotes kind of starch albumen beta-protein matter level in early days at the age that APP (K670N, the M671L) gene of sudden change turns to grow, and the extracellular AD-type A β that (afterwards) develops for brain deposits.Another gene is presenilin-1 (presenilin-1, the PS1) gene of attempting to change.Turn the dual gene growing the hybridization being and turn from suddenly change PS1M146L gene of Tg2576 and PS1 and grow offspring and to turn compared to their term single gene and grow Tg2576 mouse and deposit far beyond the fibrous A β developing high number as far back as pallium and hippocampus.
Bringing out property of Hsp70 compound of the present invention can in various time administration mouse.Mouse starts age of drug administration can be changeable.Such as, the treatment time opening 3 months large, it deposits the time can detected first for brain.10 to 100mg/kg body weight that dosage can be (such as) gives weekly once or secondary on every Wendesdays, by oral area or intravenous route.The effect of pharmacological agent can by measuring AD-type deposition at brain and testing by the function of assessment mouse in labyrinth and assess.
Embodiment 7: the measurement of heat shock protein 70 (Hsp70)
Blood plasma Hsp70 can measure through amending method by sandwich ELISA cover group (Stressgen biological reagent (StressgenBioreagents) Victoria, British Columbia, CANADA) according in tissue.Letter, the series concentration of Hsp70 and the Hsp70 standard substance of plasma sample is captured to 96-slotted eye dish (it has anti-Hsp70 antibody coated).Then the Hsp70 be captured then cultivates with the streptavidin (streptavidin) in conjunction with europium with biotinylating anti-Hsp70 antibody detecting.After each cultivation, non-binding substance shifts out by cleaning.Finally, antibody-Hsp70 complex compound is time resolved fluorescent art (time resolved fluorometry) by europium and measures.The concentration of Hsp70 calculates from typical curve.
Embodiment 8: the measurement of natural killer cell cellular cytoxicity activity
The activity of following programanalysis NK cell in individuality can be utilized.This program is rewritten from Kantakamalakul W, Jaroenpool J, Pattanapanyasat K.A novel enhanced green fluorescent protein (EGFP)-K562 flow cytometric method for measuring natural killer (NK) cell cytotoxic activity.J Immunol Methods.2003Jan 15; 272:189-197, its entire teachings includes in herein with way of reference.
Materials and methods: Human erythrocytes's leukocyte cell is (erythroleukaemic cell line), K562 obtains from U.S. Culture Collection (CCL-243, U.S.'s Culture Collection, Manassas, VA), and use 5%CO in 37 DEG C
2be incubated at 10% heat inactivation foetal calf serum (Gibco), 2mM L-glutaminate, 100 μ g/ml Streptomycin sulphates, RPMI-1640 substratum (the Cat#11875-093 Gibco Invitrogen company (Gibco Invitrogen Corp) supplementary with 100IU/ml penicillin, Carlsbad, CA) in.K562 cell is with the retroviral vector transduction of encoding green fluorescent albumen (eGFP).Stable cell selects with microbiotic (G418).After selection, the G418 resistant cell of about 99.6% is that eGFP is positive.
Individual peripheral blood monocytes (PBMC) prepares by clinical research sites and is contained in containing the BD Vacutainer cell preparation tubes accepting heparin sodium (BD Vacutainer Cell PreparationTube, production code member: 362753, Becton Dickinson, Franklin Lakes, NJ) in.
Will with 1X10
6the twice serial dilution of the 800 μ l effector cells (PBMC of patient) that the concentration of individual cell/mL starts is inserted in four points of other polystyrene 12X75-mm test tubes.Logarithmic phase growth property target cell (K562/eGFP) is adjusted to 1X10 with growth medium (RPMI-1640)
5the concentration of individual cell/mL the and then target of 100 μ L being added in vitro with effect/target (E/T) ratio providing 80: 1,40: 1,20: 1,10: 1.Cell determined by individual effect cell and independent target is be used as control group.By all test tubes with 5%CO
2be incubated at 37 DEG C about 3.5 hours.Ten ul iodinated third ingots (PI) are added to the concentration of 1mg/mL each test tube comprising effect and target control group test tube and also then within 15 minutes, cultivate in room temperature.
Cellular cytoxicity activity analyzes with FACSCalibur flowing-type cell instrument (Becton Dickinson).Obtain the linear amplification of forward (forward) and lateral scattering (side scatter) (FSC/SSC) signal, and eGFP and PI is transmitted in logarithmic amplification that is green and red fluorescence.Each sample tube collects 10,000 events without the restriction (gating for acquisition) of acquisition for analysis.The data analysis of eGFP to the two variable point coordinates figure of PI uses CELLQuest (Becton DickinsonBiosciences) software to counting with dead target cell of living.Fragment and dead cell disseminate the threshold value of (forward light scatter) by setting forward light and get rid of.
The suppression of embodiment 9:HUVEC cell migration
For checking whether that compound Human Umbilical Vein Endothelial Cells function of the present invention has an impact, under compound of the present invention exists, carry out in vitro human umbilical vein's endotheliocyte (HUVEC) migration analysis.HUVEC cell (number of passages 4) is incubated on 12-slotted eye dish, and timed interval image (time-lapse image) is with at supplementary 6-7%CO
2inverted microscope on viable cell image system carry out.Temperature maintains 37 DEG C.Within every 30 minutes, using 2X eyepiece mirror to obtain image to as many as uses 20X eyepiece to obtain image totally 30 minutes for 106 hours or every 60 seconds.Being cultivated by the HUVEC converged swipes with manufacturing gap region similarly, is then incubated at HUVEC substratum 15 totally hours and non-processor.Migration region, it is taken pictures with timed interval sequence to each slotted eye, is to be used as the basis for stdn/correction mobility.Then, the migration of cell under different process is taken a picture in the identical time with to each slotted eye generation time separation image sequence.It is analyze further by measuring the region that hidden by transport property cell that the timed interval moves.At experimental session, HUVEC cell is existence by VEGF and basic FGF and activates.Compound of the present invention (such as 100nM and 1 μM) is expected to attend the meeting fully blockades HUVEC cell migration to white space, implies that effective inhibition is held in the migration of compound of the present invention to the HUVEC cell of in vitro inducing by VEGF and basic FGF and activating.
Also HUVEC behavior may be followed the trail of during above process.Anticipate that HUVEC cell is can start shrinkage with compound treatment of the present invention after 24 hours.
The VE-calcium of the raising of embodiment 10:HUVEC cell is according to sticky connection albumen (cadherin) juncture
Immunofluorescence research is carried out to check that the intercellular VE-calcium of HUVEC is according to sticky connection albumen juncture according to sticky connection protein antibodies by the anti-VE-calcium of use.HUVEC cell processes 24 hours with DMSO or compound of the present invention (such as 10,100 and 1000nM), and fixing with immunostaining.All 1: 100 to all process DMSO concentration.Rise immunofluorescence signal in order to short, by cell with the mixture dyeing of the calcium of strain anti-human VE-more than 2 kinds according to sticky connection albumin A b, then dye with the mixture of fluorescent secondary antibodies.Compared to the cultivation of DMSO process, anticipate when using compound of the present invention, VE-calcium according to sticky connection protein staining can be extreme at position, cell-ECM juncture strong, but not in non-contact site.Compound of the present invention is expected the assembling at the cell-ECM juncture of the human endothelial cell improving activation that attends the meeting, and it may be through VE-calcium bringing out according to the accumulation of protein molecular in juncture of sticky connection.This effect can cause limited Cell motility and lower the penetrability of endotheliocyte, therefore has contribution to the cellular migration inhibition of compound of the present invention and possible anti-angiogenic generation effect.
The synthesis of embodiment 11 compound of the present invention
The synthesis of A.N ' 1, N ' 3-two (first sulphur imines (phenyl) methyl)-N ' 1, N ' 3-dimethyl propylene two hydrazides (dimethylmalonohydrazide) (compound 67)
By beaker with methylene dichloride (10mL), N-(methyl sulphonyl) imines Methoxybenzyl chloride (188m.; 1.1mmol), N ' 1, N ' 3-dimethyl propylene two hydrazides (88m.; 0.55mmol), with diisopropyl ethyl amine (0.5mL) fill, and by solution stirred overnight.Then by solution with 1N NH
4cl washs, and is used by product tubing string chromatographic analysis purifying to obtain two (first sulphur imines (phenyl) methyl)-N ' 1, the N ' 3-dimethyl propylene two hydrazides (138mg.) of N ' 1, N ' 3-in white foam.C
21h
26n
6o
6s
2eSMS calculated value: 522.1; Actual value: 523.2 (M+1).
The synthesis of N-(methyl sulphonyl) imines Methoxybenzyl chloride
By beaker with N-Toluidrin yl-benzamide (1.0g.; 5mmol) phosphorus pentachloride (1g) and chlorobenzene (20mL) are filled, and by solution in another hour of reflux.By product by tubing string chromatographic analysis purifying to obtain N-(methyl sulphonyl) imines Methoxybenzyl chloride (256mg).
The synthesis of N ' 1, N ' 3-dimethyl propylene two hydrazides
By beaker to fill from thick N ' 1, N ' 3-dicarboxyl benzyloxy-N ' 1, N ' 3-dimethyl propylene two hydrazides of following steps, methyl alcohol, 10% platinum on carbon, under being placed in hydrogen, and stirring and spend the night.Suspended substance is filtered by rankinite and is evaporated to dry to obtain N ' 1, N ' 3-dimethyl propylene two hydrazides (2.4g; 15mmol).
The synthesis of N ' 1, N ' 3-dicarboxyl benzyloxy-N ' 1, N ' 3-dimethyl propylene two hydrazides
By beaker with phenmethyl 1-methyl hydrazine carbonyl acid ester (9.0g.; 50mmol), propanedioic acid (2.5g; 25mmol), methylene dichloride (50mL), with 1-ethyl-3-(3 '-Dimethylaminopropyl) carbodiimide (10g; 5.25mmol) to fill and by solution stirring one hour.By organic solution with saturated ammonium chloride washing, and by product by tubing string chromatographic analysis purifying to obtain N ' 1, N ' 3-dicarboxyl benzyloxy-N ' 1, N ' 3-dimethyl propylene two hydrazides (15mmol).
The synthesis of B.N '-methyl-2-(2-methyl-2-(thiobenzoyl (phenylcarbonothioyl)) diazanyl)-2-oxo-N '-(thiobenzoyl) second sulfonyl hydrazide (compound 68)
(compound 68)
Dropwise 2-(chlorosulfonyl) Acetyl Chloride 98Min. (5mmol) is added N-methyl thio benzoyl hydrazine (10mmol) in 0 DEG C of solution of DCM (20mL) and pyridine (1mL).Be introduced into (20mL) in water at mixture front, hold it in room temperature totally 2 hours.Organic layer is separated, dry also to evaporate, and by the resistates obtained by tubing string chromatographic analysis purifying to obtain the compound 68 (0.8g) in faint yellow solid.
1h-NMR (CDCl
3) 10.5 (m, 1H), 7.4 (m, 10H), 4.4 (m, 1H), 3.4-3.8 (m, 8H) ppm; C
18h
20n
4o
3s
3eSMS calculated value: 436.1; Actual value: 437.2 (M+H
+).
C. the synthesis of dimethyl N, N '-methylene-bis (N '-methyl-N '-(thiobenzoyl)-phosphinylidyne hydrazine compound (phosphonohydrazidate)) (compound 30)
(compound 30)
Dropwise methylene biphosphonic acid dichlorides (9mmol) is added N-methyl thio benzoyl hydrazine (18mmol) in 0 DEG C of solution of DCM (20mL) and TEA (1mL).Anhydrous methanol (2mL) is being added mixture and in stirring at room temperature before 1 day, mixture is being remained on room temperature totally 2 hours.Enriched mixture is also divided into many parts in EtOAc (10mL) with water (10mL); Organic layer is separated, dry also to evaporate, and by the resistates obtained by tubing string chromatographic analysis purifying to obtain the compound 30 (0.20g) in faint yellow oil.
1h-NMR (CDCl
3) 8.5 (m, 2H), 7.2-7.4 (m, 10H), 3.6-4.0 (m, 6H), 3.3-3.6 (m, 8H) ppm; ESMS calculated value C
19h
26n
4o
4p
2s
2: 500.1; Actual value: 501.2 (M+H
+).
D. the synthesis of compound 69
(compound 69)
Dropwise dichloro phosphoric acid benzene (5mmol) is added N-methyl thio benzoyl hydrazine (10mmol) in 0 DEG C of solution of DCM (20mL).Before being poured into by mixture in water (20mL), hold it in room temperature totally 2 hours.Organic layer is separated, dry also to evaporate, and by the resistates obtained by tubing string chromatographic analysis purifying to obtain the compound 69 (0.8g) in faint yellow solid.
1h-NMR (CDCl
3) 8.6 (m, 4H), 7.2-7.5 (m, 16H), 3.3-3.6 (m, 6H) ppm; ESMS calculated value C
28h
26n
4o
4p
2s
2: 608.1; Actual value: 609.2 (M+H
+).
E. the synthesis of compound 70 and 71
Compound 70 and 71 is as prepared described in flow process A:
Flow process A
EDC (480mg, 2.5mmol) is added Comp.A (335mg, 2.0mmol) with dicarboxylic acid (1.0mmol) in the solution of DMF or DCM (10mL).Reaction mixture is stirred totally 12 hours.The performance level of reaction judges with TLC.By reaction mixture with DCM (25mL) dilution also Yi Shui and salt water washing.By organic layer with MgSO
4drying is also filtered.After shifting out solvent, product is column purified by chromatographic analysis.
N ' 1, N ' 3-dimethyl-N ' 1, N ' 3-bis-(thiobenzoyl)-2-(2-Phenylhydrazono)-malonyl-hydrazine (compound 70)
C
25h
24n
6o
2s
2eSMS calculated value: 504.14; Actual value: 505.2 (M+H)
+.
N ' 1, N ' 3-dimethyl-2-(2-methylhydrazono)-N ' 1, N ' 3-bis-(thiobenzoyl)-malonyl-hydrazine (compound 71)
C
20h
22n
6o
2s
2eSMS calculated value: 442.12; Actual value: 443.3 (M+H)
+.
F.2-the synthesis of methyl-N-(2-methyl-2-(thiobenzoyl) diazanyl alkylsulfonyl)-2-(thiobenzoyl) Hydrazinecarboxamidederivatives (compound 72)
Compound 72 prepares as described in flow process B
Flow process B
By Et
3n (300mg, 3.0mmol) adds comp.A (335mg, 2.0mmol) with isocyanate compound (1.0mmol) in the solution of THF or EtOH (15mL).Reaction mixture is stirred totally 12 hours.The completeness of reaction judges with TLC.Reaction mixture is concentrated under vacuo, and by resistates with DCM (25mL) dilution also Yi Shui and salt water washing.By organic layer with MgSO
4drying is also filtered.After shifting out solvent, product is column purified by chromatographic analysis.
(compound 72)
C
17h
19n
5o
3s
3eSMS calculated value: 437.07; Actual value: 438.1 (M+H)
+.
Embodiment 12: the Hsp70 by tested compound brings out
The ability that compound induction Hsp70 RNA of the present invention brings out checks by quantitative pcr analysis.Ramos B cell is with often kind of 500nM compound treatment 6 hours, and from cellular segregation RNA.Quantitative PCR is as following describing is carried out:
The details of quantitative PCR is as follows:
The RNA of the 500ng from each sample is used for cDNA synthesis, it uses iScript cDNA to synthesize cover group (iScript cDNA Synthesis Kit, Biorad, Cat#170-8882) to use standard method to carry out quantitative PCR in iCycler machinery (Biorad).The QPCR of each sample/time point is carried out with duality method.Use the following introduction for the inducibility mankind Hsp70 and gapdh:
Hsp70-F35`-AAG-GAC-ATC-AGC-CAG-AAC-AAG-CG-3’
Hsp70-R35`-AAG-AAG-TCC-TGC-AGC-AGC-TTC-TGC-3’
Gapdh-F25`-AAG-GTC-GGA-GTC-AAC-GGA-TTT-GGT-3`
Gapdh-R25`-CAT-GGT-TCA-CAC-CCA-TGA-CGA-ACA-3’
Obtain Ct value from iCycler formula and use it for equation (2-
Δ Δ C t) to measure the amount that target shows relative to gapdh.This to compare in each sample Hsp70 to the relative performance of the corresponding level of gapdh.Average two repeat slotted eye.The amount that the positive malonyl of Hsp70-bis-(N '-methyl-N ' thiobenzoyl hydrazides) (compd B) brings out is set as 100%, and be measure relative to 100% by the per-cent that the Hsp70 of compound of the present invention brings out.
The ability that the compound of the present invention induction Hsp70RNA measured by quantitative pcr analysis brings out is listed in in following table.
All this paper quote and understand point out it is the relevant teachings including publication herein with way of reference in, it is include in herein with way of reference in full.
Although the present invention is especially to show with reference to the mode of its preferably embodiment and to describe, those skilled in the art can understand can make wherein various in form with change in detail, and the scope that the present invention contains for appended claim can not be departed from.
Claims (6)
1. the compound representated by following structural formula:
2. the compound representated by following structural formula:
3. the compound representated by following structural formula:
4. a medical composition, it comprises pharmaceutically acceptable supporting agent or thinner and the compound any one of claims 1 to 3.
5. a purposes for the compound any one of claims 1 to 3, it is the pharmaceuticals for the manufacture of being used for the treatment of the individuality with cancer.
6. purposes according to claim 5, wherein this cancer is multiple drug resistance cancer.
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| US60/841,408 | 2006-08-31 | ||
| PCT/US2007/018378 WO2008024303A2 (en) | 2006-08-21 | 2007-08-20 | Compounds for treating proliferative disorders |
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