ITMI20011733A1 - Derivati dell'acido idrossamico inibitori degli enzimi istone deacetilasi, quali nuovi farmaci antiinfiammatori inibenti la sintesi di citoc - Google Patents
Derivati dell'acido idrossamico inibitori degli enzimi istone deacetilasi, quali nuovi farmaci antiinfiammatori inibenti la sintesi di citoc Download PDFInfo
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- ITMI20011733A1 ITMI20011733A1 IT2001MI001733A ITMI20011733A ITMI20011733A1 IT MI20011733 A1 ITMI20011733 A1 IT MI20011733A1 IT 2001MI001733 A IT2001MI001733 A IT 2001MI001733A IT MI20011733 A ITMI20011733 A IT MI20011733A IT MI20011733 A1 ITMI20011733 A1 IT MI20011733A1
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- hydroxamic acid
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- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 239000002253 acid Substances 0.000 title claims abstract description 11
- 229940124599 anti-inflammatory drug Drugs 0.000 title claims description 3
- 230000015572 biosynthetic process Effects 0.000 title description 7
- 238000003786 synthesis reaction Methods 0.000 title description 7
- 239000003112 inhibitor Substances 0.000 title description 2
- 108010033040 Histones Proteins 0.000 title 1
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 102000003964 Histone deacetylase Human genes 0.000 claims abstract description 6
- 108090000353 Histone deacetylase Proteins 0.000 claims abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 229930185603 trichostatin Natural products 0.000 claims description 15
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- QOSWSNDWUATJBJ-UHFFFAOYSA-N n,n'-diphenyloctanediamide Chemical compound C=1C=CC=CC=1NC(=O)CCCCCCC(=O)NC1=CC=CC=C1 QOSWSNDWUATJBJ-UHFFFAOYSA-N 0.000 claims description 3
- OYKBQNOPCSXWBL-SNAWJCMRSA-N n-hydroxy-3-[(e)-3-(hydroxyamino)-3-oxoprop-1-enyl]benzamide Chemical compound ONC(=O)\C=C\C1=CC=CC(C(=O)NO)=C1 OYKBQNOPCSXWBL-SNAWJCMRSA-N 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- OYKBQNOPCSXWBL-UHFFFAOYSA-N n-hydroxy-3-[3-(hydroxyamino)-3-oxoprop-1-enyl]benzamide Chemical compound ONC(=O)C=CC1=CC=CC(C(=O)NO)=C1 OYKBQNOPCSXWBL-UHFFFAOYSA-N 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 2
- 102000004127 Cytokines Human genes 0.000 description 15
- 108090000695 Cytokines Proteins 0.000 description 15
- 230000000770 proinflammatory effect Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 108700012920 TNF Proteins 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000007302 negative regulation of cytokine production Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000187391 Streptomyces hygroscopicus Species 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000432 density-gradient centrifugation Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000017095 negative regulation of cell growth Effects 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Descrizione del brevetto per invenzione industriale avente per titolo:
"DERIVATI DELL’ACIDO IDROSSAMICO INIBITORI DEGLI ENZIMI ISTONE DEACETILASI, QUALI NUOVI FARMACI ANTIINFI AMM AT ORI INIBENTI LA SINTESI DI CITOCHINE"
La presente invenzione ha per oggetto l’uso di derivati dell’acido idrossamico ad attività inibente gli enzimi denominati istone deacetilasi per la preparazione di medicamenti antiinfiammatori.
Sono noti alcuni derivati dell’acido idrossamico ad attività inibente gli istone deacetilasi: tra questi, i più studiati sono la suberoilanilide dell’acido idrossamico (SAHA), N-idrossi-3-[3-(idrossiamino)-3-oxo-l-propenil]-benzamide (CBHA)e la tricostatina(TSA). Altri derivati sono descritti in Proc. Nati. Acad. Sci. USA 95,3003-3007, 1998.
Tali composti sono stati studiati prevalentemente come potenziali farmaci antitumorali: la tricostatina, un antibiotico antifungino isolato da Streptomyces hygroscopicus, è un potente induttore del differenziamento di cellule eritroleucemiche murine (Cancer Res. 47, 3288-3691, 1987) mentre SAHA e CBHA sono state studiate dallo Sloan Kettering Insti tute (WO 95/31977)come agenti induttori del differenziamento di cellule neoplastiche.
L’uso terapeutico di inibitori di istone deacetilasi per il trattamento di neoplasie è descritto in
Anticancer Res. 20, 1471-1486, 2000 e in Exp.Opin.Invest. Drugs 8(10), 1611-1621, 1999.
Si è ora trovato che i noti derivati dell’ acido idrossamico ad attività inibente gli istone deacetilasi, in particolare tricostatina e SAHA, inibiscono la sintesi di citochine proinfiammatorie e possono pertanto essere utilizzati per il trattamento di malattie che possano essere alleviate da un’inibizione di tali citochine. Esempi di tali malattie su base infiammatoria e/o autoimmune comprendono sclerosi multipla, morbo di Chron e colite ulcerosa, aterosclerosi, artrite reumatoide, psoriasi e, in linea di massima, tutte le patologie caratterizzate da una componente infiammatoria.
Per gli impieghi terapeutici considerati, i derivati dell’acido idrossamico saranno somministrati a dosi variabili da 1 - 500 mg una o più volte al giorno, a seconda del tipo di patologia e delle caratteristiche farmacotossicologiche del composto considerato, che potrà essere somministrato sotto forma di opportune formulazioni per via orale, parenterale o topica.
I seguenti esempi illustrano l’invenzione in maggior dettaglio.
ESEMPIO 1- Inibizione della produzione di citochine in vitro
II trattamento di linfociti con lipopolissaride (LPS) induce la produzione di differenti citochine pro-infiammatorie, quali TNFa ed IL-Ιβ (Schindler R. et al. J. Biol. Chem. 1990; 265(18): 10232-10237; Carballo E. et al. Science 1998; 281:1001-1005).
L’effetto di SAHA e TSA è stato studiato valutando l’effetto inibitorio del composto sulla produzione di citochine da parte di cellule mononucleate del sangue periferico (PBMC) di donatori sani (da 2 a 6 donatori) stimolate con LPS.
Sono stati utilizzati campioni di sangue periferico o buffy coats da donatori sani. I campioni sono stati separati mediante centrifugazione su gradiente di densità utilizzando Ficoll-Hypaque e i PBMC così ottenuti sono stati seminati in piastre da 96 pozzetti (500.000 cellule/pozzetto) ed incubati per 60 minuti con SAHA o TSA alle varie dosi e quindi stimolati con LPS da E. coli 055:B5 (10 ng/ml) per 24 ore in presenza del composto. Al termine del trattamento le citochine proinfiammatorie TNFa, IL-Ιβ sono state misurate mediante un saggio in elettrochemiluminescenza (ECL) utilizzando anticorpi specifici commerciali.
Interferone γ (IFNy) è stato misurato mediante un saggio ELISA commercialmente disponibile.
La citochina IFNy è prodotta dai linfociti T a seguito della stimolazione degli stessi da parte di citochine proinfiammatorie ed in particolare da IL- 12 ed IL-18 (Dinarello C. A. and Moldawer L. L. Proinflammatory and antiinflammatory cytokines in rheumatoid arthritis. A primer for clinicians. 2<nd >Edition, Amgen Ine., 2000).
Su tale base è stato valutato l’effetto di SAHA e TSA sulla sintesi di IFNy indotta dalla stimolazione di PBMC con IL-12 ed IL-18 in vitro. PBMC sono stati seminati in piastre da 96 pozzetti (500.000 cellule/pozzetto) a fondo tondo, incubate con SAHA o TSA, alle varie dosi, per 60 minuti. Al termine le cellule, in presenza del composto, sono state stimolate per 48 ore mediante l’aggiunta contemporanea di IL-12 ricombinante (10 ng/ml) e di IL-18 ricombinante (20 ng/ml). Al termine la quantità di IFNy prodotta era determinata mediante un saggio ELISA commerciale.
L’effetto di SAHA e TSA alle varie dosi è stato misurato come percentuale di inibizione della produzione della citochina in esame rispetto a cellule di controllo che non sono state trattate con il composto. Mediante regressione lineare è stata quindi determinata la concentrazione in grado di indurre una inibizione della crescita cellulare del 50% (IC50).
I risultati ottenuti sono riassunti nella seguente tabella:
I risultati ottenuti indicano chiaramente che SAHA e TSA inibiscono la sintesi di tutte le citochine infiammatorie indotte da LPS con IC50 nel range nanomolare (50-200nM).
SAHA e TSA sono inoltre in grado di inibire la sintesi di IFNy da parte di cellule linfocitarie T, come dimostrato dalla loro efficacia (IC50 740 nM e 490 nM, rispettivamente) quando lo stimolo utilizzato è stata la combinazione IL-12 ed IL- 18 specifiche per tale stipite cellulare.
ESEMPIO 2 - Inibizione della produzione di citochine in vivo
E’ noto che la somministrazione sistemica di LPS ad animali da esperimento induce la produzione rapida e massiccia di citochine proinfiammatorie (Sironi M. et al. Immunopharmacol. 1992; 14(6): 1045-1050).
Topi BALB/c femmine (20-22 grammi) sono stati trattati oralmente con SAHA, alle varie dosi indicate, e dopo 60 minuti con LPS da E. Coli 055:B5 (30 mg/Kg intraperitoneo). 90 minuti dopo la somministrazione di endotossina è stato prelevato il sangue a tutti gli animali trattati (10 animali/gruppo) e le citochine misurate mediante ELISA commerciali.
I risultati ottenuti sono riportati nella seguente tabella ed espressi come percentuale di inibizione della produzione della citochina in esame:
I risultati ottenuti indicano che SAHA è attivo oralmente ed in grado di inibire in maniera dose-dipendente la sintesi di citochine proinfiammatorie, indotta in vivo nel topo, dalla somministrazione di endotossina confermando i risultati descritti in vitro.
Claims (1)
- RIVENDICAZIONI 1. Uso di derivati dell’acido idrossamico ad attività inibente gli enzimi della famiglia istone deacetilasi per la preparazione di medicamenti antiinfiammatori 2. Uso secondo la rivendicazione 1 in cui i derivati sono scelti fra suberoilanilide dell’acido idrossamico (SAHA), N-idrossi-3-[3-(idrossiamino)-3-oxo-l-propenil]-benzamide (CBHA) e tricostatina (TSA). 3. Uso secondo la rivendicazione 2 in cui i derivati sono scelti fra suberoilanilide dell’acido idrossamico (SAHA)e tricostatina(TSA). 4. Uso secondo la rivendicazione 1 o 2 per la preparazione di un medicamento per il trattamento di artrite reumatoide, morbo di Chron, colite ulcerosa, aterosclerosi, sclerosi multipla, psoriasi.
Priority Applications (23)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2001MI001733A ITMI20011733A1 (it) | 2001-08-07 | 2001-08-07 | Derivati dell'acido idrossamico inibitori degli enzimi istone deacetilasi, quali nuovi farmaci antiinfiammatori inibenti la sintesi di citoc |
| BR0212014-3A BR0212014A (pt) | 2001-08-07 | 2002-07-26 | Uso de derivados do ácido hidroxâmico inibidores da enzima histone deacetilase |
| CNA028154363A CN1538838A (zh) | 2001-08-07 | 2002-07-26 | 作为新的细胞因子合成抑制性抗炎药物的组蛋白脱乙酰酶抑制性异羟肟酸衍生物 |
| DK02764796T DK1414428T3 (da) | 2001-08-07 | 2002-07-26 | Histondeacetylaseenzym-inhiberende derivater af hydroxamsyre som hidtil ukendt cytokinsyntese-inhiberende anti-inflammatoriske lægemidler |
| PCT/EP2002/008379 WO2003013493A1 (en) | 2001-08-07 | 2002-07-26 | Histone deacetylase enzyme-inhibiting derivatives of hydroxamic acid as new cytokine synthesis-inhibiting anti-inflammatory drugs |
| PT02764796T PT1414428E (pt) | 2001-08-07 | 2002-07-26 | Derivados de ácido hidroxâmico inibidores da enzima histonadesacetilase como novos fármacos anti-inflamatórios inibidores da síntese de citoquinas |
| EP02764796A EP1414428B1 (en) | 2001-08-07 | 2002-07-26 | Histone deacetylase enzyme-inhibiting derivatives of hydroxamic acid as new cytokine synthesis-inhibiting anti-inflammatory drugs |
| SI200230840T SI1414428T1 (sl) | 2001-08-07 | 2002-07-26 | Derivati hidroksamske kisline, ki zavirajo encim histon deacetilazo, kot nova protivnetna zdravila, ki zavirajo sintezo citokina |
| MXPA04001190A MXPA04001190A (es) | 2001-08-07 | 2002-07-26 | Derivados de acido hidroxamico inhibidores de enzima histona deacetilasa como nuevos farmacos inhibidores de sintesis de citocinas anti-inflamatorios. |
| JP2003518503A JP2005506320A (ja) | 2001-08-07 | 2002-07-26 | 新しいサイトカイン合成を阻害する抗炎症薬としてのヒドロキサム酸の、ヒストンデアセチラーゼ酵素を阻害する誘導体 |
| RU2004106605/15A RU2004106605A (ru) | 2001-08-07 | 2002-07-26 | Производные гидроксамовых кислот, ингибирующие фермент деацетилазу гистонов, в качестве новых противовоспалительных лекарственных средств, ингибирующих синтез цитокинов |
| PL02365391A PL365391A1 (en) | 2001-08-07 | 2002-07-26 | Histone deacetylase enzyme-inhibiting derivatives of hydroxamic acid as new cytokine synthesis-inhibiting anti-inflammatory drugs |
| IL16007502A IL160075A0 (en) | 2001-08-07 | 2002-07-26 | Histone deacetylase enzyme-inhibiting derivatives of hydroxamic acid as new cytokine synthesis-inhibiting anti-inflammatory drugs |
| US10/486,152 US20040157930A1 (en) | 2001-08-07 | 2002-07-26 | Histone deacetylase enzyme-inhibiting derivatives of hydroxamic acid as new cytokine synthesis-inhibiting anti-inflammatory drugs |
| DE60232797T DE60232797D1 (de) | 2001-08-07 | 2002-07-26 | Histon deazetylase enzym-hemmende hydroxamsäurederivate als neue entzündungshemmer zur hemmung der zytokinsynthese |
| HU0401167A HUP0401167A2 (hu) | 2001-08-07 | 2002-07-26 | Hiszton-dezacetiláz enzimet gátló hidroxámsav-származékok, mint új, citokin szintézist gátló gyulladás elleni gyógyszerek |
| KR10-2004-7001946A KR20040035724A (ko) | 2001-08-07 | 2002-07-26 | 신규 사이토카인 합성-억제 항염증제로서의 히드록삼산의히스톤 디아세틸라제 효소-억제 유도체 |
| AT02764796T ATE435013T1 (de) | 2001-08-07 | 2002-07-26 | Histon deazetylase enzym-hemmende hydroxamsäurederivate als neue entzündungshemmer zur hemmung der zytokinsynthese |
| CA002456533A CA2456533A1 (en) | 2001-08-07 | 2002-07-26 | Histone deacetylase enzyme-inhibiting derivatives of hydroxamic acid as new cytokine synthesis-inhibiting anti-inflammatory drugs |
| ES02764796T ES2328468T3 (es) | 2001-08-07 | 2002-07-26 | Derivados de acido hidroxamico que inhiben la enzima histona desacetilasa como nuevos farmacos antiinflamatorios que inhiben la sintesis de citoquinas. |
| IS7124A IS7124A (is) | 2001-08-07 | 2004-01-26 | Histón deasetýlasa ensím-hamlandi afleiður af hýdroxamsýru sem ný frumuboða efnasmíðahamlandi bólgueyðandi lyf |
| NO20040513A NO20040513L (no) | 2001-08-07 | 2004-01-29 | Histondeacetylase-enzyminhiberende derivater av hydroksaminsyre som nye cytokinsynteseinhiberende anti-inflammatoriske medikamenter. |
| CY20091100978T CY1109391T1 (el) | 2001-08-07 | 2009-09-21 | Παραγωγα του υδροξαμικου οξεος, αναστολεις του ενζυμου ιστονοδεακετυλαση, που χρησιμοποιουνται ως νεα αντιφλεγμονωδη φαρμακα αναστολεις της συνθεσης της κιτοκινης |
Applications Claiming Priority (1)
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| IT2001MI001733A ITMI20011733A1 (it) | 2001-08-07 | 2001-08-07 | Derivati dell'acido idrossamico inibitori degli enzimi istone deacetilasi, quali nuovi farmaci antiinfiammatori inibenti la sintesi di citoc |
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| ITMI20011733A0 ITMI20011733A0 (it) | 2001-08-07 |
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| JP (1) | JP2005506320A (it) |
| KR (1) | KR20040035724A (it) |
| CN (1) | CN1538838A (it) |
| AT (1) | ATE435013T1 (it) |
| BR (1) | BR0212014A (it) |
| CA (1) | CA2456533A1 (it) |
| CY (1) | CY1109391T1 (it) |
| DE (1) | DE60232797D1 (it) |
| DK (1) | DK1414428T3 (it) |
| ES (1) | ES2328468T3 (it) |
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| IL (1) | IL160075A0 (it) |
| IS (1) | IS7124A (it) |
| IT (1) | ITMI20011733A1 (it) |
| MX (1) | MXPA04001190A (it) |
| NO (1) | NO20040513L (it) |
| PL (1) | PL365391A1 (it) |
| PT (1) | PT1414428E (it) |
| RU (1) | RU2004106605A (it) |
| SI (1) | SI1414428T1 (it) |
| WO (1) | WO2003013493A1 (it) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US8026280B2 (en) | 2001-03-27 | 2011-09-27 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
| US7842727B2 (en) | 2001-03-27 | 2010-11-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
| US7312247B2 (en) | 2001-03-27 | 2007-12-25 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
| AU2003219803B8 (en) * | 2002-02-15 | 2005-08-25 | Sloan-Kettering Institute For Cancer Research | Method of treating TRX mediated diseases |
| WO2003070691A1 (fr) * | 2002-02-21 | 2003-08-28 | Osaka Industrial Promotion Organization | Derive de n-hydroxycarboxamide |
| JP4732693B2 (ja) | 2002-03-04 | 2011-07-27 | メルク・エイチ・デイ・エイ・シー・リサーチ，エル・エル・シー | 最終分化を誘導する方法 |
| US7456219B2 (en) | 2002-03-04 | 2008-11-25 | Merck Hdac Research, Llc | Polymorphs of suberoylanilide hydroxamic acid |
| CA2486303C (en) | 2002-05-22 | 2013-04-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors based on alpha-ketoepoxide compounds |
| JP2006508986A (ja) | 2002-11-20 | 2006-03-16 | エルラント ゲネ セラペウチクス エルエルシー | ヒストンデアセチラーゼ阻害剤による肺細胞の治療方法 |
| ITMI20030025A1 (it) * | 2003-01-10 | 2004-07-11 | Italfarmaco Spa | Derivati dell'acido idrossammico ad attivita' antinfiammatoria. |
| ITMI20030064A1 (it) | 2003-01-17 | 2004-07-18 | Italfarmaco Spa | Uso dei derivati dell'acido idrossamico per la preparazione |
| DE602004021573D1 (de) | 2003-04-07 | 2009-07-30 | Pharmacyclics Inc | Hydroxamate als therapeutische mittel |
| EP1491188A1 (en) * | 2003-06-25 | 2004-12-29 | G2M Cancer Drugs AG | Topical use of valproic acid for the prevention or treatment of skin disorders |
| NZ545935A (en) * | 2003-08-26 | 2009-02-28 | Merck Hdac Res Llc | Method of treating cancer with HDAC inhibitors |
| ES2562778T3 (es) * | 2003-12-02 | 2016-03-08 | The Ohio State University Research Foundation | Ácidos grasos de cadena corta unidos a motivos quelantes de Zn2+ como una clase novedosa de inhibidores de histona deacetilasa |
| US7368476B2 (en) * | 2004-04-07 | 2008-05-06 | Pharmacyclics, Inc. | Hydroxamates as therapeutic agents |
| JP2008505969A (ja) * | 2004-07-12 | 2008-02-28 | メルク エンド カムパニー インコーポレーテッド | ヒストン脱アセチル化酵素の阻害剤 |
| GB2417682A (en) * | 2004-08-18 | 2006-03-08 | Univ East Anglia | Histone deacetylse inhibitor for treating connective tissue disorders |
| ZA200800901B (en) | 2005-07-14 | 2010-05-26 | Takeda San Diego Inc | Histone deacetylase inhibitors |
| WO2007109178A2 (en) | 2006-03-16 | 2007-09-27 | Pharmacyclics, Inc. | Indole derivatives as inhibitors of histone deacetylase |
| US20110150825A1 (en) * | 2006-11-14 | 2011-06-23 | Pharmacyclics, Inc. | Uses of selective inhibitors of hdac8 for treatment of inflammatory conditions |
| WO2008060721A1 (en) * | 2006-11-14 | 2008-05-22 | Pharmacyclics, Inc. | Uses of selective inhibitors of hdac8 for treatment of t-cell proliferative disorders |
| PT2099442E (pt) | 2006-12-26 | 2015-02-10 | Pharmacyclics Inc | Métodos de utilização de inibidores de histona desacetilase e monitorização de biomarcadores em terapia de combinação |
| EP2993473A1 (en) | 2007-01-30 | 2016-03-09 | Pharmacyclics, Inc. | Methods for determining cancer resistance to histone deacetylase inhibitors |
| US9827212B2 (en) * | 2009-03-18 | 2017-11-28 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating asthma and other lung diseases |
| US8603521B2 (en) | 2009-04-17 | 2013-12-10 | Pharmacyclics, Inc. | Formulations of histone deacetylase inhibitor and uses thereof |
| EP2464967B1 (en) * | 2009-08-14 | 2013-06-12 | Cellzome Ag | Methods for the identification and characterization of hdac interacting compounds |
| WO2012018499A2 (en) * | 2010-08-05 | 2012-02-09 | Acetylon Pharmaceuticals | Specific regulation of cytokine levels by hdac6 inhibitors |
| US20140051716A1 (en) * | 2011-03-09 | 2014-02-20 | Cereno Scientific Ab | Compounds and methods for improving impaired endogenous fibrinolysis using histone deacetylase inhibitors |
| EP2755648B1 (en) | 2011-09-13 | 2017-03-08 | Pharmacyclics LLC | Formulations of histone deacetylase inhibitor in combination with bendamustine and uses thereof |
| WO2013114413A1 (en) * | 2012-02-03 | 2013-08-08 | Italfarmaco S.P.A. | Diethyl- [6- (4-hydroxycarbamoyl-phenyl-carbamoyloxy-methyl) - naphthalen-2-yl-methyl] -ammonium chloride for use in the treatment of muscular dystrophy |
| CN102793693A (zh) * | 2012-09-07 | 2012-11-28 | 天津医科大学 | 伏立诺他在制备治疗自身免疫及炎症性疾病药物方面的应用 |
| GB201417828D0 (en) | 2014-10-08 | 2014-11-19 | Cereno Scient Ab | New methods and compositions |
| CN109414423A (zh) | 2016-04-08 | 2019-03-01 | 赛伦诺科技有限公司 | 包含丙戊酸的延迟释放药物制剂和其用途 |
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| US5700811A (en) | 1991-10-04 | 1997-12-23 | Sloan-Kettering Institute For Cancer Research | Potent inducers of terminal differentiation and method of use thereof |
| US5318964A (en) * | 1992-06-11 | 1994-06-07 | Hoffmann-La Roche Inc. | Hydroxamic derivatives and pharmaceutical compositions |
| PT757984E (pt) * | 1995-08-08 | 2003-02-28 | Ono Pharmaceutical Co | Derivados de acido hidroxamico uteis para inibir a gelatinase |
| US6777217B1 (en) * | 1996-03-26 | 2004-08-17 | President And Fellows Of Harvard College | Histone deacetylases, and uses related thereto |
| IT1283637B1 (it) * | 1996-05-14 | 1998-04-23 | Italfarmaco Spa | Composti ad attivita' antinfiammatoria ed immunosoppressiva |
| WO2002055017A2 (en) * | 2000-11-21 | 2002-07-18 | Wake Forest University | Method of treating autoimmune diseases |
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2001
- 2001-08-07 IT IT2001MI001733A patent/ITMI20011733A1/it unknown
-
2002
- 2002-07-26 CA CA002456533A patent/CA2456533A1/en not_active Abandoned
- 2002-07-26 AT AT02764796T patent/ATE435013T1/de active
- 2002-07-26 RU RU2004106605/15A patent/RU2004106605A/ru not_active Application Discontinuation
- 2002-07-26 BR BR0212014-3A patent/BR0212014A/pt not_active IP Right Cessation
- 2002-07-26 MX MXPA04001190A patent/MXPA04001190A/es unknown
- 2002-07-26 PL PL02365391A patent/PL365391A1/xx not_active Application Discontinuation
- 2002-07-26 DE DE60232797T patent/DE60232797D1/de not_active Expired - Lifetime
- 2002-07-26 IL IL16007502A patent/IL160075A0/xx unknown
- 2002-07-26 CN CNA028154363A patent/CN1538838A/zh active Pending
- 2002-07-26 US US10/486,152 patent/US20040157930A1/en not_active Abandoned
- 2002-07-26 EP EP02764796A patent/EP1414428B1/en not_active Expired - Lifetime
- 2002-07-26 KR KR10-2004-7001946A patent/KR20040035724A/ko not_active Application Discontinuation
- 2002-07-26 DK DK02764796T patent/DK1414428T3/da active
- 2002-07-26 HU HU0401167A patent/HUP0401167A2/hu unknown
- 2002-07-26 SI SI200230840T patent/SI1414428T1/sl unknown
- 2002-07-26 PT PT02764796T patent/PT1414428E/pt unknown
- 2002-07-26 WO PCT/EP2002/008379 patent/WO2003013493A1/en active Application Filing
- 2002-07-26 JP JP2003518503A patent/JP2005506320A/ja active Pending
- 2002-07-26 ES ES02764796T patent/ES2328468T3/es not_active Expired - Lifetime
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2004
- 2004-01-26 IS IS7124A patent/IS7124A/is unknown
- 2004-01-29 NO NO20040513A patent/NO20040513L/no unknown
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2009
- 2009-09-21 CY CY20091100978T patent/CY1109391T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BR0212014A (pt) | 2004-08-03 |
| ITMI20011733A0 (it) | 2001-08-07 |
| ATE435013T1 (de) | 2009-07-15 |
| PT1414428E (pt) | 2009-08-25 |
| JP2005506320A (ja) | 2005-03-03 |
| WO2003013493A8 (en) | 2004-02-26 |
| WO2003013493A1 (en) | 2003-02-20 |
| ES2328468T3 (es) | 2009-11-13 |
| MXPA04001190A (es) | 2005-02-17 |
| PL365391A1 (en) | 2005-01-10 |
| DE60232797D1 (de) | 2009-08-13 |
| HUP0401167A2 (hu) | 2004-11-29 |
| IL160075A0 (en) | 2004-06-20 |
| DK1414428T3 (da) | 2009-08-31 |
| EP1414428B1 (en) | 2009-07-01 |
| SI1414428T1 (sl) | 2009-10-31 |
| IS7124A (is) | 2004-01-26 |
| CN1538838A (zh) | 2004-10-20 |
| RU2004106605A (ru) | 2005-05-10 |
| KR20040035724A (ko) | 2004-04-29 |
| EP1414428A1 (en) | 2004-05-06 |
| NO20040513L (no) | 2004-03-24 |
| CA2456533A1 (en) | 2003-02-20 |
| CY1109391T1 (el) | 2014-07-02 |
| US20040157930A1 (en) | 2004-08-12 |
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