CA2783647A1 - Inhibiteurs de l'histone deacetylase - Google Patents

Inhibiteurs de l'histone deacetylase Download PDF

Info

Publication number: CA2783647A1
Authority: CA; Canada
Prior art keywords: alkyl; alkoxy; acid; hydroxyl; hydrocarbon chain
Prior art date: 2001-03-27
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA2783647A

Other languages

English (en)

Inventor

Hsuan-Yin Lan-Hargest

Robert J. Kaufman

Norbert L. Wiech

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Errant Gene Therapeutics LLC

Original Assignee

Errant Gene Therapeutics LLC

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2001-03-27

Filing date

2002-03-25

Publication date

2002-10-03

2001-03-27 Priority claimed from US09/812,944 external-priority patent/US6495719B2/en

2001-03-27 Priority claimed from US09/812,945 external-priority patent/US7312247B2/en

2001-12-26 Priority claimed from US10/025,947 external-priority patent/US8026280B2/en

2002-03-25 Application filed by Errant Gene Therapeutics LLC filed Critical Errant Gene Therapeutics LLC

2002-03-25 Priority claimed from CA2442366A external-priority patent/CA2442366C/fr

2002-10-03 Publication of CA2783647A1 publication Critical patent/CA2783647A1/fr

Status Abandoned legal-status Critical Current

Links

229940121372 histone deacetylase inhibitor Drugs 0.000 title description 4
239000003276 histone deacetylase inhibitor Substances 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims abstract description 144
239000002253 acid Substances 0.000 claims abstract description 90
108090000353 Histone deacetylase Proteins 0.000 claims abstract description 35
102000003964 Histone deacetylase Human genes 0.000 claims abstract description 35
201000011452 Adrenoleukodystrophy Diseases 0.000 claims abstract description 16
201000003883 Cystic fibrosis Diseases 0.000 claims abstract description 12
108090000623 proteins and genes Proteins 0.000 claims abstract description 12
206010028980 Neoplasm Diseases 0.000 claims abstract description 10
102000009030 Member 1 Subfamily D ATP Binding Cassette Transporter Human genes 0.000 claims abstract description 8
108010049137 Member 1 Subfamily D ATP Binding Cassette Transporter Proteins 0.000 claims abstract description 8
201000011510 cancer Diseases 0.000 claims abstract description 6
208000034737 hemoglobinopathy Diseases 0.000 claims abstract description 5
208000018337 inherited hemoglobinopathy Diseases 0.000 claims abstract description 5
125000000217 alkyl group Chemical group 0.000 claims description 168
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 104
125000003545 alkoxy group Chemical group 0.000 claims description 102
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 102
125000001188 haloalkyl group Chemical group 0.000 claims description 88
210000004027 cell Anatomy 0.000 claims description 83
229910052739 hydrogen Inorganic materials 0.000 claims description 78
239000001257 hydrogen Substances 0.000 claims description 78
125000000304 alkynyl group Chemical group 0.000 claims description 76
125000003342 alkenyl group Chemical group 0.000 claims description 63
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 63
238000000034 method Methods 0.000 claims description 62
150000002430 hydrocarbons Chemical class 0.000 claims description 58
-1 monocyclic aryl Chemical group 0.000 claims description 48
125000005843 halogen group Chemical group 0.000 claims description 34
108010033040 Histones Proteins 0.000 claims description 33
229920006395 saturated elastomer Polymers 0.000 claims description 28
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 23
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 23
102000006947 Histones Human genes 0.000 claims description 22
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 22
125000004122 cyclic group Chemical group 0.000 claims description 22
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 21
230000000694 effects Effects 0.000 claims description 18
229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 18
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
125000006239 protecting group Chemical group 0.000 claims description 17
125000003118 aryl group Chemical group 0.000 claims description 15
229910052717 sulfur Inorganic materials 0.000 claims description 15
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
125000000753 cycloalkyl group Chemical group 0.000 claims description 14
229910052760 oxygen Inorganic materials 0.000 claims description 14
150000003839 salts Chemical class 0.000 claims description 14
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 13
125000001072 heteroaryl group Chemical group 0.000 claims description 13
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 12
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 12
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 12
125000004432 carbon atom Chemical group C* 0.000 claims description 12
125000004093 cyano group Chemical group *C#N 0.000 claims description 12
125000000392 cycloalkenyl group Chemical group 0.000 claims description 12
208000035475 disorder Diseases 0.000 claims description 12
125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 11
125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 11
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 10
UWVPQVBQNXJYSP-CDWOPPGASA-N (2e,4e,6e)-7-phenylhepta-2,4,6-trienoic acid Chemical compound OC(=O)\C=C\C=C\C=C\C1=CC=CC=C1 UWVPQVBQNXJYSP-CDWOPPGASA-N 0.000 claims description 8
125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 8
MYHHTDSAFYISLX-UHFFFAOYSA-N 8-phenylocta-3,5,7-trienoic acid Chemical compound OC(=O)CC=CC=CC=CC1=CC=CC=C1 MYHHTDSAFYISLX-UHFFFAOYSA-N 0.000 claims description 8
125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 8
230000002401 inhibitory effect Effects 0.000 claims description 8
ZSAPOECVQGXVKJ-UHFFFAOYSA-N 5-[4-(dimethylamino)phenyl]penta-2,4-dienoic acid Chemical compound CN(C)C1=CC=C(C=CC=CC(O)=O)C=C1 ZSAPOECVQGXVKJ-UHFFFAOYSA-N 0.000 claims description 7
239000004215 Carbon black (E152) Substances 0.000 claims description 7
125000005741 alkyl alkenyl group Chemical group 0.000 claims description 7
229930195733 hydrocarbon Natural products 0.000 claims description 7
230000001404 mediated effect Effects 0.000 claims description 7
HVXXQBBWVWERDN-NKZTZDQQSA-N (2e,4e)-5-(furan-2-yl)penta-2,4-dienoic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=CO1 HVXXQBBWVWERDN-NKZTZDQQSA-N 0.000 claims description 6
JIMZSMYOVXQKMC-UHFFFAOYSA-N 4-chloro-5-phenylpenta-2,4-dienoic acid Chemical compound OC(=O)C=CC(Cl)=CC1=CC=CC=C1 JIMZSMYOVXQKMC-UHFFFAOYSA-N 0.000 claims description 6
FEIQOMCWGDNMHM-KBXRYBNXSA-N (2e,4e)-5-phenylpenta-2,4-dienoic acid Chemical compound OC(=O)\C=C\C=C\C1=CC=CC=C1 FEIQOMCWGDNMHM-KBXRYBNXSA-N 0.000 claims description 5
DHVXVHMLJYPEMC-UHFFFAOYSA-N 6-phenylhexa-3,5-dienoic acid Chemical compound OC(=O)CC=CC=CC1=CC=CC=C1 DHVXVHMLJYPEMC-UHFFFAOYSA-N 0.000 claims description 5
DBBYYRWVNDQECM-CDWOPPGASA-N CG-1521 Chemical compound ONC(=O)\C=C\C=C\C=C\C1=CC=CC=C1 DBBYYRWVNDQECM-CDWOPPGASA-N 0.000 claims description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
FEIQOMCWGDNMHM-UHFFFAOYSA-N cinnamylideneacetic acid Natural products OC(=O)C=CC=CC1=CC=CC=C1 FEIQOMCWGDNMHM-UHFFFAOYSA-N 0.000 claims description 5
125000005842 heteroatom Chemical group 0.000 claims description 5
238000000338 in vitro Methods 0.000 claims description 5
125000001624 naphthyl group Chemical group 0.000 claims description 5
TZORWMLNTLTFDW-UHFFFAOYSA-M potassium;2-oxo-8-phenylocta-3,5,7-trienoate Chemical compound [K+].[O-]C(=O)C(=O)C=CC=CC=CC1=CC=CC=C1 TZORWMLNTLTFDW-UHFFFAOYSA-M 0.000 claims description 5
QBUCMPDJJMSFCR-XBLVEGMJSA-N (2e,4e)-3-methyl-5-phenylpenta-2,4-dienoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C1=CC=CC=C1 QBUCMPDJJMSFCR-XBLVEGMJSA-N 0.000 claims description 4
NWKUGDBRICNTTN-XBLVEGMJSA-N (2e,4e)-4-methyl-5-phenylpenta-2,4-dienoic acid Chemical compound OC(=O)/C=C/C(/C)=C/C1=CC=CC=C1 NWKUGDBRICNTTN-XBLVEGMJSA-N 0.000 claims description 4
UVDDFTZLVFIQFL-VOTSOKGWSA-N (e)-n-hydroxy-3-phenylprop-2-enamide Chemical compound ONC(=O)\C=C\C1=CC=CC=C1 UVDDFTZLVFIQFL-VOTSOKGWSA-N 0.000 claims description 4
208000002903 Thalassemia Diseases 0.000 claims description 4
230000006197 histone deacetylation Effects 0.000 claims description 4
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
125000000168 pyrrolyl group Chemical group 0.000 claims description 4
229930195734 saturated hydrocarbon Natural products 0.000 claims description 4
125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
125000001544 thienyl group Chemical group 0.000 claims description 4
201000004525 Zellweger Syndrome Diseases 0.000 claims description 3
102000015395 alpha 1-Antitrypsin Human genes 0.000 claims description 3
108010050122 alpha 1-Antitrypsin Proteins 0.000 claims description 3
229940024142 alpha 1-antitrypsin Drugs 0.000 claims description 3
125000002541 furyl group Chemical group 0.000 claims description 3
208000023269 peroxisome biogenesis disease Diseases 0.000 claims description 3
CGKSVGCSSAMADF-UHFFFAOYSA-M potassium;2-oxo-6-phenylhexa-3,5-dienoate Chemical compound [K+].[O-]C(=O)C(=O)C=CC=CC1=CC=CC=C1 CGKSVGCSSAMADF-UHFFFAOYSA-M 0.000 claims description 3
208000007056 sickle cell anemia Diseases 0.000 claims description 3
230000029663 wound healing Effects 0.000 claims description 3
208000010362 Protozoan Infections Diseases 0.000 claims description 2
125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 2
230000003779 hair growth Effects 0.000 claims description 2
230000007420 reactivation Effects 0.000 claims description 2
241001430294 unidentified retrovirus Species 0.000 claims description 2
125000001183 hydrocarbyl group Chemical group 0.000 claims 51
125000004435 hydrogen atom Chemical class [H]* 0.000 claims 32
125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims 2
MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims 1
238000001727 in vivo Methods 0.000 claims 1
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 abstract description 12
230000014509 gene expression Effects 0.000 abstract description 9
230000005764 inhibitory process Effects 0.000 abstract description 9
230000002068 genetic effect Effects 0.000 abstract description 3
208000014951 hematologic disease Diseases 0.000 abstract description 3
208000030159 metabolic disease Diseases 0.000 abstract description 3
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 abstract description 2
125000002843 carboxylic acid group Chemical group 0.000 abstract description 2
230000005760 tumorsuppression Effects 0.000 abstract description 2
229910052725 zinc Inorganic materials 0.000 abstract description 2
239000011701 zinc Substances 0.000 abstract description 2
230000004572 zinc-binding Effects 0.000 abstract description 2
239000000243 solution Substances 0.000 description 110
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 100
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
238000006243 chemical reaction Methods 0.000 description 56
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
150000002431 hydrogen Chemical class 0.000 description 45
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
230000015572 biosynthetic process Effects 0.000 description 30
238000003786 synthesis reaction Methods 0.000 description 30
238000012360 testing method Methods 0.000 description 29
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 26
239000011541 reaction mixture Substances 0.000 description 25
239000000203 mixture Substances 0.000 description 24
239000007787 solid Substances 0.000 description 24
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QDSFNOHWQKVVEB-UHFFFAOYSA-N 4-(diethoxyphosphorylmethyl)morpholine Chemical compound CCOP(=O)(OCC)CN1CCOCC1 QDSFNOHWQKVVEB-UHFFFAOYSA-N 0.000 description 7
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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 description 1
WILBTFWIBAOWLN-UHFFFAOYSA-N triethyl(triethylsilyloxy)silane Chemical compound CC[Si](CC)(CC)O[Si](CC)(CC)CC WILBTFWIBAOWLN-UHFFFAOYSA-N 0.000 description 1
GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
229910052721 tungsten Inorganic materials 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229920002554 vinyl polymer Polymers 0.000 description 1
238000010792 warming Methods 0.000 description 1
239000012224 working solution Substances 0.000 description 1
DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1

Landscapes

Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

CA2783647A 2001-03-27 2002-03-25 Inhibiteurs de l'histone deacetylase Abandoned CA2783647A1 (fr)

Applications Claiming Priority (9)

Application Number	Priority Date	Filing Date	Title
US81294001A	2001-03-27	2001-03-27
US09/812,945		2001-03-27
US09/812,940		2001-03-27
US09/812,944 US6495719B2 (en)	2001-03-27	2001-03-27	Histone deacetylase inhibitors
US09/812,945 US7312247B2 (en)	2001-03-27	2001-03-27	Histone deacetylase inhibitors
US09/812,944		2001-03-27
US10/025,947 US8026280B2 (en)	2001-03-27	2001-12-26	Histone deacetylase inhibitors
US10/025,947		2001-12-26
CA2442366A CA2442366C (fr)	2001-03-27	2002-03-25	Inhibiteurs de l'histone deacetylase

Related Parent Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2442366A Division CA2442366C (fr)	2001-03-27	2002-03-25	Inhibiteurs de l'histone deacetylase

Publications (1)

Publication Number	Publication Date
CA2783647A1 true CA2783647A1 (fr)	2002-10-03

Family

ID=46671159

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA2783647A Abandoned CA2783647A1 (fr)	2001-03-27	2002-03-25	Inhibiteurs de l'histone deacetylase

Country Status (1)

Country	Link
CA (1)	CA2783647A1 (fr)

2002
- 2002-03-25 CA CA2783647A patent/CA2783647A1/fr not_active Abandoned

Legal Events

Date	Code	Title	Description
2012-07-20	EEER	Examination request
2017-05-10	FZDE	Dead	Effective date: 20170329

Publication	Publication Date	Title
US6495719B2 (en)	2002-12-17	Histone deacetylase inhibitors
US8420698B2 (en)	2013-04-16	Histone deacetylase inhibitors
US8138225B2 (en)	2012-03-20	Histone deacetylase inhibitors based on alpha-ketoepoxide compounds
US20110288168A1 (en)	2011-11-24	Histone deacetylase inhibitors
CA2486385C (fr)	2013-12-10	Inhibiteurs d'histone desacetylase a base de composes de trihalomethylcarbonyle
CA2442366C (fr)	2012-09-25	Inhibiteurs de l'histone deacetylase
CA2486402C (fr)	2013-04-30	Inhibiteurs d'histone desacetylase bases sur des composes alpha-chalcogenmethylcarbonyle
US8026280B2 (en)	2011-09-27	Histone deacetylase inhibitors
US20100234455A1 (en)	2010-09-16	Histone Deacetylase Inhibitors
CA2783647A1 (fr)	2002-10-03	Inhibiteurs de l'histone deacetylase