OA12016A - Tricyclic inhibitors of poly(adp-ribose)polymerases. - Google Patents

Tricyclic inhibitors of poly(adp-ribose)polymerases. Download PDF

Info

Publication number: OA12016A
Authority: OA; OAPI
Prior art keywords: aryl; alkynyl; heterocycloalkyl; alkyl; cycloalkyl
Prior art date: 1999-08-31

Application number

OA1200200064A

Other languages

English (en)

Inventor

Stephen Evan Webber

Donald James Skalitzky

Jayashree Tikhe

Robert Arnold Kumpf

Joseph Timothy Marakovits

Walter Brian Eastman

Original Assignee

Agouron Pharma

Cancer Res Campaign

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.)

1999-08-31

Filing date

2000-08-31

Publication date

2006-04-19

2000-08-31 Application filed by Agouron Pharma, Cancer Res Campaign filed Critical Agouron Pharma

2006-04-19 Publication of OA12016A publication Critical patent/OA12016A/en

Links

108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 title claims description 75
102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 title claims description 74
229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 title claims description 67
239000003112 inhibitor Substances 0.000 title description 12
150000001875 compounds Chemical class 0.000 claims abstract description 283
230000000694 effects Effects 0.000 claims abstract description 27
238000000034 method Methods 0.000 claims description 193
125000003118 aryl group Chemical group 0.000 claims description 180
125000000304 alkynyl group Chemical group 0.000 claims description 139
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 133
125000000753 cycloalkyl group Chemical group 0.000 claims description 132
125000001072 heteroaryl group Chemical group 0.000 claims description 125
125000003342 alkenyl group Chemical group 0.000 claims description 124
-1 alkeayl Chemical group 0.000 claims description 121
125000000217 alkyl group Chemical group 0.000 claims description 96
125000000547 substituted alkyl group Chemical group 0.000 claims description 94
229910052736 halogen Inorganic materials 0.000 claims description 53
150000002367 halogens Chemical class 0.000 claims description 53
125000001424 substituent group Chemical group 0.000 claims description 47
230000005764 inhibitory process Effects 0.000 claims description 44
125000004093 cyano group Chemical group *C#N 0.000 claims description 36
229940002612 prodrug Drugs 0.000 claims description 35
239000000651 prodrug Substances 0.000 claims description 35
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 33
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
229910052760 oxygen Inorganic materials 0.000 claims description 30
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
239000003795 chemical substances by application Substances 0.000 claims description 27
230000002401 inhibitory effect Effects 0.000 claims description 27
229910052717 sulfur Inorganic materials 0.000 claims description 27
102000004190 Enzymes Human genes 0.000 claims description 24
108090000790 Enzymes Proteins 0.000 claims description 24
231100000135 cytotoxicity Toxicity 0.000 claims description 21
230000003013 cytotoxicity Effects 0.000 claims description 21
125000003545 alkoxy group Chemical group 0.000 claims description 11
125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 10
238000003556 assay Methods 0.000 claims description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
125000004104 aryloxy group Chemical group 0.000 claims description 7
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
125000005842 heteroatom Chemical group 0.000 claims description 7
239000001301 oxygen Substances 0.000 claims description 7
239000008194 pharmaceutical composition Substances 0.000 claims description 7
125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
108010017601 Tankyrases Proteins 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 claims 13
102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims 13
125000005017 substituted alkenyl group Chemical group 0.000 claims 4
102100037664 Poly [ADP-ribose] polymerase tankyrase-1 Human genes 0.000 claims 2
238000004519 manufacturing process Methods 0.000 claims 2
SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 1
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238000005481 NMR spectroscopy Methods 0.000 description 298
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229910052757 nitrogen Inorganic materials 0.000 description 246
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IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
239000000243 solution Substances 0.000 description 68
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LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
229910052943 magnesium sulfate Inorganic materials 0.000 description 27
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JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
239000012044 organic layer Substances 0.000 description 23
ZGLDQGIONSGJCN-UHFFFAOYSA-N diazepin-5-one Chemical compound O=C1C=CN=NC=C1 ZGLDQGIONSGJCN-UHFFFAOYSA-N 0.000 description 21
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239000002253 acid Substances 0.000 description 20
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KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
238000000746 purification Methods 0.000 description 17
230000035484 reaction time Effects 0.000 description 17
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 16
101150041968 CDC13 gene Proteins 0.000 description 16
241000124008 Mammalia Species 0.000 description 16
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
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FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
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239000003921 oil Substances 0.000 description 14
235000019198 oils Nutrition 0.000 description 14
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
238000004809 thin layer chromatography Methods 0.000 description 14
239000012661 PARP inhibitor Substances 0.000 description 13
229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 13
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
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BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
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FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
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IWFWSTSIZXLBFI-UHFFFAOYSA-N tert-butyl 2-(4-formylphenyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C1=CC=C(C=O)C=C1 IWFWSTSIZXLBFI-UHFFFAOYSA-N 0.000 description 1
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WARKYKQCOXTIAO-UHFFFAOYSA-N tributyl(2-ethoxyethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)\C=C/OCC WARKYKQCOXTIAO-UHFFFAOYSA-N 0.000 description 1
SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
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LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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OA1200200064A 1999-08-31 2000-08-31 Tricyclic inhibitors of poly(adp-ribose)polymerases. OA12016A (en)

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US15214299P	1999-08-31	1999-08-31

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- 2000-08-31 PL PL00354242A patent/PL354242A1/xx not_active Application Discontinuation
- 2000-08-31 CZ CZ2002613A patent/CZ2002613A3/cs unknown
- 2000-08-31 NZ NZ516793A patent/NZ516793A/en unknown
- 2000-08-31 AR ARP000104549A patent/AR035162A1/es unknown
- 2000-08-31 HR HR20020271A patent/HRP20020271A2/hr not_active Application Discontinuation
- 2000-08-31 EP EP00961437A patent/EP1208104B1/en not_active Expired - Lifetime
- 2000-08-31 UA UA2002042574A patent/UA73144C2/uk unknown
- 2000-08-31 EA EA200200306A patent/EA200200306A1/ru unknown
- 2000-08-31 KR KR1020027002629A patent/KR20020038742A/ko not_active Abandoned
- 2000-08-31 IL IL14786300A patent/IL147863A0/xx unknown
- 2000-08-31 CN CN00815066A patent/CN1384835A/zh active Pending
- 2000-08-31 CA CA002382404A patent/CA2382404C/en not_active Expired - Fee Related
- 2000-08-31 YU YU15102A patent/YU15102A/sh unknown
- 2000-08-31 MX MXPA02002138A patent/MXPA02002138A/es active IP Right Grant
- 2000-08-31 JP JP2001519702A patent/JP4272375B2/ja not_active Expired - Lifetime
- 2000-08-31 PT PT00961437T patent/PT1208104E/pt unknown
- 2000-08-31 OA OA1200200064A patent/OA12016A/en unknown
- 2000-08-31 HU HU0202703A patent/HUP0202703A3/hu unknown
- 2000-08-31 DK DK00961437T patent/DK1208104T3/da active
- 2000-08-31 PE PE2000000896A patent/PE20010538A1/es not_active Application Discontinuation
- 2000-08-31 DZ DZ003216A patent/DZ3216A1/fr active
- 2000-08-31 UY UY26323A patent/UY26323A1/es not_active Application Discontinuation
- 2000-08-31 SV SV2000000162A patent/SV2003000162A/es unknown
- 2000-08-31 DE DE60017575T patent/DE60017575T2/de not_active Expired - Lifetime
- 2000-08-31 SK SK259-2002A patent/SK2592002A3/sk unknown
- 2000-08-31 WO PCT/US2000/023882 patent/WO2001016136A2/en not_active Ceased
- 2000-08-31 AU AU73389/00A patent/AU781826B2/en not_active Ceased
- 2000-09-20 DO DO2000000069A patent/DOP2000000069A/es unknown
2002
- 2002-01-28 NO NO20020421A patent/NO322475B1/no unknown
- 2002-01-30 ZA ZA200200830A patent/ZA200200830B/en unknown
- 2002-02-01 CR CR6577A patent/CR6577A/es not_active Application Discontinuation
- 2002-02-27 IS IS6289A patent/IS6289A/is unknown
- 2002-03-29 BG BG106562A patent/BG106562A/bg unknown
- 2002-03-29 MA MA26577A patent/MA25876A1/fr unknown

Also Published As

Publication number	Publication date
JP2003513015A (ja)	2003-04-08
ZA200200830B (en)	2003-03-26
CO5200769A1 (es)	2002-09-27
HUP0202703A2 (hu)	2002-12-28
PT1208104E (pt)	2005-04-29
AR035162A1 (es)	2004-05-05
NZ516793A (en)	2004-03-26
GEP20043268B (en)	2004-06-25
CN1384835A (zh)	2002-12-11
HK1045509A1 (en)	2002-11-29
MXPA02002138A (es)	2003-08-20
EA200200306A1 (ru)	2002-08-29
AU781826B2 (en)	2005-06-16
NO322475B1 (no)	2006-10-09
DE60017575T2 (de)	2005-06-09
DK1208104T3 (da)	2005-05-02
SK2592002A3 (en)	2002-10-08
MY135910A (en)	2008-07-31
DE60017575D1 (de)	2005-02-24
BG106562A (bg)	2003-03-31
MA25876A1 (fr)	2003-10-01
KR20020038742A (ko)	2002-05-23
NO20020421D0 (no)	2002-01-28
PL354242A1 (en)	2003-12-29
IL147863A0 (en)	2002-08-14
AP1553A (en)	2006-01-18
CA2382404C (en)	2009-03-24
IS6289A (is)	2002-02-27
AU7338900A (en)	2001-03-26
DZ3216A1 (fr)	2001-03-08
WO2001016136A3 (en)	2001-06-21
SI1208104T1 (en)	2005-06-30
JP4272375B2 (ja)	2009-06-03
CA2382404A1 (en)	2001-03-08
DOP2000000069A (es)	2002-08-30
US6548494B1 (en)	2003-04-15
WO2001016136A2 (en)	2001-03-08
SV2003000162A (es)	2003-07-29
YU15102A (sh)	2004-12-31
WO2001016136B1 (en)	2001-11-15
UY26323A1 (es)	2001-04-30
CZ2002613A3 (cs)	2002-08-14
ES2234657T3 (es)	2005-07-01
UA73144C2 (en)	2005-06-15
PE20010538A1 (es)	2001-05-22
EP1208104A2 (en)	2002-05-29
GT200000145A (es)	2002-02-21
CR6577A (es)	2003-12-05
EP1208104B1 (en)	2005-01-19
HUP0202703A3 (en)	2004-12-28
ECSP003637A (es)	2002-03-25
NO20020421L (no)	2002-04-25
HRP20020271A2 (en)	2005-12-31
HK1045509B (en)	2005-04-29
ATE287406T1 (de)	2005-02-15
PA8501801A1 (es)	2002-08-26
EE200200100A (et)	2003-06-16
BR0015051A (pt)	2002-06-25

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