CA2078129C - O6-benzylated guanine, guanosine and 2'- deoxyguanosine compounds possessing o6-alkylguanine-dna alkyltransferase depleting activity - Google Patents
O6-benzylated guanine, guanosine and 2'- deoxyguanosine compounds possessing o6-alkylguanine-dna alkyltransferase depleting activityInfo
- Publication number
- CA2078129C CA2078129C CA002078129A CA2078129A CA2078129C CA 2078129 C CA2078129 C CA 2078129C CA 002078129 A CA002078129 A CA 002078129A CA 2078129 A CA2078129 A CA 2078129A CA 2078129 C CA2078129 C CA 2078129C
- Authority
- CA
- Canada
- Prior art keywords
- carbon atoms
- alkyl
- benzyl group
- phenyl
- hydrogen
- Prior art date
- 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.)
- Expired - Lifetime
Links
- 102000002226 Alkyl and Aryl Transferases Human genes 0.000 title claims abstract description 71
- 108010014722 Alkyl and Aryl Transferases Proteins 0.000 title claims abstract description 71
- 230000000779 depleting effect Effects 0.000 title claims description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 title abstract description 62
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 title abstract description 17
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 title abstract description 9
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 title abstract description 9
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 title abstract description 9
- 229940029575 guanosine Drugs 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 47
- 239000001257 hydrogen Substances 0.000 claims abstract description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 25
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002295 alkylating antineoplastic agent Substances 0.000 claims abstract description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 82
- -1 nitro, phenyl Chemical group 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical group 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 18
- 239000003814 drug Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 150000002431 hydrogen Chemical group 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000000304 alkynyl group Chemical group 0.000 claims description 13
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 10
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- NVKGVBZZSJFQLM-UHFFFAOYSA-N 1-(2-chloroethyl)-1-nitrosourea Chemical group NC(=O)N(N=O)CCCl NVKGVBZZSJFQLM-UHFFFAOYSA-N 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 239000011737 fluorine Substances 0.000 claims 3
- 125000001153 fluoro group Chemical group F* 0.000 claims 3
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
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- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 52
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- BXJHWYVXLGLDMZ-UHFFFAOYSA-N 6-O-methylguanine Chemical compound COC1=NC(N)=NC2=C1NC=N2 BXJHWYVXLGLDMZ-UHFFFAOYSA-N 0.000 description 8
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- 229940100198 alkylating agent Drugs 0.000 description 6
- 239000002168 alkylating agent Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
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- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 3
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- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
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- 230000035755 proliferation Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
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- 238000004007 reversed phase HPLC Methods 0.000 description 1
- FVLVBPDQNARYJU-UHFFFAOYSA-N semustine Chemical compound CC1CCC(NC(=O)N(CCCl)N=O)CC1 FVLVBPDQNARYJU-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- LFQULJPVXNYWAG-UHFFFAOYSA-N sodium;phenylmethanolate Chemical compound [Na]OCC1=CC=CC=C1 LFQULJPVXNYWAG-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
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- 239000008227 sterile water for injection Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
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- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 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
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Genetics & Genomics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US492,468 | 1990-03-13 | ||
| US07/492,468 US5091430A (en) | 1990-03-13 | 1990-03-13 | O6 -substituted guanine compounds and methods for depleting O6 -alkylguanine-DNA alkyltransferase levels |
| US07/616,913 US5352669A (en) | 1990-03-13 | 1990-11-21 | O6 -benzylated guanine, guanosine and 2'-deoxyguanosine compounds possessing O6 -alkylguanine-DNA alkyltransferase depleting activity |
| US616,913 | 1990-11-21 | ||
| PCT/US1991/001680 WO1991013898A1 (en) | 1990-03-13 | 1991-03-13 | O6-benzylated guanine, guanosine and 2'-deoxyguanosine compounds possessing o6-alkylguanine-dna alkyltransferase depleting activity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2078129A1 CA2078129A1 (en) | 1991-09-14 |
| CA2078129C true CA2078129C (en) | 1999-05-04 |
Family
ID=27050758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002078129A Expired - Lifetime CA2078129C (en) | 1990-03-13 | 1991-03-13 | O6-benzylated guanine, guanosine and 2'- deoxyguanosine compounds possessing o6-alkylguanine-dna alkyltransferase depleting activity |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US5352669A (en, 2012) |
| EP (1) | EP0523100B1 (en, 2012) |
| JP (1) | JP2829440B2 (en, 2012) |
| AT (1) | ATE141925T1 (en, 2012) |
| CA (1) | CA2078129C (en, 2012) |
| DE (1) | DE69121706T2 (en, 2012) |
| DK (1) | DK0523100T3 (en, 2012) |
| ES (1) | ES2091322T3 (en, 2012) |
| GR (1) | GR3021277T3 (en, 2012) |
| WO (1) | WO1991013898A1 (en, 2012) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5731304A (en) * | 1982-08-23 | 1998-03-24 | Cancer Research Campaign Technology | Potentiation of temozolomide in human tumour cells |
| US5691307A (en) * | 1990-03-13 | 1997-11-25 | The United States Of America As Represented By The Department Of Health And Human Services | O6 -substituted guanine compositions and methods for depleting O6 |
| GB9015914D0 (en) * | 1990-07-19 | 1990-09-05 | Wellcome Found | Heterocyclic compounds |
| ZA94248B (en) * | 1993-01-14 | 1994-07-13 | Cancer Res Campaign Tech | Potentiation of temozolomide in human tumour cells |
| RU2154646C2 (ru) * | 1993-06-08 | 2000-08-20 | Кэнсер Рисерч Кэмпейн Текнолоджи Лимитед | Производные о6-алкилгуанина и фармацевтическая композиция |
| US6043228A (en) * | 1993-06-08 | 2000-03-28 | Cancer Research Campaign Technology Limited | O6 -substituted guanine derivatives, a process for their preparation and their use in treating tumor cells |
| US5929046A (en) * | 1994-06-08 | 1999-07-27 | Cancer Research Campaign Technology Limited | Pyrimidine and purine derivatives and their use in treating tumour cells |
| US5525606A (en) | 1994-08-01 | 1996-06-11 | The United States Of America As Represented By The Department Of Health And Human Services | Substituted 06-benzylguanines and 6(4)-benzyloxypyrimidines |
| US5965126A (en) * | 1996-03-25 | 1999-10-12 | The Penn State Research Foundation | use of mutant alkyltransferases for gene therapy to protect from toxicity of therapeutic alkylating agents |
| US6060458A (en) * | 1998-02-13 | 2000-05-09 | The United States Of America As Represented By The Department Of Health And Human Services | Oligodeoxyribonucleotides comprising O6 -benzylguanine and their use |
| WO2003084957A1 (en) * | 2002-04-08 | 2003-10-16 | Sumika Fine Chemicals Co., Ltd. | Crystal and solvate of 2-amino-6-benzyloxypurine and production methods thereof |
| KR20050062588A (ko) * | 2002-10-03 | 2005-06-23 | 에콜 폴리테크니크 페데랄레 드 로잔 | Ｏ6-알킬구아닌-ｄｎａ 알킬트랜스퍼라제용 기질 |
| AU2004313931A1 (en) * | 2004-01-06 | 2005-07-28 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | 2-amino-O4-substituted pteridines and their use as inactivators of O6-alkylguanine-DNA alkyltransferase |
| US7825096B2 (en) * | 2004-09-08 | 2010-11-02 | The United States Of America As Represented By The Department Of Health And Human Services | O6-alkylguanine-DNA alkyltransferase inactivators and beta-glucuronidase cleavable prodrugs |
| CN100350975C (zh) * | 2005-02-03 | 2007-11-28 | 山东蓝金生物工程有限公司 | 抗癌药物组合物 |
| GB0502573D0 (en) * | 2005-02-08 | 2005-03-16 | Topotarget As | Therapeutic compounds |
| CN100526315C (zh) | 2005-06-16 | 2009-08-12 | 浙江医药股份有限公司新昌制药厂 | N2-喹啉或异喹啉取代的嘌呤衍生物及其制备方法和其用途 |
| WO2008137207A2 (en) * | 2007-05-02 | 2008-11-13 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Inactivators of o6-alkylguanine-dna alkyltransferase |
| CN107098906B (zh) * | 2017-05-19 | 2020-05-05 | 四川大学 | 苄基鸟嘌呤衍生物及其有机盐类化合物和药物组合物及其应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL64501A (en) * | 1980-12-22 | 1985-07-31 | Astra Laekemedel Ab | 9-substituted 4-hydroxybutyl guanine derivatives,their preparation and antiviral use |
| EP0184473A1 (en) * | 1984-10-26 | 1986-06-11 | Merck & Co. Inc. | Regioselective synthesis of 9-substituted purine acyclonucleoside derivatives |
| US4801710A (en) * | 1984-10-26 | 1989-01-31 | Merck & Co., Inc. | Regioselective synthesis of 9-substituted purine acyclonucleoside derivatives |
| US5723609A (en) * | 1988-03-30 | 1998-03-03 | E. R. Squibb & Sons, Inc. | Bis (hydroxymethyl) cyclobutyl purines |
-
1990
- 1990-11-21 US US07/616,913 patent/US5352669A/en not_active Expired - Lifetime
-
1991
- 1991-03-13 CA CA002078129A patent/CA2078129C/en not_active Expired - Lifetime
- 1991-03-13 ES ES91906818T patent/ES2091322T3/es not_active Expired - Lifetime
- 1991-03-13 DK DK91906818.9T patent/DK0523100T3/da active
- 1991-03-13 EP EP91906818A patent/EP0523100B1/en not_active Expired - Lifetime
- 1991-03-13 AT AT91906818T patent/ATE141925T1/de not_active IP Right Cessation
- 1991-03-13 DE DE69121706T patent/DE69121706T2/de not_active Expired - Lifetime
- 1991-03-13 WO PCT/US1991/001680 patent/WO1991013898A1/en active IP Right Grant
- 1991-03-13 JP JP3507224A patent/JP2829440B2/ja not_active Expired - Lifetime
-
1996
- 1996-10-07 GR GR960402636T patent/GR3021277T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GR3021277T3 (en) | 1997-01-31 |
| JP2829440B2 (ja) | 1998-11-25 |
| EP0523100A4 (en) | 1993-03-17 |
| EP0523100A1 (en) | 1993-01-20 |
| DE69121706D1 (de) | 1996-10-02 |
| EP0523100B1 (en) | 1996-08-28 |
| DK0523100T3 (en, 2012) | 1997-02-10 |
| CA2078129A1 (en) | 1991-09-14 |
| AU646452B2 (en) | 1994-02-24 |
| DE69121706T2 (de) | 1997-01-23 |
| JPH05504972A (ja) | 1993-07-29 |
| WO1991013898A1 (en) | 1991-09-19 |
| US5352669A (en) | 1994-10-04 |
| AU7582191A (en) | 1991-10-10 |
| ES2091322T3 (es) | 1996-11-01 |
| ATE141925T1 (de) | 1996-09-15 |
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| EEER | Examination request | ||
| MKEX | Expiry |