CN1740182A - 新的双氨基化膦酸酯前药 - Google Patents
新的双氨基化膦酸酯前药 Download PDFInfo
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- CN1740182A CN1740182A CNA2005100930590A CN200510093059A CN1740182A CN 1740182 A CN1740182 A CN 1740182A CN A2005100930590 A CNA2005100930590 A CN A2005100930590A CN 200510093059 A CN200510093059 A CN 200510093059A CN 1740182 A CN1740182 A CN 1740182A
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- alkyl
- aryl
- rudimentary
- aralkyl
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- 229940002612 prodrug Drugs 0.000 title abstract description 74
- 239000000651 prodrug Substances 0.000 title abstract description 74
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 title abstract description 10
- 239000003112 inhibitor Substances 0.000 claims abstract description 28
- 101710099475 3'-phosphoadenosine 5'-phosphate phosphatase Proteins 0.000 claims abstract description 26
- 101710196411 Fructose-1,6-bisphosphatase Proteins 0.000 claims abstract description 26
- 101710186733 Fructose-1,6-bisphosphatase, chloroplastic Proteins 0.000 claims abstract description 26
- 101710109119 Fructose-1,6-bisphosphatase, cytosolic Proteins 0.000 claims abstract description 26
- 101710198902 Fructose-1,6-bisphosphate aldolase/phosphatase Proteins 0.000 claims abstract description 26
- 239000008103 glucose Substances 0.000 claims abstract description 25
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 22
- 210000004369 blood Anatomy 0.000 claims abstract description 15
- 239000008280 blood Substances 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 338
- 125000003118 aryl group Chemical group 0.000 claims description 320
- 150000001875 compounds Chemical class 0.000 claims description 272
- 229910052757 nitrogen Inorganic materials 0.000 claims description 214
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 205
- -1 aralkoxy Chemical group 0.000 claims description 194
- 125000001188 haloalkyl group Chemical group 0.000 claims description 146
- 125000002723 alicyclic group Chemical group 0.000 claims description 136
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 107
- 229910052760 oxygen Inorganic materials 0.000 claims description 99
- 125000004429 atom Chemical group 0.000 claims description 96
- 125000001072 heteroaryl group Chemical group 0.000 claims description 86
- 125000004122 cyclic group Chemical group 0.000 claims description 82
- 229910052717 sulfur Inorganic materials 0.000 claims description 75
- 125000003545 alkoxy group Chemical group 0.000 claims description 71
- 238000002360 preparation method Methods 0.000 claims description 69
- 229910052799 carbon Inorganic materials 0.000 claims description 67
- 125000004432 carbon atom Chemical group C* 0.000 claims description 58
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 57
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 57
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 50
- 125000003342 alkenyl group Chemical group 0.000 claims description 47
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 125000000304 alkynyl group Chemical group 0.000 claims description 44
- 150000002367 halogens Chemical class 0.000 claims description 39
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 35
- 239000003814 drug Substances 0.000 claims description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 33
- 229910052698 phosphorus Inorganic materials 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000004171 alkoxy aryl group Chemical group 0.000 claims description 28
- 125000004414 alkyl thio group Chemical group 0.000 claims description 28
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- 125000005842 heteroatom Chemical group 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 25
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 25
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 24
- 239000001301 oxygen Substances 0.000 claims description 24
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 23
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 22
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 22
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 20
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 20
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 19
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 19
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 18
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 18
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 16
- 125000004423 acyloxy group Chemical group 0.000 claims description 16
- 125000001769 aryl amino group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 16
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 16
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000004437 phosphorous atom Chemical group 0.000 claims description 16
- 239000011574 phosphorus Substances 0.000 claims description 16
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 15
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 14
- 125000000962 organic group Chemical group 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
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- 241001465754 Metazoa Species 0.000 claims description 12
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 125000005647 linker group Chemical group 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 8
- 150000003462 sulfoxides Chemical class 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 150000001409 amidines Chemical class 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 claims description 6
- 230000004110 gluconeogenesis Effects 0.000 claims description 6
- 230000002440 hepatic effect Effects 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 4
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000000344 gluconeogenetic effect Effects 0.000 claims description 4
- 208000007345 glycogen storage disease Diseases 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 150000000182 1,3,5-triazines Chemical class 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 206010022489 Insulin Resistance Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 201000001421 hyperglycemia Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 208000024891 symptom Diseases 0.000 claims description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 3
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 2
- 230000001133 acceleration Effects 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 206010003497 Asphyxia Diseases 0.000 claims 1
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- 206010012655 Diabetic complications Diseases 0.000 claims 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
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- 238000000034 method Methods 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 63
- 125000003368 amide group Chemical group 0.000 description 49
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 47
- 239000000203 mixture Substances 0.000 description 42
- 125000001118 alkylidene group Chemical group 0.000 description 39
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 36
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 16
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 16
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- YRMZUOPMHMPNPG-UHFFFAOYSA-N methyl 1,3-thiazole-2-carboxylate Chemical compound COC(=O)C1=NC=CS1 YRMZUOPMHMPNPG-UHFFFAOYSA-N 0.000 description 14
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- A61P3/00—Drugs for disorders of the metabolism
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
- C07F9/4461—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4465—Amides thereof the amide moiety containing a substituent or a structure which is considered as characteristic of aliphatic amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
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| CN00819044A Expired - Fee Related CN100595204C (zh) | 1999-12-22 | 2000-12-22 | 双氨基化膦酸酯前药 |
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Cited By (1)
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|---|---|---|---|---|
| CN107849071A (zh) * | 2015-08-10 | 2018-03-27 | 默沙东公司 | 抗病毒的β氨基酸酯膦酰二胺化合物 |
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- 2000-12-22 AU AU52447/01A patent/AU784370B2/en not_active Ceased
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- 2000-12-22 HU HU0204092A patent/HUP0204092A3/hu unknown
- 2000-12-22 CZ CZ20022172A patent/CZ301401B6/cs not_active IP Right Cessation
- 2000-12-22 KR KR1020027008017A patent/KR100875335B1/ko not_active Expired - Fee Related
- 2000-12-22 NZ NZ519219A patent/NZ519219A/en not_active IP Right Cessation
- 2000-12-22 WO PCT/IB2000/002071 patent/WO2001047935A2/en not_active Ceased
- 2000-12-22 RU RU2002119708/04A patent/RU2273642C2/ru not_active IP Right Cessation
- 2000-12-22 CN CNA2005100930590A patent/CN1740182A/zh active Pending
- 2000-12-22 US US09/747,182 patent/US6965033B2/en not_active Expired - Lifetime
- 2000-12-22 CA CA002396713A patent/CA2396713A1/en not_active Abandoned
- 2000-12-22 SK SK889-2002A patent/SK8892002A3/sk not_active Application Discontinuation
- 2000-12-22 BR BR0017048-8A patent/BR0017048A/pt not_active Application Discontinuation
- 2000-12-22 PL PL00356525A patent/PL356525A1/xx not_active Application Discontinuation
- 2000-12-22 CN CN00819044A patent/CN100595204C/zh not_active Expired - Fee Related
- 2000-12-22 JP JP2001549405A patent/JP2003519154A/ja active Pending
- 2000-12-22 HK HK03101952.1A patent/HK1049841A1/zh unknown
- 2000-12-22 IL IL14988700A patent/IL149887A0/xx unknown
- 2000-12-22 MX MXPA02006156A patent/MXPA02006156A/es active IP Right Grant
-
2002
- 2002-05-31 ZA ZA200204399A patent/ZA200204399B/xx unknown
- 2002-06-18 NO NO20022932A patent/NO20022932L/no not_active Application Discontinuation
-
2004
- 2004-07-28 US US10/900,718 patent/US20050004077A1/en not_active Abandoned
-
2005
- 2005-12-12 RU RU2005138719/04A patent/RU2005138719A/ru not_active Application Discontinuation
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2009
- 2009-03-26 US US12/411,951 patent/US20090192121A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107849071A (zh) * | 2015-08-10 | 2018-03-27 | 默沙东公司 | 抗病毒的β氨基酸酯膦酰二胺化合物 |
| CN107849071B (zh) * | 2015-08-10 | 2021-03-09 | 默沙东公司 | 抗病毒的β氨基酸酯膦酰二胺化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| IL149887A0 (en) | 2002-11-10 |
| US6965033B2 (en) | 2005-11-15 |
| PL356525A1 (en) | 2004-06-28 |
| HUP0204092A2 (hu) | 2003-03-28 |
| US20090192121A1 (en) | 2009-07-30 |
| HK1049841A1 (zh) | 2003-05-30 |
| AU5244701A (en) | 2001-07-09 |
| JP2003519154A (ja) | 2003-06-17 |
| AU784370B2 (en) | 2006-03-23 |
| CN1434828A (zh) | 2003-08-06 |
| WO2001047935A2 (en) | 2001-07-05 |
| US20050004077A1 (en) | 2005-01-06 |
| NO20022932D0 (no) | 2002-06-18 |
| KR20020063248A (ko) | 2002-08-01 |
| EP1240174A2 (en) | 2002-09-18 |
| WO2001047935A3 (en) | 2002-03-21 |
| CN100595204C (zh) | 2010-03-24 |
| NO20022932L (no) | 2002-08-22 |
| US20020173490A1 (en) | 2002-11-21 |
| KR100875335B1 (ko) | 2008-12-22 |
| RU2002119708A (ru) | 2004-03-20 |
| CA2396713A1 (en) | 2001-07-05 |
| BR0017048A (pt) | 2002-11-05 |
| CZ20022172A3 (cs) | 2003-01-15 |
| RU2273642C2 (ru) | 2006-04-10 |
| ZA200204399B (en) | 2003-11-26 |
| HUP0204092A3 (en) | 2005-02-28 |
| RU2005138719A (ru) | 2007-06-20 |
| MXPA02006156A (es) | 2003-09-22 |
| SK8892002A3 (en) | 2003-04-01 |
| CZ301401B6 (cs) | 2010-02-17 |
| NZ519219A (en) | 2004-03-26 |
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