ES2338760T3 - Pirimidinas inhibidoras de la replicacion del vih. - Google Patents
Pirimidinas inhibidoras de la replicacion del vih. Download PDFInfo
- Publication number
- ES2338760T3 ES2338760T3 ES02018455T ES02018455T ES2338760T3 ES 2338760 T3 ES2338760 T3 ES 2338760T3 ES 02018455 T ES02018455 T ES 02018455T ES 02018455 T ES02018455 T ES 02018455T ES 2338760 T3 ES2338760 T3 ES 2338760T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- amino
- cyano
- substituted
- alkyloxy
- 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
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- 150000003230 pyrimidines Chemical class 0.000 title description 6
- 230000010076 replication Effects 0.000 title description 4
- 230000002401 inhibitory effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 170
- -1 cyano, aminocarbonyl Chemical group 0.000 claims abstract description 97
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 79
- 125000001424 substituent group Chemical group 0.000 claims abstract description 45
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 44
- 125000005843 halogen group Chemical group 0.000 claims abstract description 42
- 125000003118 aryl group Chemical group 0.000 claims abstract description 41
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 38
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 32
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 19
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims abstract description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 17
- 125000000714 pyrimidinyl group Chemical group 0.000 claims abstract description 17
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 16
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims abstract description 15
- 125000003373 pyrazinyl group Chemical group 0.000 claims abstract description 15
- 125000002098 pyridazinyl group Chemical group 0.000 claims abstract description 15
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 13
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims abstract description 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims abstract description 10
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims abstract description 8
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 6
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims abstract description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000002541 furyl group Chemical group 0.000 claims abstract description 5
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims abstract description 5
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims abstract description 5
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims abstract description 5
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 5
- 125000003277 amino group Chemical group 0.000 claims abstract 3
- 239000002904 solvent Substances 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 42
- 238000002360 preparation method Methods 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 20
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- 239000012298 atmosphere Substances 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 12
- 230000000798 anti-retroviral effect Effects 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 208000031886 HIV Infections Diseases 0.000 claims description 7
- 208000037357 HIV infectious disease Diseases 0.000 claims description 7
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 7
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 5
- 125000006684 polyhaloalkyl group Polymers 0.000 claims description 5
- 206010061598 Immunodeficiency Diseases 0.000 claims description 4
- 208000029462 Immunodeficiency disease Diseases 0.000 claims description 4
- 241000700605 Viruses Species 0.000 claims description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 4
- 230000007813 immunodeficiency Effects 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- 230000036436 anti-hiv Effects 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims description 2
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 claims 1
- 230000009385 viral infection Effects 0.000 claims 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 abstract description 6
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 abstract description 2
- 150000001204 N-oxides Chemical class 0.000 abstract description 2
- 125000001118 alkylidene group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000001041 indolyl group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 67
- 239000000543 intermediate Substances 0.000 description 56
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 51
- 239000000460 chlorine Substances 0.000 description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 31
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 229920000858 Cyclodextrin Polymers 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000000523 sample Substances 0.000 description 19
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 239000012300 argon atmosphere Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
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- 238000003818 flash chromatography Methods 0.000 description 9
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- 125000006239 protecting group Chemical group 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
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- 125000004432 carbon atom Chemical group C* 0.000 description 7
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
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- 150000002170 ethers Chemical class 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 229920003169 water-soluble polymer Polymers 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/80—Oxygen atoms
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10779298P | 1998-11-10 | 1998-11-10 | |
| US107792P | 1998-11-10 | ||
| US14396299P | 1999-07-15 | 1999-07-15 | |
| US143962P | 1999-07-15 | ||
| PCT/EP1999/007417 WO2000027825A1 (en) | 1998-11-10 | 1999-09-24 | Hiv replication inhibiting pyrimidines |
| WOEP99/07417 | 1999-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2338760T3 true ES2338760T3 (es) | 2010-05-12 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02018455T Expired - Lifetime ES2338760T3 (es) | 1998-11-10 | 1999-11-01 | Pirimidinas inhibidoras de la replicacion del vih. |
| ES99203590T Expired - Lifetime ES2193664T3 (es) | 1998-11-10 | 1999-11-01 | Pirimidinas inhibidoras de la replicacion del vih. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES99203590T Expired - Lifetime ES2193664T3 (es) | 1998-11-10 | 1999-11-01 | Pirimidinas inhibidoras de la replicacion del vih. |
Country Status (41)
Families Citing this family (129)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000027825A1 (en) * | 1998-11-10 | 2000-05-18 | Janssen Pharmaceutica N.V. | Hiv replication inhibiting pyrimidines |
| GB9914258D0 (en) * | 1999-06-18 | 1999-08-18 | Celltech Therapeutics Ltd | Chemical compounds |
| DE19945982A1 (de) * | 1999-09-24 | 2001-03-29 | Knoll Ag | Geschwindigkeitsbestimmte Partikel |
| PL207590B1 (pl) | 1999-09-24 | 2011-01-31 | Janssen Pharmaceutica Nv | Cząstka stanowiąca dyspersję stałą oraz postać dawkowania, sposób ich otrzymywania i zastosowanie |
| AU770600B2 (en) | 1999-10-07 | 2004-02-26 | Amgen, Inc. | Triazine kinase inhibitors |
| HUP0301117A3 (en) | 2000-02-17 | 2004-01-28 | Amgen Inc Thousand Oaks | Imidazole derivatives kinase inhibitors, their use, process for their preparation and pharmaceutical compositions containing them |
| ES2559273T3 (es) | 2000-05-08 | 2016-02-11 | Janssen Pharmaceutica Nv | Profármacos de pirimidinas que inhiben la replicación del VIH |
| WO2001085700A2 (en) | 2000-05-08 | 2001-11-15 | Janssen Pharmaceutica N.V. | Hiv replication inhibiting pyrimidines and triazines |
| CN100339846C (zh) * | 2000-11-01 | 2007-09-26 | 斯雷普内姆斯·Com公司 | 对域名数据的状态变化进行实时监测并即时注册的系统及方法 |
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| ES2559273T3 (es) * | 2000-05-08 | 2016-02-11 | Janssen Pharmaceutica Nv | Profármacos de pirimidinas que inhiben la replicación del VIH |
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1999
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