NO327639B1 - HIV-hemmende pyrimidinderivater - Google Patents
HIV-hemmende pyrimidinderivater Download PDFInfo
- Publication number
- NO327639B1 NO327639B1 NO20040633A NO20040633A NO327639B1 NO 327639 B1 NO327639 B1 NO 327639B1 NO 20040633 A NO20040633 A NO 20040633A NO 20040633 A NO20040633 A NO 20040633A NO 327639 B1 NO327639 B1 NO 327639B1
- Authority
- NO
- Norway
- Prior art keywords
- formula
- alkyl
- cyano
- substituted
- 6alkyl
- Prior art date
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- 230000002401 inhibitory effect Effects 0.000 title description 7
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title description 3
- 150000003230 pyrimidines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 295
- 239000000203 mixture Substances 0.000 claims description 209
- 239000002904 solvent Substances 0.000 claims description 206
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 113
- 125000000217 alkyl group Chemical group 0.000 claims description 99
- -1 homopiperazinyl Chemical group 0.000 claims description 96
- 238000002360 preparation method Methods 0.000 claims description 74
- 125000001424 substituent group Chemical group 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 55
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 47
- 239000000243 solution Substances 0.000 claims description 39
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 33
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
- 238000004519 manufacturing process Methods 0.000 claims description 30
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 239000001257 hydrogen Substances 0.000 claims description 26
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 24
- 150000001412 amines Chemical group 0.000 claims description 24
- 239000007962 solid dispersion Substances 0.000 claims description 24
- 239000003054 catalyst Substances 0.000 claims description 23
- 229920000858 Cyclodextrin Polymers 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 238000011282 treatment Methods 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 18
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 125000002950 monocyclic group Chemical group 0.000 claims description 18
- 125000002619 bicyclic group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 229920003169 water-soluble polymer Polymers 0.000 claims description 16
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 15
- 150000001204 N-oxides Chemical class 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 239000002245 particle Substances 0.000 claims description 13
- 208000031886 HIV Infections Diseases 0.000 claims description 12
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- YIBOMRUWOWDFLG-UHFFFAOYSA-N 4-[[4-[4-(2-cyanoethenyl)-2,6-dimethylanilino]pyrimidin-2-yl]amino]benzonitrile Chemical compound CC1=CC(C=CC#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-UHFFFAOYSA-N 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- 229940097362 cyclodextrins Drugs 0.000 claims description 10
- 239000006104 solid solution Substances 0.000 claims description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 208000037357 HIV infectious disease Diseases 0.000 claims description 9
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 208000015181 infectious disease Diseases 0.000 claims description 6
- 229920000642 polymer Polymers 0.000 claims description 6
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 230000008020 evaporation Effects 0.000 claims description 5
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 5
- 239000002243 precursor Substances 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 4
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229920013820 alkyl cellulose Polymers 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000006185 dispersion Substances 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
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- 230000009466 transformation Effects 0.000 claims description 4
- 125000005943 1,2,3,6-tetrahydropyridyl group Chemical group 0.000 claims description 3
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 3
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 3
- 238000000844 transformation Methods 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 3
- KYPOHTVBFVELTG-OWOJBTEDSA-N (e)-but-2-enedinitrile Chemical compound N#C\C=C\C#N KYPOHTVBFVELTG-OWOJBTEDSA-N 0.000 claims description 2
- GFISDBXSWQMOND-UHFFFAOYSA-N 2,5-dimethoxyoxolane Chemical compound COC1CCC(OC)O1 GFISDBXSWQMOND-UHFFFAOYSA-N 0.000 claims description 2
- 244000215068 Acacia senegal Species 0.000 claims description 2
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- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 2
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- 238000006485 reductive methylation reaction Methods 0.000 claims description 2
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- 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
- C07D239/48—Two nitrogen atoms
-
- 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
- A61K31/495—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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
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- C07C257/12—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to hydrogen atoms
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- 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
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Applications Claiming Priority (3)
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EP01203090 | 2001-08-13 | ||
EP02077748 | 2002-06-10 | ||
PCT/EP2002/008953 WO2003016306A1 (en) | 2001-08-13 | 2002-08-09 | Hiv inhibiting pyrimidines derivatives |
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NO20040633L NO20040633L (no) | 2004-03-12 |
NO327639B1 true NO327639B1 (no) | 2009-09-07 |
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NO20040633A NO327639B1 (no) | 2001-08-13 | 2004-02-12 | HIV-hemmende pyrimidinderivater |
NO20083770A NO337142B1 (no) | 2001-08-13 | 2008-09-02 | Intermediat for fremstilling av pyrimidinderivater med HIV-replikasjonshemmende egenskaper |
NO2012010C NO2012010I2 (no) | 2001-08-13 | 2012-05-23 | Rilpivirin samt farmasøytisk akseptable addisjonssalter derav innbefattende hydrokloridsaltet av Rilpivirin |
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NO20083770A NO337142B1 (no) | 2001-08-13 | 2008-09-02 | Intermediat for fremstilling av pyrimidinderivater med HIV-replikasjonshemmende egenskaper |
NO2012010C NO2012010I2 (no) | 2001-08-13 | 2012-05-23 | Rilpivirin samt farmasøytisk akseptable addisjonssalter derav innbefattende hydrokloridsaltet av Rilpivirin |
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EP (3) | EP3808743B1 (sh) |
JP (4) | JP2005507380A (sh) |
KR (2) | KR100817453B1 (sh) |
CN (2) | CN100509801C (sh) |
AP (1) | AP1610A (sh) |
AR (1) | AR036387A1 (sh) |
AT (1) | ATE517891T1 (sh) |
AU (1) | AU2002329238C1 (sh) |
BE (3) | BE2012C020I2 (sh) |
BR (3) | BRPI0211909B8 (sh) |
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IL (2) | IL160328A0 (sh) |
JO (1) | JO3429B1 (sh) |
LT (2) | LT3808743T (sh) |
LU (2) | LU92001I2 (sh) |
MX (1) | MXPA04001401A (sh) |
MY (1) | MY189572A (sh) |
NO (3) | NO327639B1 (sh) |
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OA (1) | OA12652A (sh) |
PA (1) | PA8552901A1 (sh) |
PL (2) | PL402388A1 (sh) |
PT (1) | PT1419152E (sh) |
SI (2) | SI1419152T1 (sh) |
UA (1) | UA78221C2 (sh) |
WO (1) | WO2003016306A1 (sh) |
ZA (1) | ZA200401159B (sh) |
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