USH1142H - Optically active cyclobutyl pyrimidine - Google Patents

Optically active cyclobutyl pyrimidine Download PDF

Info

Publication number: USH1142H
Authority: US; United States
Prior art keywords: mixture; water; compound; formula; bis
Prior art date: 1990-11-05
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.): Abandoned

Application number

US07/608,780

Other languages

English (en)

Inventor

William A. Slusarchyk

Robert Zahler

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

ER Squibb and Sons LLC

Original Assignee

ER Squibb and Sons LLC

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.)

1990-11-05

Filing date

1990-11-05

Publication date

1993-02-02

1990-11-05 Application filed by ER Squibb and Sons LLC filed Critical ER Squibb and Sons LLC

1990-11-05 Priority to US07/608,780 priority Critical patent/USH1142H/en

1990-11-05 Assigned to E. R. SQUIBB & SONS, INC. reassignment E. R. SQUIBB & SONS, INC. ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: SLUSARCHYK, WILLIAM A., ZAHLER, ROBERT

1991-10-18 Priority to CA002053730A priority patent/CA2053730A1/fr

1991-11-04 Priority to EP91118740A priority patent/EP0484843A1/fr

1991-11-05 Priority to JP3288601A priority patent/JPH04300872A/ja

1993-02-02 Application granted granted Critical

1993-02-02 Publication of USH1142H publication Critical patent/USH1142H/en

Status Abandoned legal-status Critical Current

Links

QIGOWOORIOSGGG-UHFFFAOYSA-N 2-cyclobutylpyrimidine Chemical compound C1CCC1C1=NC=CC=N1 QIGOWOORIOSGGG-UHFFFAOYSA-N 0.000 title 1
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 13
150000001875 compounds Chemical class 0.000 abstract description 54
241000700588 Human alphaherpesvirus 1 Species 0.000 abstract description 8
241000701085 Human alphaherpesvirus 3 Species 0.000 abstract description 8
239000003443 antiviral agent Substances 0.000 abstract description 2
101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
101150035983 str1 gene Proteins 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
239000000203 mixture Substances 0.000 description 45
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
239000007787 solid Substances 0.000 description 21
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
239000000243 solution Substances 0.000 description 20
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
229910052757 nitrogen Inorganic materials 0.000 description 13
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
239000002904 solvent Substances 0.000 description 12
229910052786 argon Inorganic materials 0.000 description 10
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
239000000706 filtrate Substances 0.000 description 9
239000000047 product Substances 0.000 description 9
229910052938 sodium sulfate Inorganic materials 0.000 description 9
235000011152 sodium sulphate Nutrition 0.000 description 9
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 8
238000001704 evaporation Methods 0.000 description 8
230000008020 evaporation Effects 0.000 description 8
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
239000000741 silica gel Substances 0.000 description 7
229910002027 silica gel Inorganic materials 0.000 description 7
239000000725 suspension Substances 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
239000012267 brine Substances 0.000 description 6
238000001035 drying Methods 0.000 description 6
150000002148 esters Chemical class 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
239000010410 layer Substances 0.000 description 6
239000011347 resin Substances 0.000 description 6
229920005989 resin Polymers 0.000 description 6
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
238000003756 stirring Methods 0.000 description 6
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
238000006243 chemical reaction Methods 0.000 description 5
208000015181 infectious disease Diseases 0.000 description 5
239000000463 material Substances 0.000 description 5
239000003921 oil Substances 0.000 description 5
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
208000036142 Viral infection Diseases 0.000 description 4
238000004113 cell culture Methods 0.000 description 4
238000004587 chromatography analysis Methods 0.000 description 4
238000001816 cooling Methods 0.000 description 4
WFPZPJSADLPSON-UHFFFAOYSA-N dinitrogen tetraoxide Chemical compound [O-][N+](=O)[N+]([O-])=O WFPZPJSADLPSON-UHFFFAOYSA-N 0.000 description 4
238000010828 elution Methods 0.000 description 4
229910052740 iodine Inorganic materials 0.000 description 4
239000011630 iodine Substances 0.000 description 4
-1 lithium trisiamylborohydride Chemical compound 0.000 description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
239000012074 organic phase Substances 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
239000002002 slurry Substances 0.000 description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical class CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 4
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 4
229940035893 uracil Drugs 0.000 description 4
230000009385 viral infection Effects 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
241000700605 Viruses Species 0.000 description 3
WQGJJEUYJRYIAN-RKDXNWHRSA-N [(1s,2s)-3,3-diethoxy-2-(hydroxymethyl)cyclobutyl]methanol Chemical compound CCOC1(OCC)C[C@H](CO)[C@H]1CO WQGJJEUYJRYIAN-RKDXNWHRSA-N 0.000 description 3
238000003556 assay Methods 0.000 description 3
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
239000012230 colorless oil Substances 0.000 description 3
238000001914 filtration Methods 0.000 description 3
239000012044 organic layer Substances 0.000 description 3
239000011877 solvent mixture Substances 0.000 description 3
SJJWJJUEUFAHNH-RNFRBKRXSA-N (1r,2s)-3,3-diethoxycyclobutane-1,2-dicarboxylic acid Chemical compound CCOC1(OCC)C[C@@H](C(O)=O)[C@@H]1C(O)=O SJJWJJUEUFAHNH-RNFRBKRXSA-N 0.000 description 2
IJXJGQCXFSSHNL-QMMMGPOBSA-N (R)-(-)-2-Phenylglycinol Chemical compound OC[C@H](N)C1=CC=CC=C1 IJXJGQCXFSSHNL-QMMMGPOBSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
239000012448 Lithium borohydride Substances 0.000 description 2
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
RYWNYUWMBMTYBG-IAGOWNOFSA-N [(1s,2s)-2-(benzoyloxymethyl)-3-oxocyclobutyl]methyl benzoate Chemical compound C([C@H]1C(=O)C[C@@H]1COC(=O)C=1C=CC=CC=1)OC(=O)C1=CC=CC=C1 RYWNYUWMBMTYBG-IAGOWNOFSA-N 0.000 description 2
PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
239000000538 analytical sample Substances 0.000 description 2
PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 2
239000003638 chemical reducing agent Substances 0.000 description 2
238000002425 crystallisation Methods 0.000 description 2
230000008025 crystallization Effects 0.000 description 2
WGFWKACUXHRZOU-GHMZBOCLSA-N diethyl (1r,2s)-3,3-diethoxycyclobutane-1,2-dicarboxylate Chemical compound CCOC(=O)[C@@H]1CC(OCC)(OCC)[C@H]1C(=O)OCC WGFWKACUXHRZOU-GHMZBOCLSA-N 0.000 description 2
IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 description 2
YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 2
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
238000004108 freeze drying Methods 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
229910052739 hydrogen Inorganic materials 0.000 description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
238000011534 incubation Methods 0.000 description 2
125000002346 iodo group Chemical group I* 0.000 description 2
229910017604 nitric acid Inorganic materials 0.000 description 2
230000020477 pH reduction Effects 0.000 description 2
LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
235000015497 potassium bicarbonate Nutrition 0.000 description 2
229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
239000011736 potassium bicarbonate Substances 0.000 description 2
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
238000002360 preparation method Methods 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
229920006395 saturated elastomer Polymers 0.000 description 2
235000017281 sodium acetate Nutrition 0.000 description 2
WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
229910000342 sodium bisulfate Inorganic materials 0.000 description 2
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 2
125000002348 vinylic group Chemical group 0.000 description 2
RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
QVXSVWNNXWNZSV-UHFFFAOYSA-N 2-(chloromethyl)-4,6-dinitrophenol Chemical compound OC1=C(CCl)C=C([N+]([O-])=O)C=C1[N+]([O-])=O QVXSVWNNXWNZSV-UHFFFAOYSA-N 0.000 description 1
MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
101100177155 Arabidopsis thaliana HAC1 gene Proteins 0.000 description 1
241000124008 Mammalia Species 0.000 description 1
101150108015 STR6 gene Proteins 0.000 description 1
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
238000002441 X-ray diffraction Methods 0.000 description 1
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
239000003377 acid catalyst Substances 0.000 description 1
239000000443 aerosol Substances 0.000 description 1
239000003513 alkali Substances 0.000 description 1
IMNFDUFMRHMDMM-UHFFFAOYSA-N anhydrous n-heptane Natural products CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
229940040526 anhydrous sodium acetate Drugs 0.000 description 1
238000002832 anti-viral assay Methods 0.000 description 1
230000000840 anti-viral effect Effects 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
239000002585 base Substances 0.000 description 1
230000037396 body weight Effects 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
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238000004440 column chromatography Methods 0.000 description 1
229940125904 compound 1 Drugs 0.000 description 1
239000007822 coupling agent Substances 0.000 description 1
239000006071 cream Substances 0.000 description 1
239000012043 crude product Substances 0.000 description 1
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NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
238000004090 dissolution Methods 0.000 description 1
238000004821 distillation Methods 0.000 description 1
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UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
239000000284 extract Substances 0.000 description 1
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239000003889 eye drop Substances 0.000 description 1
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239000006260 foam Substances 0.000 description 1
239000000499 gel Substances 0.000 description 1
239000011521 glass Substances 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
238000000338 in vitro Methods 0.000 description 1
230000005764 inhibitory process Effects 0.000 description 1
239000007927 intramuscular injection Substances 0.000 description 1
238000010255 intramuscular injection Methods 0.000 description 1
238000007912 intraperitoneal administration Methods 0.000 description 1
239000007928 intraperitoneal injection Substances 0.000 description 1
238000001990 intravenous administration Methods 0.000 description 1
230000026045 iodination Effects 0.000 description 1
238000006192 iodination reaction Methods 0.000 description 1
239000006210 lotion Substances 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
238000012423 maintenance Methods 0.000 description 1
238000000034 method Methods 0.000 description 1
125000004492 methyl ester group Chemical group 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
XEWVCDMEDQYCHX-UHFFFAOYSA-N n,n-diethylethanamine;hydron;iodide Chemical compound [I-].CC[NH+](CC)CC XEWVCDMEDQYCHX-UHFFFAOYSA-N 0.000 description 1
239000002674 ointment Substances 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
239000003880 polar aprotic solvent Substances 0.000 description 1
239000002798 polar solvent Substances 0.000 description 1
239000000843 powder Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
239000011369 resultant mixture Substances 0.000 description 1
239000000523 sample Substances 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
238000011894 semi-preparative HPLC Methods 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
229940087562 sodium acetate trihydrate Drugs 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Substances [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 1
238000001665 trituration Methods 0.000 description 1
238000010792 warming Methods 0.000 description 1

Classifications

- 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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals

Definitions

[1R-(1 ⁇ (E),2 ⁇ ,3 ⁇ )]-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-bromoethenyl)-2,4(1H,3H)-pyrimidinedione is an antiviral agent that is active against herpes simplex virus 1 and varicella-zoster virus. It can be used to treat viral infections in humans and other mammals.
the compounds of this invention may be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), orally or topically depending on whether the preparation is used to treat internal or external viral infections.
the compounds may be administered orally or parenterally in an amount effective to treat the infection.
the dosage will, of course, depend on the severity of the infection, but will likely be in the range of about 1.0 to 50 mg/kg of body weight.
the desired dose may be administered several times daily at appropriate intervals.
compositions may be applied to the infected part of the body of the patient topically as an ointment, cream, aerosol, gel, powder, lotion, suspension or solution (e.g. as in eye drops).
concentration of the compound in the vehicle will, or course, depend on the severity of the infection, but will likely be in the range of about 0.1 to 7% by weight.
the compound of formula 1 can be prepared as follows: Reaction of diethylfumarate and ketene diethylacetal in hot t-butanol, yields the compound of formula ##STR3## as a racemic mixture (see K. C. Brannock et al., J. Org. Chem., 29, 940 (1964)). Treatment of the compound of formula 2 with alkali (e.g.
This material was dissolved in ethyl acetate (70 ml) and water (70 ml), and the pH was adjusted from 3.2 to 7.0 using 1N potassium hydroxide.
This material was applied in ethyl acetate (45 ml) to a column of Merck silica gel (285 g, packed in toluene). Elution with toluene, and then 2 and 4% isopropyl alcohol in toluene, afforded 701 mg of the title compound.

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

US07/608,780 1990-11-05 1990-11-05 Optically active cyclobutyl pyrimidine Abandoned USH1142H (en)

Priority Applications (4)

Application Number	Priority Date	Filing Date	Title
US07/608,780 USH1142H (en)	1990-11-05	1990-11-05	Optically active cyclobutyl pyrimidine
CA002053730A CA2053730A1 (fr)	1990-11-05	1991-10-18	Cyclobutylpyrimidine optiquement active
EP91118740A EP0484843A1 (fr)	1990-11-05	1991-11-04	Une cyclobutyl pyrimidine optiquement active
JP3288601A JPH04300872A (ja)	1990-11-05	1991-11-05	光学活性シクロブチルピリミジン

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US07/608,780 USH1142H (en)	1990-11-05	1990-11-05	Optically active cyclobutyl pyrimidine

Publications (1)

Publication Number	Publication Date
USH1142H true USH1142H (en)	1993-02-02

Family

ID=24437964

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
US07/608,780 Abandoned USH1142H (en)	1990-11-05	1990-11-05	Optically active cyclobutyl pyrimidine

Country Status (4)

Country	Link
US (1)	USH1142H (fr)
EP (1)	EP0484843A1 (fr)
JP (1)	JPH04300872A (fr)
CA (1)	CA2053730A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
KR950011530A (ko) *	1993-10-21	1995-05-15	도바 다다스	사이클로프로판 유도체 및 이를 함유하는 항바이러스제
KR0151811B1 (ko) *	1993-12-21	1998-10-15	강박광	신규한 항바이러스성 2,4-피리미딘디온 유도체 및 그의 제조방법
IL117574A0 (en) *	1995-04-03	1996-07-23	Bristol Myers Squibb Co	Processes for the preparation of cyclobutanone derivatives
WO1998052930A1 (fr) *	1997-05-20	1998-11-26	Nippon Kayaku Kabushiki Kaisha	Nouveaux derives de cyclobutane et leur procede de production

Citations (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4564618A (en)	1982-09-17	1986-01-14	Glaxo Group Limited	5-Halovinyl-2'-deoxyuridine derivatives
EP0335355A2 (fr)	1988-03-30	1989-10-04	E.R. Squibb & Sons, Inc.	Bis-(hydroxyméthyl) cyclobutyl purines et pyrimidines
EP0358154A3 (fr)	1988-09-09	1990-09-05	Nippon Kayaku Kabushiki Kaisha	Dérivé de cyclobutane et procédé pour sa production
US5064961A (en)	1989-12-18	1991-11-12	E. R. Squibb & Sons, Inc.	Process for preparing an optically active cyclobutane nucleoside
EP0366059A3 (fr)	1988-10-25	1991-12-18	Bristol-Myers Squibb Company	Des analogues de nucléoside carbocyclique

1990
- 1990-11-05 US US07/608,780 patent/USH1142H/en not_active Abandoned
1991
- 1991-10-18 CA CA002053730A patent/CA2053730A1/fr not_active Abandoned
- 1991-11-04 EP EP91118740A patent/EP0484843A1/fr not_active Withdrawn
- 1991-11-05 JP JP3288601A patent/JPH04300872A/ja not_active Withdrawn

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4564618A (en)	1982-09-17	1986-01-14	Glaxo Group Limited	5-Halovinyl-2'-deoxyuridine derivatives
EP0335355A2 (fr)	1988-03-30	1989-10-04	E.R. Squibb & Sons, Inc.	Bis-(hydroxyméthyl) cyclobutyl purines et pyrimidines
EP0358154A3 (fr)	1988-09-09	1990-09-05	Nippon Kayaku Kabushiki Kaisha	Dérivé de cyclobutane et procédé pour sa production
EP0366059A3 (fr)	1988-10-25	1991-12-18	Bristol-Myers Squibb Company	Des analogues de nucléoside carbocyclique
US5064961A (en)	1989-12-18	1991-11-12	E. R. Squibb & Sons, Inc.	Process for preparing an optically active cyclobutane nucleoside

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Bodenteich et al. Chem. Abst. 108-187146r (1958).
Griengl et al. Journal of Medicinal Chemistry vol. 28, No. 11, p. 1679 (1985).
Haralambidis et al. Chem. Abst. 111-39836n (1989).

Also Published As

Publication number	Publication date
EP0484843A1 (fr)	1992-05-13
JPH04300872A (ja)	1992-10-23
CA2053730A1 (fr)	1992-05-06

Legal Events

Date

Code

Title

Description

1990-11-05

AS

Assignment

Owner name: E. R. SQUIBB & SONS, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:SLUSARCHYK, WILLIAM A.;ZAHLER, ROBERT;REEL/FRAME:005506/0934

Effective date: 19901102

1993-01-21

STCF

Information on status: patent grant

Free format text: PATENTED CASE

Publication	Publication Date	Title
RU2055076C1 (ru)	1996-02-27	Бис-(гидроксиметил)-циклобутил-пурины или пиримидины и их фармацевтически приемлемые соли
EP0141927B1 (fr)	1991-10-30	Dérivés de guanine antiviraux
US5064961A (en)	1991-11-12	Process for preparing an optically active cyclobutane nucleoside
US4855466A (en)	1989-08-08	Purinyl cyclobutanes
US5059690A (en)	1991-10-22	Purinyl tetrahydrofurans
EP0159264A2 (fr)	1985-10-23	Composés antiviraux
US5126345A (en)	1992-06-30	Bis (hydroxymethyl) cyclobutyl triazolopyrimidines
US5414096A (en)	1995-05-09	Antiviral tetrahydropyrans
DE3650384T2 (de)	1996-06-13	Antivirale Purin-Derivate und Verfahren zu ihrer Herstellung.
EP0502690A2 (fr)	1992-09-09	Dérivé de cyclopropane
USH1142H (en)	1993-02-02	Optically active cyclobutyl pyrimidine
US5874578A (en)	1999-02-23	Process for preparing guanine-containing antiviral agents and purinyl salts useful in such process
US5130462A (en)	1992-07-14	Cyclobutane derivatives
EP0072977A1 (fr)	1983-03-02	Procédé de préparation de la 2-bêta-D-ribofuranosylthiazol-4-carboxamide
US4564618A (en)	1986-01-14	5-Halovinyl-2'-deoxyuridine derivatives
EP0082668A1 (fr)	1983-06-29	5-(2-Halogénovinyl)-2'-déoxyuridines, leurs méthodes de préparation, compositions pharmaceutiques les contenant et leur emploi dans le traitement d'infections virales
US5136090A (en)	1992-08-04	Biphenyl-5,5'-bis-alkanoic acid derivatives, their production and aldose reductase inhibitors containing the same
US5374625A (en)	1994-12-20	Adenine and guanine derivatives for the treatment of hepatitis virus infections
KR0155556B1 (ko)	1998-11-16	치환된 디벤조푸란 및 이것의 사용방법
US5198583A (en)	1993-03-30	Optically active cyclobutane nucleoside and intermediates, therefor
DE69122437T2 (de)	1997-03-13	Purinyl und Pyrimidinyltetrahydrofurane
US5256806A (en)	1993-10-26	Intermediates for the preparation of optically active cyclobutane nucleoside
US5145960A (en)	1992-09-08	Pyrimidinyl tetrahydrofurans
US4205169A (en)	1980-05-27	N-[4-Azido-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinyl]acetamide and congeners
US5272152A (en)	1993-12-21	Purinyl and pyrimidinyl tetrahydrofurans

USH1142H - Optically active cyclobutyl pyrimidine - Google Patents

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Definitions

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Priority Applications (4)

Applications Claiming Priority (1)

Publications (1)

Family

ID=24437964

Family Applications (1)

Country Status (4)

Families Citing this family (4)

Citations (5)

Patent Citations (5)

Non-Patent Citations (3)

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