CN102850282A - Preparation method and purpose of 3-alkoxy-substituent-2-pyrazinyl formamide compounds - Google Patents
Preparation method and purpose of 3-alkoxy-substituent-2-pyrazinyl formamide compounds Download PDFInfo
- Publication number
- CN102850282A CN102850282A CN2012102185056A CN201210218505A CN102850282A CN 102850282 A CN102850282 A CN 102850282A CN 2012102185056 A CN2012102185056 A CN 2012102185056A CN 201210218505 A CN201210218505 A CN 201210218505A CN 102850282 A CN102850282 A CN 102850282A
- Authority
- CN
- China
- Prior art keywords
- virus
- pyrazine
- oxygen base
- formyl ammonia
- pyrazine formyl
- 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.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention related to 3-alkoxy-substituent-2-pyrazinyl formamide compounds with a structure represented by the general formula I, and an application thereof in preparing antiviral medicines. The compounds provided by the invention perform antiviral effects in vivo through a process of being metabolized into T1105 or T705 by esterase or P450 enzyme. Compared with prototype medicines T1105 or T705, the compounds with the general formula I have substantial advantages of high bioavailability and long in-vivo action time.
Description
Technical field
The present invention relates to pyrazine formyl ammoniac compounds, its preparation method and for the preparation of the purposes of antiviral.
Background technology
3-oxo-3,4-dihydro-2-pyrazine formyl ammonia (T1105) and 6-fluorine 3-oxo-3,4-dihydro-2-pyrazine formyl ammonia (T705) (seeing following formula) is the RNA polymerase inhibitor of a viroid, has preferably antivirus action.
It is reported, T705 use separately or and neuraminidase inhibitor, for example Ro 64-0796/002 is united use, has well to resisiting influenza virus effect (Antimicrobial Agents and Chemotherapy, 2007, Vol.51, No.3,845-851; Antimicrobial Agents and Chemotherapy, 2010, p.126133, PCT patent: WO2000010569).T1105 shows extraordinary effect to foot-and-mouth disease virus resistant (PCT patent: WO20071139081) in vivo with in the external model.T705 also has good curative effect to other RNA viruses associated diseases in addition.For example, T705 has therapeutic action (Antiviral Research 82 (2009) 169 171) to the west type equine encephalitis of mouse model; T705 has therapeutic action (Antimicrobial Agents and Chemotherapy, 2009, p.202 209) to the yellow jack of hamster; T705 infects the disease that causes to arenavirus and bunyavirus therapeutic action (Antimicrobial Agents and Chemotherapy, 2007, p.3168 3176) is arranged with external in vivo.T705 is to there being therapeutic action (Antiviral Research 80 (2008) 377 379) by the rodent of West Nile virus infection; T705 infects Phlebovirus therapeutic action (Antiviral Research 86 (2010) 121 127).
3-oxo-3,4-dihydro-2-pyrazine formyl ammonia (T1105) and 6-fluorine 3-oxo-3,4-dihydro-2-pyrazine formyl ammonia (T705) has similar structure and mechanism of action, can be converted in vivo the form of corresponding ribonucleoside triphosphote, suppress competitively viral rna polymerase by simulation guanosine triphosphate (GTP) and bring into play antivirus action (ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2005, Vol.49, No.3, p.981 986).
Although T1105 and T705 have good antivirus action in external model, all there are some bad pharmacokinetic properties in these two compounds, are unfavorable for the performance of their drug effects.For example the oral absorption of T1105 is very poor, and the interior elimination of body is also very fast, and it is in the external activity that shows good foot-and-mouth disease virus resistant, IC50 is 1.6ug/mL, but the pig oral administration, every day twice, the dosage that reach 200mg/Kg just can reach the effect of desirable anti-foot and mouth disease.The oral absorption of T705 is fine, but eliminates comparatively fast, has short problem of transformation period, causes its dosage larger, and every day, oral dosage was 800mg-2400mg.
Summary of the invention
In order to overcome the bad pharmacokinetic properties such as the bioavailability that 3-oxo-pyrazine-2-formyl ammoniac compounds T1105 and T705 exist is not high, the transformation period is short, the invention provides the 6-R with general formula I structure
1-3-O-R
2-2-pyrazine formyl ammoniac compounds, this compounds can be converted into the form of T1105 or T705 in vivo and bring into play antiviral effect, can obviously improve simultaneously the oral administration biaavailability of compound, and prolongs compound action time in vivo.
A first aspect of the present invention relates to compound, its pharmaceutically useful salt or the solvate with general formula I structure,
Wherein
R
1Represent hydrogen or halogen; Described halogen is fluorine, chlorine, bromine or iodine;
R
2Be selected from: alkyl; The alkyl that alkoxyl group replaces; Cycloalkyl; The alkyl that aromatic base replaces or the alkyl that replaces with the aryl of substituted radical, described substituting group are selected from alkoxyl group, alkyl, cycloalkyl, halogen, nitro, itrile group, hydroxyl or amino etc., preferred alkoxyl group; The phenyl of phenyl or replacement, described substituting group are selected from alkoxyl group, alkyl, cycloalkyl, halogen, nitro, itrile group, hydroxyl or amino etc., preferred alkoxyl group.
According to compound, its pharmaceutically useful salt or solvate of first aspect, described alkyl is C
1-10Alkyl is the straight or branched alkyl with 1～10 carbon atom, for example is C
1-6Alkyl, described alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl, isopentyl, n-hexyl, n-octyl etc.;
But described cycloalkyl refers to having 3 to 12 carbon atoms and having the cyclic alkyl of one or more rings of saturated or undersaturated non-aromatic, for example is C
3-6Cycloalkyl, described cycloalkyl comprise such as adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group, cyclohexenyl etc., preferred cyclopentyl and cyclohexyl;
Described alkoxyl group refers to " alkyl-O-", described alkyl described as defined above, and comprising such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy etc., preferred methoxyl group and oxyethyl group;
Described aromatic base refers to have 6 to 12 carbon atoms and has single ring (for example phenyl) or the monovalent aromatic family carbon ring group of a plurality of condensed ring (for example naphthyl or anthryl), wherein condensed ring can be aromatic or can not be aromatic (for example 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-ketone-7-base etc.), prerequisite is that tie point is aryl, preferred phenyl;
Wherein said replacement can be single and replace or polysubstituted, described polysubstituted for example be two replacements.
According to compound, its pharmaceutically useful salt or solvate of first aspect, it is selected from:
(1) 3-n-propyl oxygen base-3-oxo-2-pyrazine formyl ammonia;
(2) 3-sec.-propyl oxygen base-2-pyrazine formyl ammonia;
(3) 3-isobutyl-oxygen base-2-pyrazine formyl ammonia;
(4) 3-n-pentyl oxygen base-2-pyrazine formyl ammonia;
(5) 3-isopentyl oxygen base-2-pyrazine formyl ammonia;
(6) 3-n-hexyl oxygen base-2-pyrazine formyl ammonia;
(7) 3-cyclohexyl oxygen base-2-pyrazine formyl ammonia;
(8) 3-n-octyl oxygen base-2-pyrazine formyl ammonia;
(9) 3-[2-(oxyethyl group)-oxyethyl group]-2-pyrazine formyl ammonia;
(10) 3-[2-(methoxyl group)-oxyethyl group]-2-pyrazine formyl ammonia;
(11) 3-(benzyl oxygen base)-2-pyrazine formyl ammonia;
(12) 3-(to methoxy-benzyl oxygen base)-2-pyrazine formyl ammonia;
(13) 3-(p-methoxyphenyl oxygen base)-2-pyrazine formyl ammonia;
(14) 6-fluoro-3-ethyl oxygen base-2-pyrazine formyl ammonia;
(15) 6-fluoro-3-normal-butyl oxygen base-2-pyrazine formyl ammonia;
(16) 6-fluoro-3-benzyl oxygen base-2-pyrazine formyl ammonia;
(17) 6-fluoro-3-[(is to methoxy-benzyl)-the oxygen base]-2-pyrazine formyl ammonia;
(18) 6-fluoro-3-n-hexyl oxygen base-2-pyrazine formyl ammonia;
(19) 6-fluoro-3-n-octyl oxygen base-2-pyrazine formyl ammonia;
(20) 6-fluoro-3-[(3-methoxyl group)-benzyl]-2-pyrazine formyl ammonia; With
(21) 6-fluoro-3-[2-(oxyethyl group)-propoxy-]-2-pyrazine formyl ammonia.
A second aspect of the present invention relates to pharmaceutical composition, and it comprises each described compound of first aspect present invention, its pharmaceutically useful salt or solvate, and pharmaceutically acceptable carrier.
According to the pharmaceutical composition of second aspect present invention, it can be made into following preparation: solid preparation, injection, external preparation, spray, liquid preparation or compound preparation etc.
A third aspect of the present invention relate to each described compound of first aspect present invention, its pharmaceutically useful salt or solvate or each described pharmaceutical composition of second aspect present invention in the preparation antiviral purposes or prevent and/or treat purposes in the medicine of virus infection associated diseases in preparation.Wherein said medicine can be used for Mammals, for example is people or artiodactyl, and described artiodactyl can be pig, ox or sheep etc.
Purposes according to third aspect present invention, wherein said virus mainly comprises various types of RNA viruses, it includes but not limited to following virus: influenza virus (Influenza Virus), HCV virus (Hepatitis C Virus), bunyavirus (Bunyavirus), sand fly virus (Phlebovirus), foot and mouth disease virus (Foot and Mouth Disease Virus), west nile virus (West Nile virus), arenavirus (Arenavirus), western equine encephalitis virus (Western Equine Encephalitis Virus), or yellow fever virus (Yellow Fever Virus).
Wherein the virus infection associated diseases is such as being influenza, hepatitis C, singapore hemorrhagic fever, hemorrhagic fever (such as being hemorrahgic fever with renal syndrome), encephalitis, sandfly fever, foot and mouth disease, West nile virus disease, lymphocytic choriomeningitis, La Sare, Argentinian hemorrhagic fever, Bolivian hemorrhagic fever, west horse type encephalitis and yellow jack etc.
Fourth aspect present invention relates to each described compound of a first aspect of the present invention, its pharmaceutically useful salt or solvate prevent and/or treat the medicine of Mammals foot and mouth disease in preparation purposes.
Described Mammals for example is people or artiodactyl, and described artiodactyl can be pig, ox or sheep etc.
A fifth aspect of the present invention relates to the preparation method of each described compound of a first aspect of the present invention, and it comprises:
(i) 6-R
1-3-halo-2-pyrazine formyl ammonia, at anhydrous non-proton and organic solvent, such as toluene, DMF, acetonitrile, DME, THF, in the benzene etc., at organic bases, such as triethylamine, DBU, diisopropylethylamine etc., or mineral alkali are such as salt of wormwood, under the existence of cesium carbonate etc., with R
2The OH reaction obtains 6-R
1-3-O-R
2-2-pyrazine formyl ammonia; Perhaps
R wherein
1And R
2Definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine or iodine;
(ii) 6-R
1-3-halo-2-pyrazine formonitrile HCN is at anhydrous non-proton and organic solvent, such as toluene, and DMF, acetonitrile, DME, THF, in the benzene etc., at organic bases, such as triethylamine, DBU, diisopropylethylamine etc., or mineral alkali are such as Na, under the existence of NaH etc., with R
2The OH reaction obtains 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN; 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN is under alkaline condition, and is lower such as NaOH or salt of wormwood existence, uses hydrogen peroxide oxidation, obtains 6-R
1-3-O-R
2-2-pyrazine formyl ammonia;
R wherein
1And R
2Definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine or iodine.
The invention still further relates to the method that prevents and/or treats the virus infection associated diseases, described method comprises to first aspect present invention each described compound, its pharmaceutically useful salt or solvate or the of the present invention pharmaceutical composition of the individuality that needs are arranged to prevent and/or treat significant quantity.
Wherein said virus mainly comprises various types of RNA viruses, it includes but not limited to following virus: influenza virus (Influenza Virus), HCV virus (Hepatitis C Virus), bunyavirus (Bunyavirus), sand fly virus (Phlebovirus), foot and mouth disease virus (Foot and Mouth Disease Virus), west nile virus (West Nile virus), arenavirus (Arenavirus), western equine encephalitis virus (Western Equine Encephalitis Virus), or yellow fever virus (Yellow Fever Virus).
Wherein the virus infection associated diseases is such as being influenza, hepatitis C, singapore hemorrhagic fever, hemorrhagic fever (such as being hemorrahgic fever with renal syndrome), encephalitis, sandfly fever, foot and mouth disease, West nile virus disease, lymphocytic choriomeningitis, La Sare, Argentinian hemorrhagic fever, Bolivian hemorrhagic fever, west horse type encephalitis and yellow jack etc.
Wherein said have the individuality that needs for example can be Mammals, and such as people or artiodactyl, described artiodactyl can be pig, ox or sheep etc.
Compound of the present invention or pharmaceutical composition can use separately, or mix with tap water or mix with animal-feed, are used for artiodactyl, such as prevention and the treatment of the foot and mouth disease of pig, ox, sheep etc.
The beneficial effect of the invention
Compound involved in the present invention, be that T1105 or T705 bring into play antivirus action by esterase or P450 enzymes metabolism in vivo, compare with prototype medicine T1105 or T705, it is high that compound of Formula I of the present invention has bioavailability, and the interior long action time of body etc. are advantage obviously.
Description of drawings
Fig. 1 is compound 14,15,16,17 after the mouse stomach administration drug-time curve of T705 in the body.
Fig. 2 is compound 1,2,3,4,5 after the mouse stomach administration drug-time curve of T1105 (T1105 is oral under 0.0637 mmol/10ml/kg dosage, does not detect T1105 in blood plasma) in the body.
Embodiment
Below in conjunction with embodiment embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only is used for explanation the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person among the embodiment carries out according to the condition of normal condition or manufacturers's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 13-(n-propyl oxygen base)-preparation (method 1) of 2-pyrazine formyl ammonia (compound 1).
In drying, in the there-necked flask with thermometer, prolong and drying tube, add anhydrous propyl alcohol 30mL, add sodium 146mg(6.34mmol), stirring at room or slightly be heated to the completely dissolve of sodium grain adds the good 3-chloro-2-pyrazine formyl ammonia 500mg(3.17mmol of purifying), be warming up to 80 ℃, reaction 20min, after being cooled to room temperature, add glacial acetic acid 1mL, be evaporated to dried, Flash chromatography column separation (methylene chloride/methanol wash-out) obtains target compound behind the silica gel mixed sample
1HNMR(CDCl
3) δ 1.50 (3H, t, J=7.2Hz),
4.58(2H,q,J=7.2Hz),6.07(1H,brs),7.62(1H,brs),8.26(1H,s),8.28(1H,s)；
EIMS(m/e,100),167(M
+,25),150(60),123(35),96(40),80(40),68(100).
Embodiment 23-(n-propyl oxygen base)-preparation (method 2) of 2-pyrazine formyl ammonia (compound 1).
Step 13-(n-propyl oxygen base)-preparation of 2-pyrazine formonitrile HCN
In drying, in the there-necked flask with thermometer, prolong and drying tube, add dry DMF 10mL, add 3-chloro-pyrazine-2-formonitrile HCN (978mg, 7.00mmol), stirring and dissolving, add anhydrous n-propyl alcohol (841mg, 14mmol) and anhydrous triethylamine (1.5ml, approximately 11.85mmol), be warming up to 80-120C reaction 2 hours, after being cooled to room temperature, dilute with water, ethyl acetate extraction, washing, sodium chloride solution is washed, be evaporated to driedly, obtain crude product without separation, be directly used in next step reaction after the drying.
Step 23-(n-propyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 1)
In the there-necked flask with thermometer, add 3-(n-propyl oxygen base)-2-pyrazine formonitrile HCN (980mg, the approximately 6mmol) dissolve with ethanol of 60mL95%, ice-water bath is down to 5C, adds 30% H
2O
2With the NaOH aqueous solution of 6N, stirring reaction is 2 hours under the ice-water bath, and is extremely neutral with the 1NHC adjust pH, outside under the condition of warm 45-50C, be evaporated to dried, Flash column chromatography behind the silica gel mixed sample (methylene chloride/methanol wash-out), obtaining title compound is white solid
1HNMR(CDCl
3) δ 1.50 (3H, t, J=7.2Hz),
4.58(2H,q,J=7.2Hz),6.07(1H,brs),7.62(1H,brs),8.26(1H,s),8.28(1H,s);EIMS(m/e,100),167(M
+,25),150(60),123(35),96(40),80(40),68(100).
Embodiment 33-(sec.-propyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 2)
Method just replaces n-propyl alcohol with Virahol with embodiment 1, obtains title compound,
1HNMR(CDCl
3) δ 1.45 (6H, d, J=6.0Hz), 5.50 (2H, t, J=7.2Hz), 6.14 (1H, brs), 7.69 (1H, brs), 8.27 (1H, d, J=2.4Hz), 8.29 (1H, d, J=2.4Hz); ESIMS (m/e) 182 (MH
+).
Embodiment 43-(isobutyl-oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 3)
Method just replaces n-propyl alcohol with isopropylcarbinol with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 1.06 (3H, d, J=6.8Hz), 2.20 (1H, m) 4.28 (2H, d, J=6.8Hz), 6.17 (1H, brs), 7.63 (1H, brs), 8.27 (2H, ABsystem, J=2.4Hz); EIMS (m/e, 100), 195 (M
+, 25), 178 (33), 140 (53), 123 (80), 96 (56), 68 (100).
Embodiment 5The preparation of 3-n-pentyl oxygen base-2-pyrazine formyl ammonia (compound 4)
Method just replaces n-propyl alcohol with Pentyl alcohol with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 0.93 (3H, t, J=7.2Hz), 1.43 (4H, m), 1.87 (2H, m), 4.50 (2H, t, J=6.8Hz), 6.08 (1H, brs), 7.62 (1H, brs), 8.28 (2H, s); ESIMS (m/e) 210 (MH
+).
Embodiment 6The preparation of 3-isopentyl oxygen base-2-pyrazine formyl ammonia (compound 5)
Method just replaces n-propyl alcohol with primary isoamyl alcohol with embodiment 1, obtains title compound.
1HNMR(CCl
3),0.97(3H,d,J=6.4Hz),1.79(3H,m),4.55(2H,t,J=6.8Hz),6.01(1H,brs),7.62(1H,brs),8.28(2H,s);ESIMS(m/e)210(MH
+).
Embodiment 7The preparation of 3-n-hexyl oxygen base-2-pyrazine formyl ammonia (compound 6)
Method just replaces n-propyl alcohol with n-hexyl alcohol with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 0.90 (3H, m), 1.30-1.54 (6H, m), 1.87 (2H, m), 4.5 (2H, t, J=6.8Hz), 5.90 (1H, brs), 7.63 (1H, brs), 8.28 (2H, s); ESIMS (m/e) 222 (MH
+).
Embodiment 8The preparation of 3-cyclohexyl oxygen base-2-pyrazine formyl ammonia (compound 7)
Method just replaces n-propyl alcohol with hexalin with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 1.06 (3H, d, J=6.8Hz), 2.20 (1H, m), 4.28 (2H, d, J=6.8Hz), 6.17 (1H, brs), 7.63 (1H, brs), 8.27 (2H, AB system, J=2.4Hz); ESIMS (m/e) 222 (MH
+).
Embodiment 9The preparation of 3-n-octyl oxygen base-2-pyrazine formyl ammonia (compound 8)
Method just replaces n-propyl alcohol with n-Octanol with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 0.88 (3H, m), 1.20-1.50 (10H, m), 1.87 (2H, m), 4.50 (2H, t, J=6.8Hz), 5.99 (1H, brs), 7.63 (1H, brs), 8.28 (2H, s); ESIMS (m/e) 252 (MH
+).
Embodiment 10The 3-[2-(oxyethyl group)-oxyethyl group]-preparation of 2-pyrazine formyl ammonia (compound 9)
Method just replaces n-propyl alcohol with ethoxy ethanol with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 1.22 (3H, t, J=7.2Hz), 3.62 (2H, q, J=7.2Hz), 3.85 (2H, t, J=4.8Hz), 4.65 (2H, t, J=4.8Hz), (6.24 1H, brs), 7.78 (1H, brs), (8.26 1H, d, J=2.8Hz), (8.34 1H, d, J=2.8Hz); ESIMS (m/e) 212 (MH
+).
Embodiment 11The 3-[2-(methoxyl group)-oxyethyl group]-preparation of 2-pyrazine formyl ammonia (compound 10)
Method just replaces n-propyl alcohol with methyl cellosolve with embodiment 1, obtains title compound,
1HNMR (CCl
3) δ 3.46 (3H, s), 3.82 (2H, t, J=4.8Hz), 4.66 (2H, t, J=4.8Hz), 6.06 (1H, brs), 7.72 (1H, brs), 8.27 (1H, d, J=2.4Hz), 8.33 (1H, d, J=2.4Hz); ESIMS (m/e) 198 (MH
+).
Embodiment 123-(benzyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 11)
Method just replaces n-propyl alcohol with phenylcarbinol with embodiment 1, obtains title compound,
1HNMR(CDCl
3) δ 5.58(2H, s), 5.87 (1H, brs), 7.32-7.52 (5H, m), 7.60 (1H, brs), 8.30 (2H, m) .EIMS (m/e, 100), 229 (M
+, 30), 212 (350), 91 (100).
Embodiment 13The preparation of 3-(to methoxybenzyl oxygen base)-2-pyrazine formyl ammonia (compound 12)
Method just so that methoxybenzyl is replaced n-propyl alcohol, obtains title compound with embodiment 1,
1HNMR (CDCl
3) δ (ppm), 3.82 (3H, s), 5.51 (2H, s), 6.00 (1H, brs), 6.90 (2H, d, J=8.8Hz), 7.43 (2H, d, J=8.8Hz), 7.59 (1H, brs), 8.30 (2H, s); ESIMS (m/e), 260 (MH
+)
Embodiment 14The preparation method of 3-(p-methoxyphenyl oxygen base)-2-pyrazine formyl ammonia (compound 13) just so that mequinol is replaced n-propyl alcohol, obtains title compound with embodiment 1,
1HNMR (CDCl
3) δ 3.83 (3H, s), 5.90 (1H, brs), (6.97 2H, d, J=8.8Hz), 7.10 (2H, d, J=8.8Hz), 7.65 (1H, br s), (8.25 1H, d, J=2.4Hz), 8.321H, d, J=2.4Hz) .EIMS (m/e, 100), 245 (M+, 39), 124 (100).
Embodiment 15The preparation (method 1) of 6-fluoro-3-ethyl oxygen base-2-pyrazine formyl ammonia (compound 14)
Step 1The preparation of 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN
In drying, in the there-necked flask with thermometer, prolong and drying tube, add dry toluene 10mL, add 3,6-two fluoro-pyrazine-2-formonitrile HCN (1000mg, 7.09mmol), stirring and dissolving adds dehydrated alcohol (653mg, 14.18mmol) and anhydrous triethylamine (1.5ml, about 11.85mmol), be warming up to 80C reaction 2 hours, be cooled to room temperature after, be evaporated to dried, Flash chromatography column separation (ethyl acetate/petroleum ether wash-out) obtains target compound 1020mg behind the silica gel mixed sample, is white solid
1HNMR (CDCl
3) δ 1.48 (3H, t, J=7.2Hz), 4.54 (2H, q, J=7.2Hz), 8.20 (1H, d, J=8.0Hz) EIMS(m/e, 100), 167 (M
+, 40), 139 (86), 119 (100).
Step 2The preparation of 6-fluoro-3-ethyl oxygen base-2-pyrazine formyl ammonia (compound 14)
In the there-necked flask with thermometer, add 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN (1020mg, 6mmol) dissolve with ethanol of 60mL95%, ice-water bath is down to 5C, the H2O2 of adding 30% and the NaOH aqueous solution of 6N, stirring reaction is 2 hours under the ice-water bath, and is extremely neutral with the 1NHC adjust pH, outside under the condition of warm 45-50C, be evaporated to dried, Flash column chromatography behind the silica gel mixed sample (methylene chloride/methanol wash-out), obtaining title compound is white solid
1HNMR (CDCl
3) δ 1.50 (3H, t, J=6.8Hz), 4.56 (2H, q, J=6.8Hz), 6.20 (1H, brs), 7.53 (1H, brs), 8.14 (1H, d, J=8.8Hz), EIMS(m/e, 100), 185 (M
+, 38), 170 (88), 114 (90), 86 (100).
Embodiment 16The preparation (method 2) of 6-fluoro-3-ethyl oxygen base-2-pyrazine formyl ammonia (compound 14)
In drying, in the there-necked flask with thermometer, prolong and drying tube, add dry toluene 5mL, add 3,6-, two fluoro-pyrazine-2-formyl ammonia (159mg, 1.13mmol), stirring and dissolving adds dehydrated alcohol (92mg, 2mmol) and anhydrous triethylamine (202mg, 2mmol), be warming up to 80C reaction 2 hours, be cooled to room temperature after, be evaporated to dried, Flash chromatography column separation (ethyl acetate/petroleum ether wash-out) obtains target compound 105mg behind the silica gel mixed sample, is white solid
1HNMR and EIMS are with the product of embodiment 15.
Embodiment 17The preparation of 6-fluoro-3-butyl oxygen base-2-pyrazine formyl ammonia (compound 15).
Step 1The preparation of 6-fluoro-3-butyl oxygen base-2-pyrazine formonitrile HCN
Method just replaces ethanol with butanols with embodiment 15 steps 1, obtains 6-fluoro-3-butyl oxygen base-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 0.99 (3H, t, J=7.2Hz), 1.52 (2H, m), 1.83 (2H, m), 4.56 (2H, t, J=6.4Hz), 8.20 (1H, d, J=8.4Hz); EIMS(m/e, 100), 195 (M
+, 40), 139 (86), 119 (100).
Step 2The preparation of 6-fluoro-3-butyl oxygen base-2-pyrazine formyl ammonia
Method just replaces 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN with 6-fluoro-3-butyl oxygen base-2-pyrazine formonitrile HCN with embodiment 15 steps 2, obtains 6-fluoro-3-butyl oxygen base-2-pyrazine formyl ammonia.
1HNMR(CDCl
3)δ0.99(3H,t,J=7.2Hz),1.52(2H,m),1.86(2H,m),4.50(2H,t,J=6.8Hz),7.01(1H,brs),7.59(1H,brs),8.14(1H,d,J=8.8Hz)EIMS（m/e,100）213(M
+,22),140(33)，57（100）。
Embodiment 18The preparation of 6-fluoro-3-benzyloxy-2-pyrazine formyl ammonia (compound 16).
Step 1The preparation of 6-fluoro-3-benzyloxy-2-pyrazine formonitrile HCN
Method just replaces ethanol with benzylalcohol with embodiment 15 steps 1, obtains 6-fluoro-3-benzyloxy-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 5.53 (2H, s), 7.38-7.49 (5H, m), 8.20 (1H, d, J=8Hz) EIMS(m/e, 100) 229 (M
+, 45), 91 (100)
Step 2The preparation of 6-fluoro-3-benzyloxy-2-pyrazine formyl ammonia
Method just replaces 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN with 6-fluoro-3-benzyloxy-2-pyrazine formonitrile HCN with embodiment 15 steps 2, obtains 6-fluoro-3-benzyloxy-2-pyrazine formyl ammonia.
1HNMR(CDCl
3)δ5.56(2H,s),7.35-7.50(5H,m),6.00(1H,brs),7.55(1H,br?s),8.15(1H,d,J=8.8Hz);EIMS(m/e,100)247(M
+,15),?230(22),91(100)。
Embodiment 19The preparation of 6-fluoro-3-(to the methoxy benzyloxy)-2-pyrazine formyl ammonia (compound 17)
Step 1The preparation of 6-fluoro-3-(to the methoxy benzyloxy)-2-pyrazine formonitrile HCN
Method just replaces ethanol with p-methoxybenzyl alcohol with embodiment 15 steps 1, obtains 6-fluoro-3-(to the methoxy benzyloxy)-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 3.82 (3H, s), 5.46 (2H, s), 6.92 (2H, d, J=8.8Hz), 8.20 (1H, d, J=8.0Hz); EIMS(m/e, 100) 259 (M
+, 5), 121 (100).
Step 2The preparation of 6-fluoro-3-(to the methoxy benzyloxy)-2-pyrazine formyl ammonia
Method just replaces 6-fluoro-3-oxyethyl group-2-pyrazine formonitrile HCN with 6-fluoro-3-(to the methoxy benzyloxy)-2-pyrazine formonitrile HCN with embodiment 15 steps 2, obtains 6-fluoro-3-(to the methoxy benzyloxy)-2-pyrazine formyl ammonia,
1HNMR (CDCl
3) δ 3.31 (3H, s), 5.49 (2H, s), 6.24 (1H, brs), 6.91 (2H, d, J=8.8Hz), 7.41 (2H, d, J=8.8Hz), 7.50 (1H, brs), 8.15 (1H, d, J=8.4Hz); EIMS(m/e, 100) 222 (M
+, 15), 121 (100)
Embodiment 206-fluoro-3-(n-hexyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 18)
Step 16-fluoro-3-(n-hexyl oxygen base)-preparation of 2-pyrazine formonitrile HCN
Method just so that n-hexyl alcohol is replaced ethanol, obtains 6-fluoro-3-(n-hexyl oxygen base with embodiment 15 steps 1)-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 0.91 (3H, m), 1.30-1.52 (6H, m), 1.81 (2H, m), 4.44 (2H, t, J=6.8Hz), 8.19 (1H, d, J=8.4Hz)
Step 26-fluoro-3-(n-hexyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 18)
Method is with embodiment 15 steps 2, just with 6-fluoro-3-(n-hexyl oxygen base)-2-pyrazine formonitrile HCN replacement 6-fluoro-3-oxyethyl group-2-pyrazine formonitrile HCN, obtain 6-fluoro-3-(n-hexyl oxygen base)-2-pyrazine formyl,
1HNMR (CDCl
3) δ 0.88 (3H, m), 1.30-1.52 (6H, m), 1.86 (2H, m), 4.49 (2H, t, J=6.8Hz), 6.15 (1H, brs), 7.53 (1H, brs), 8.13 (1H, d, J=8.4Hz); ESIMS 242 (MH
+)
Embodiment 216-fluoro-3-(n-octyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 19)
Step 16-fluoro-3-(n-octyl oxygen base)-preparation of 2-pyrazine formonitrile HCN
Method just so that n-Octanol is replaced ethanol, obtains 6-fluoro-3-(n-octyl oxygen base with embodiment 15 steps 1)-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 0.88 (3H, m), 1.24-1.50 (10H, m), 1.84 (2H, m), 4.44 (2H, t, J=6.8Hz), 8.19 (1H, d, J=8.0Hz);
Step 26-fluoro-3-(n-octyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 19)
Method is with embodiment 15 steps 2, just with 6-fluoro-3-(n-octyl oxygen base)-2-pyrazine formonitrile HCN replacement 6-fluoro-3-oxyethyl group-2-pyrazine formonitrile HCN, obtain 6-fluoro-3-(n-octyl oxygen base)-2-pyrazine formyl ammonia,
1HNMR(CDCl
3) δ 0.90 (3H, m), 1.20-1.50 (10H, m), 1.86 (2H, m), 4.48 (2H, t, J=6.8Hz), 6.11 (1H, brs), 7.52 (1H, brs), 8.15 (1H, d, J=8.4Hz); ESIMS270 (MH
+).
Embodiment 226-fluoro-3-(3-methoxy-benzyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 20)
Step 16-fluoro-3-(3-methoxy-benzyl oxygen base)-preparation of 2-pyrazine formonitrile HCN
Method just so that 3-methoxyl group benzylalcohol is replaced ethanol, obtains 6-fluoro-3-(3-methoxy-benzyl oxygen base with embodiment 15 steps 1)-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 3.83 (3H, s), 6.88-6.91(1H, m), 7.00-7.05 (1H, m) 7.26-7.32 (1H, m), 8.19 (1H, d, J=8.4Hz);
Step 26-fluoro-3-(3-methoxy-benzyl oxygen base)-preparation of 2-pyrazine formyl ammonia (compound 20)
Method is with embodiment 15 steps 2, just with 6-fluoro-3-(3-methoxy-benzyl oxygen base)-2-pyrazine formonitrile HCN replacement 6-fluoro-3-oxyethyl group-2-pyrazine formonitrile HCN, obtain 6-fluoro-3-(3-methoxy-benzyl oxygen base)-2-pyrazine formyl ammonia,
1HNMR(CDCl
3) δ 3.82 (3H, s), 5.53 (2H, s), 6.15(1H, brs), 6.86-6.90 (1H, m), 7.40-7.80 (1H, m), 7.26-7.32 (1H, m), 7.46 (1H, brs), 8.14 (1H, d, J=8.8Hz); ESIMS278 (MH
+).
Embodiment 236-fluoro-3-[(3-ethoxycarbonyl propyl) oxygen base]-preparation of 2-pyrazine formyl ammonia (compound 21)
Step 16-fluoro-3-[(3-ethoxycarbonyl propyl) oxygen base]-preparation of 2-pyrazine formonitrile HCN
Method just so that 3-oxyethyl group propyl alcohol is replaced ethanol, obtains 6-fluoro-3-[(3-ethoxycarbonyl propyl with embodiment 15 steps 1) the oxygen base]-2-pyrazine formonitrile HCN,
1HNMR (CDCl
3) δ 1.19 (3H, t, J=7.2Hz), 2.13 (2H, m), 3.51 (2H.q.J=6.8Hz), 3.61 (2H, t, J=6.0Hz), 4.56(2H, t, J=6.0Hz), 8.19 (1H, d, J=8.4Hz)
Step 26-fluoro-3-[(3-ethoxycarbonyl propyl) oxygen base]-preparation of 2-pyrazine formyl ammonia (compound 21)
Method is with embodiment 15 steps 2, just with 6-fluoro-3-[(3-ethoxycarbonyl propyl) the oxygen base]-2-pyrazine formonitrile HCN replacement 6-fluoro-3-oxyethyl group-2-pyrazine formonitrile HCN, obtain 6-fluoro-3-[(3-ethoxycarbonyl propyl) the oxygen base]-2-pyrazine formyl ammonia,
1HNMR(CDCl
3) δ 1.87 (3H, t, J=7.2Hz), 2.13 (2H, quintet, J=6.0Hz), 3.51 (2H.q.J=7.2Hz), (3.62 2H, t, J=6.0Hz), 4.59(2H, t, J=6.0Hz), (5.91 1H, brs), 7.80 (1H, brs) 8.13 (1H, d, J=8.4Hz); ESIMS 230 (MH
+).
Experimental example 1
24 KM mouse (male, 27 ± 2g), be divided at random 8 groups by body weight, 3 every group.By the dosage (being equivalent to 10mg/10ml/kg for T705 or T1105) of 0.0637mmol/10ml/kg respectively oral administration gavage give test-compound.In the administration different time points eye socket 20 μ L that take a blood sample, add mark acetonitrile solution in the 20 μ L positively charged ions, mark acetonitrile solution in the 20 μ L negatively charged ion, 40 μ L acetonitriles, vibration, the centrifugal 10min of 18000g, get supernatant LC/MS/MS sample introduction, measure respectively the concentration of corresponding test-compound and T705 or T1105.
Table 1 is time dependent data of the Plasma Concentration of T705 in the body after the mouse stomach administration such as compound T705 and compound 14,15,16,17,18,19,20,21 grades.Fig. 1 is compound 14,15,16,17 after the mouse stomach administration drug-time curve of T705 in the body.Show that compound 16 can obviously prolong the transformation period of T705.
Table 2 is compounds 1,2,3,4,5,6,7,8,9,10,11 after the mouse stomach administration time dependent data of the Plasma Concentration of T1105 in the body.Fig. 2 is compound 1-5 drug-time curve of T1105 in the body after the mouse stomach administration.The result shows and all can obviously improve the oral administration biaavailability of T1105 by compound 1-11 (T1105 is oral gastric infusion under 0.0637mmol/10ml/kg dosage, does not detect T1105 in blood plasma, illustrates simultaneously that also the T1105 oral absorption is very poor.
Time dependent data of the Plasma Concentration of T705 in the body after the mouse stomach administration such as table 1 compound T705 and compound 14,15,16,17,18,19,20,21 grades
Table 2 compound 1,2,3,4,5,6,7,8,9,10,11 after the mouse stomach administration time dependent data of the Plasma Concentration of T1105 in the body
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (10)
1. compound, its pharmaceutically useful salt or solvate of having the general formula I structure,
Wherein
R
1Represent hydrogen, halogen etc.;
R
2Be selected from: alkyl; The alkyl that alkoxyl group replaces; Cycloalkyl; The alkyl that aromatic base replaces or the alkyl that replaces with the aryl of substituted radical, described substituting group are selected from alkoxyl group, alkyl, cycloalkyl, halogen, nitro, itrile group, hydroxyl or amino etc., preferred alkoxyl group; The phenyl of phenyl or replacement, described substituting group are selected from alkoxyl group, alkyl, cycloalkyl, halogen, nitro, itrile group, hydroxyl or amino etc., preferred alkoxyl group.
2. according to claim 1 compound, its pharmaceutically useful salt or solvate, it is selected from:
(1) 3-n-propyl oxygen base-3-oxo-2-pyrazine formyl ammonia;
(2) 3-sec.-propyl oxygen base-2-pyrazine formyl ammonia;
(3) 3-isobutyl-oxygen base-2-pyrazine formyl ammonia;
(4) 3-n-pentyl oxygen base-2-pyrazine formyl ammonia;
(5) 3-isopentyl oxygen base-2-pyrazine formyl ammonia;
(6) 3-n-hexyl oxygen base-2-pyrazine formyl ammonia;
(7) 3-cyclohexyl oxygen base-2-pyrazine formyl ammonia;
(8) 3-n-octyl oxygen base-2-pyrazine formyl ammonia;
(9) 3-[2-(oxyethyl group)-oxyethyl group]-2-pyrazine formyl ammonia;
(10) 3-[2-(methoxyl group)-oxyethyl group]-2-pyrazine formyl ammonia;
(11) 3-(benzyl oxygen base)-2-pyrazine formyl ammonia;
(12) 3-(to methoxy-benzyl oxygen base)-2-pyrazine formyl ammonia;
(13) 3-(p-methoxyphenyl oxygen base)-2-pyrazine formyl ammonia;
(14) 6-fluoro-3-ethyl oxygen base-2-pyrazine formyl ammonia;
(15) 6-fluoro-3-normal-butyl oxygen base-2-pyrazine formyl ammonia;
(16) 6-fluoro-3-benzyl oxygen base-2-pyrazine formyl ammonia;
(17) 6-fluoro-3-[(is to methoxy-benzyl)-the oxygen base]-2-pyrazine formyl ammonia;
(18) 6-fluoro-3-n-hexyl oxygen base-2-pyrazine formyl ammonia;
(19) 6-fluoro-3-n-octyl oxygen base-2-pyrazine formyl ammonia;
(20) 6-fluoro-3-[(3-methoxyl group)-benzyl]-2-pyrazine formyl ammonia;
(21) 6-fluoro-3-[2-(oxyethyl group)-propoxy-]-2-pyrazine formyl ammonia.
3. pharmaceutical composition, it comprises claim 1 or 2 described compounds, its pharmaceutically useful salt or solvate, and pharmaceutically acceptable carrier.
4. according to claim 3 pharmaceutical composition, it can be made into following preparation: solid preparation, injection, external preparation, spray, liquid preparation or compound preparation.
Claim 1 or 2 compound, its pharmaceutically useful salt or solvate in the preparation antiviral purposes or prevent and/or treat purposes in the medicine of virus infection associated diseases in preparation.
6. the purposes of claim 5, wherein said virus is RNA viruses, preferably, described virus comprises: influenza virus (Influenza Virus), HCV virus (Hepatitis C Virus), bunyavirus (Bunyavirus), sand fly virus (Phlebovirus), foot and mouth disease virus (Foot and Mouth Disease Virus), west nile virus (West Nile virus), arenavirus (Arenavirus), western equine encephalitis virus (Western Equine Encephalitis Virus), or yellow fever virus (Yellow Fever Virus).
7. claim 1 or 2 compound, its pharmaceutically useful salt or solvate prevent and/or treat purposes in the medicine of Mammals foot and mouth disease in preparation.
8. method that prevents and/or treats the virus infection associated diseases, described method comprise to the individuality that needs are arranged with the claim 1 that prevents and/or treats significant quantity or compound, its pharmaceutically useful salt or solvate of 2.
9. the method for claim 8, wherein said virus is RNA viruses, preferably, described virus comprises: influenza virus (Influenza Virus), HCV virus (Hepatitis C Virus), bunyavirus (Bunyavirus), sand fly virus (Phlebovirus), foot and mouth disease virus (Foot and Mouth Disease Virus), west nile virus (West Nile virus), arenavirus (Arenavirus), western equine encephalitis virus (Western Equine Encephalitis Virus), or yellow fever virus (Yellow Fever Virus).
10. the preparation method of claim 1 or 2 compound, it comprises:
(i) 6-R
1-3-halo-2-pyrazine formyl ammonia, at anhydrous non-proton and organic solvent, such as toluene, DMF, acetonitrile, DME, THF, in the benzene etc., at organic bases, such as triethylamine, DBU, diisopropylethylamine etc., or mineral alkali are such as salt of wormwood, under the existence of cesium carbonate etc., with R
2The OH reaction obtains 6-R
1-3-O-R
2-2-pyrazine formyl ammonia;
R wherein
1And R
2Definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine, iodine; Perhaps
(ii) 6-R
1-3-halo-2-pyrazine formonitrile HCN is at anhydrous non-proton and organic solvent, such as toluene, and DMF, acetonitrile, DME, THF, in the benzene etc., at organic bases, such as triethylamine, DBU, diisopropylethylamine etc., or mineral alkali are such as Na, under the existence of NaH etc., with R
2The OH reaction obtains 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN; 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN is under alkaline condition, and is lower such as NaOH or salt of wormwood existence, uses hydrogen peroxide oxidation, obtains 6-R
1-3-O-R
2-2-pyrazine formyl ammonia;
R wherein
1And R
2Definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine, iodine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210218505.6A CN102850282B (en) | 2011-07-01 | 2012-06-28 | 3-substituted oxy-2-Zinamide compounds and uses thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101828167 | 2011-07-01 | ||
| CN201110182816 | 2011-07-01 | ||
| CN201110182816.7 | 2011-07-01 | ||
| CN201210218505.6A CN102850282B (en) | 2011-07-01 | 2012-06-28 | 3-substituted oxy-2-Zinamide compounds and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102850282A true CN102850282A (en) | 2013-01-02 |
| CN102850282B CN102850282B (en) | 2015-09-16 |
Family
ID=47397316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210218505.6A Active CN102850282B (en) | 2011-07-01 | 2012-06-28 | 3-substituted oxy-2-Zinamide compounds and uses thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102850282B (en) |
| WO (1) | WO2013004141A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111349049A (en) * | 2020-02-28 | 2020-06-30 | 江苏阿尔法药业有限公司 | Favipiravir and synthesis process of intermediate thereof |
| CN113563273A (en) * | 2020-04-28 | 2021-10-29 | 中国人民解放军军事科学院军事医学研究院 | Antiviral pyrazinamide derivative and preparation method thereof |
| CN116687932A (en) * | 2022-02-25 | 2023-09-05 | 中国人民解放军军事科学院军事医学研究院 | Medical application of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate |
| WO2023169119A1 (en) * | 2022-03-10 | 2023-09-14 | 中国人民解放军军事科学院军事医学研究院 | Solid form of compound, preparation method therefor, and use thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1313768A (en) * | 1998-08-20 | 2001-09-19 | 富山化学工业株式会社 | Nitrogenous heterocyclic carboxamide derivatives or salts thereof and antivirual agents containing both |
| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| CN101454295A (en) * | 2006-05-31 | 2009-06-10 | 富山化学工业株式会社 | Anti-foot-and-mouth disease virus agent for animal belonging to family suidae or sheep, and method for prevention or treatment of foot-and-mouth disease in animal belonging to family suidae or sheep |
| US20090233934A1 (en) * | 2005-12-22 | 2009-09-17 | Masatsugu Oda | Pyrazinecarboxamide Derivatives and Plant Disease Controlling Agents Containing the Same |
-
2012
- 2012-06-28 CN CN201210218505.6A patent/CN102850282B/en active Active
- 2012-06-28 WO PCT/CN2012/077679 patent/WO2013004141A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1313768A (en) * | 1998-08-20 | 2001-09-19 | 富山化学工业株式会社 | Nitrogenous heterocyclic carboxamide derivatives or salts thereof and antivirual agents containing both |
| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| US20090233934A1 (en) * | 2005-12-22 | 2009-09-17 | Masatsugu Oda | Pyrazinecarboxamide Derivatives and Plant Disease Controlling Agents Containing the Same |
| CN101454295A (en) * | 2006-05-31 | 2009-06-10 | 富山化学工业株式会社 | Anti-foot-and-mouth disease virus agent for animal belonging to family suidae or sheep, and method for prevention or treatment of foot-and-mouth disease in animal belonging to family suidae or sheep |
Non-Patent Citations (19)
| Title |
|---|
| CHEMICAL ABSTRACTS SERVICE: "RN1272909-35-9", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1273735-80-0", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1275278-43-7", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1282819-10-6", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1282961-13-0", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1283306-26-2", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1283664-67-4", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN1284386-22-6", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN23902-78-5", 《STN CAPLUS数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN23902-78-5", 《STN REGISTRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN874832-16-3", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN87542-55-0", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN87542-56-1", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN87542-57-2", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN87542-58-3", 《STN REGISRY数据库》 * |
| CHEMICAL ABSTRACTS SERVICE: "RN87542-59-4", 《STN REGISRY数据库》 * |
| NOVACEK L，等: ""Antituberculotics. X. Functional derivatives of 3-substituted 2-pyrazinecarboxylic acids"", 《CESKO-SLOVENSKA FARMACIE》 * |
| PANCECHOWSKA-KSEPKO，D.，等: ""Pyrazine Derivatives XIX Synthesis and Tuberculostatic Activity of Some Derivatives of 3-phenoxy-2-pyrazinecarboxylic Acids"", 《ACTA POLONIAE PHARMACEUTICA》 * |
| WOLFGANG HOLZER，等: ""Derivatives of pyrazinecarboxylic acid: 1H, 13C and 15N NMR spectroscopic investigations"", 《MAGNETIC RESONANCE IN CHEMISTRY》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111349049A (en) * | 2020-02-28 | 2020-06-30 | 江苏阿尔法药业有限公司 | Favipiravir and synthesis process of intermediate thereof |
| CN111349049B (en) * | 2020-02-28 | 2022-11-11 | 江苏阿尔法药业股份有限公司 | Favipiravir and synthesis process of intermediate thereof |
| CN113563273A (en) * | 2020-04-28 | 2021-10-29 | 中国人民解放军军事科学院军事医学研究院 | Antiviral pyrazinamide derivative and preparation method thereof |
| CN113563273B (en) * | 2020-04-28 | 2023-12-26 | 中国人民解放军军事科学院军事医学研究院 | Antiviral pyrazinamide derivative and preparation method thereof |
| CN116687932A (en) * | 2022-02-25 | 2023-09-05 | 中国人民解放军军事科学院军事医学研究院 | Medical application of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate |
| CN116687932B (en) * | 2022-02-25 | 2024-03-29 | 中国人民解放军军事科学院军事医学研究院 | Medical application of ((3-carbamoyl-5-fluoropyrazin-2-yl) oxy) methyl isobutyrate |
| WO2023169119A1 (en) * | 2022-03-10 | 2023-09-14 | 中国人民解放军军事科学院军事医学研究院 | Solid form of compound, preparation method therefor, and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2013004141A1 (en) | 2013-01-10 |
| CN102850282B (en) | 2015-09-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2021202967B2 (en) | Phosphoramidates for the treatment of Hepatitis B virus | |
| CN101759683B (en) | Preparation method of hydrindene amide compound, medical composition comprising hydrindene amide compound and application thereof as protein kinase inhibitor | |
| CN108290869B (en) | Heterocyclic indoles for use in influenza virus infection | |
| TWI481604B (en) | Novel 5-fluorouracil derivatives | |
| CN103313974A (en) | Benzimidazole respiratory syncytial virus inhibitors | |
| AU2017281531A1 (en) | Phosphoramidates for the treatment of hepatitis B virus | |
| CN102850282B (en) | 3-substituted oxy-2-Zinamide compounds and uses thereof | |
| JP7035118B2 (en) | Lactam compound derivatives and their applications | |
| EP3048108A1 (en) | Thienopiperidine derivative and use thereof | |
| CN101384593A (en) | 3-deazapurine derivatives as tlr7 modulators | |
| CN107163044A (en) | Naphthylethylenedione compound with protease modification activity and derivative thereof | |
| CN105085373A (en) | Purification method of apremilast product | |
| CN105777808B (en) | Tizoxanide phosphate and alkyl sulfonic ester and its application in pharmacy | |
| CN101531653A (en) | Salts of 3-(4-amino-1-oxo-1,3-dihydro-iso-indol-2-yl)piperdine-2,6-dione and derivatives thereof, polymorph of the salts, preparation and application thereof | |
| CN103420980A (en) | Dabigatran derivatives | |
| CN108794517B (en) | Arginase inhibitor and preparation method and application thereof | |
| CN107311933B (en) | Benzimidazole derivative, preparation method and application thereof | |
| CN105367558A (en) | Andrographolide derivative and preparation method and application thereof | |
| JP5932827B2 (en) | Thiazoleamine derivatives and their use as anti-picornavirus infectious agents | |
| CN106588909A (en) | Preparation of quinoline-based derivative, and applications of quinoline-based derivative in anti-inflammation | |
| CN103435562A (en) | 6-substituted benzodiazepine-2,4-diketone compound and application thereof | |
| CN115518058A (en) | Application of N-cycloalkyl substituted aromatic methylamine compound in preparation of antiviral drug, structure and preparation method | |
| WO2020151296A1 (en) | Dinucleotide precursor for drug and preparation method therefor | |
| HUE027605T2 (en) | Substituted furancarboxamides, and use thereof | |
| CN103288906A (en) | A 3,5 - bis-O-benzoyl-2-C-methyl-C-methyl C-4 - (1,2,4 - triazolyl) uridine and a synthesis method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |