CN102850282B - 3-substituted oxy-2-Zinamide compounds and uses thereof - Google Patents
3-substituted oxy-2-Zinamide compounds and uses thereof Download PDFInfo
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Abstract
The present invention relates to a kind of 3-alkoxyl group with general formula I and replace-2-Zinamide compounds and the application in preparation antiviral thereof; Compound involved in the present invention is that T1105 or T705 plays antivirus action by esterase or P450 enzymes metabolism in vivo.Compared with proto-drug T1105 or T705, it is high that compound of Formula I involved in the present invention has bioavailability, the obviously advantage such as long action time in body.
Description
Technical field
The present invention relates to Zinamide compounds, its preparation method and the purposes for the preparation of antiviral thereof.
Background technology
3-oxo-3,4-dihydro-2-Zinamide (T1105) and 6-fluorine 3-oxo-3,4-dihydro-2-Zinamide (T705) (See Figure) is the RNA polymerase inhibitor of a viroid, has good antivirus action.
It is reported, T705 be used alone or and neuraminidase inhibitor, such as Ro 64-0796/002, conbined usage, has well resisiting influenza virus effect (Antimicrobial Agents andChemotherapy, 2007, Vol.51, No.3,845-851; AntimicrobialAgents and Chemotherapy, 2010, p.126 – 133, PCT patent: WO2000010569).T1105 shows the extraordinary effect to foot-and-mouth disease virus resistant (PCT patent: WO20071139081) in vivo with in external model.In addition T705 also has good curative effect to other RNA viruses associated diseases.Such as, the west type equine encephalitis of T705 to mouse model has therapeutic action (Antiviral Research 82 (2009) 169 – 171); The yellow jack of T705 to hamster has therapeutic action (Antimicrobial Agents and Chemotherapy, 2009, p.202 – 209); T705 infects to arenavirus and bunyavirus the disease caused have therapeutic action (Antimicrobial Agents and Chemotherapy, 2007, p.3168 – 3176) 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-Zinamide (T1105) and 6-fluorine 3-oxo-3,4-dihydro-2-Zinamide (T705) has similar structure and mechanism of action, the form of corresponding ribonucleoside triphosphote can be converted in vivo, suppress viral rna polymerase competitively by simulation guanosine triphosphate (GTP) and play antivirus action (ANTIMICROBIALAGENTS AND CHEMOTHERAPY, 2005, Vol.49, No.3, p.981 – 986).
Although T1105 and T705 has good antivirus action in model in vitro, all there are some bad pharmacokinetic properties in these two compounds, is unfavorable for the performance of their drug effects.The oral absorption of such as T1105 is very poor, and eliminate also very fast in body, it shows the activity of good foot-and-mouth disease virus resistant in vitro, IC50 is 1.6ug/mL, but pig oral administration, twice daily, the dosage that reach 200mg/Kg just can reach the effect of desirable resistant to foot and mouth disease.The oral absorption of T705 is fine, but eliminates very fast, and there is transformation period short problem, cause its dosage comparatively large, every day, oral dosage was 800mg-2400mg.
Summary of the invention
In order to the pharmacokinetic property that to overcome that the bioavailability that 3-oxo-pyrazine-2-Carbox amide T1105 and T705 exists is not high, the transformation period is short etc. bad, the invention provides the 6-R with general formula I
1-3-O-R
2-2-Zinamide compounds, this compounds can be converted into the form of T1105 or T705 in vivo and play antiviral effect, can significantly improve the oral administration biaavailability of compound simultaneously, and extends compound action time in vivo.
A first aspect of the present invention relate to there is general formula I compound, its pharmaceutically useful salt or solvate,
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 replaced with the aryl of substituted radical, described substituting group is 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 is 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, such as, be 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.;
Such as, but described cycloalkyl refers to having 3 to 12 carbon atoms and having the cyclic alkyl of one or more ring of saturated or undersaturated non-aromatic, is C
3-6cycloalkyl, described cycloalkyl comprises such as adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, ring octyl group, cyclohexenyl etc., preferred cyclopentyl and cyclohexyl;
Described alkoxyl group refers to " alkyl-O-", and the definition of described alkyl is described above, comprising such as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, tert.-butoxy, sec-butoxy, n-pentyloxy etc., and preferred methoxyl group and oxyethyl group;
Described aromatic base refers to have 6 to 12 carbon atoms and the monovalent aromatic carbocyclic group with single ring (such as phenyl) or multiple condensed ring (such as naphthyl or anthryl), wherein condensed ring can be aromatic or can not be aromatic (such as 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H)-one-7-base etc.), prerequisite is tie point is aryl, preferred phenyl;
Wherein said replacement can be monosubstituted or polysubstituted, described polysubstituted be such as two replacements.
According to compound, its pharmaceutically useful salt or solvate of first aspect, it is selected from:
(1) 3-n-propyl oxygen base-3-2-Zinamide;
(2) 3-sec.-propyl oxygen base-2-Zinamide;
(3) 3-isobutyl-oxygen base-2-Zinamide;
(4) 3-n-pentyl oxygen base-2-Zinamide;
(5) 3-isopentyl oxygen base-2-Zinamide;
(6) 3-n-hexyl oxygen base-2-Zinamide;
(7) 3-cyclohexyl oxygen base-2-Zinamide;
(8) 3-n-octyl oxygen base-2-Zinamide;
(9) 3-[2-(oxyethyl group)-oxyethyl group]-2-Zinamide;
(10) 3-[2-(methoxyl group)-oxyethyl group]-2-Zinamide;
(11) 3-(benzyl oxygen base)-2-Zinamide;
(12) 3-(to methoxy-benzyl oxygen base)-2-Zinamide;
(13) 3-(p-methoxyphenyl oxygen base)-2-Zinamide;
(14) 6-fluoro-3-ethyl oxygen base-2-Zinamide;
(15) 6-fluoro-3-butyl oxygen base-2-Zinamide;
(16) 6-fluoro-3-benzyl oxygen base-2-Zinamide;
(17) the fluoro-3-of 6-[(to methoxy-benzyl)-oxygen base]-2-Zinamide;
(18) 6-fluoro-3-n-hexyl oxygen base-2-Zinamide;
(19) 6-fluoro-3-n-octyl oxygen base-2-Zinamide;
(20) the fluoro-3-of 6-[(3-methoxyl group)-benzyl oxygen base]-2-Zinamide; With
(21) the fluoro-3-of 6-[(3-ethoxycarbonyl propyl)-oxygen base]-2-Zinamide.
A second aspect of the present invention relates to pharmaceutical composition, and it comprises compound described in any one of first aspect present invention, its pharmaceutically useful salt or solvate, and pharmaceutically acceptable carrier.
Pharmaceutical composition according to a second aspect of the 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 relates to purposes in preparation antiviral of compound, its pharmaceutically useful salt or solvate described in any one of first aspect present invention or the pharmaceutical composition described in any one of second aspect present invention or is preparing the purposes prevented and/or treated in the medicine of virus infection associated diseases.Wherein said medicine can be used for Mammals, such as, be people or artiodactyl, and described artiodactyl can be pig, ox or sheep etc.
Purposes according to a third aspect of the 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 (YellowFever Virus).
Wherein virus infection associated diseases is such as influenza, hepatitis C, singapore hemorrhagic fever, hemorrhagic fever (such as 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 compound, its pharmaceutically useful salt or the solvate related to described in any one of a first aspect of the present invention prevents and/or treats the purposes of the medicine of Mammals foot and mouth disease in preparation.
Described Mammals is such as 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 the compound described in any one of a first aspect of the present invention, and it comprises:
(i) 6-R
1-3-halo-2-Zinamide, at anhydrous aprotic and organic solvent, as toluene, DMF, acetonitrile, DME, THF, in benzene etc., at organic bases, as triethylamine, DBU, diisopropylethylamine etc., or mineral alkali, as salt of wormwood, under the existence of cesium carbonate etc., with R
2oH reacts, and obtains 6-R
1-3-O-R
2-2-Zinamide; Or
Wherein R
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 aprotic and organic solvent, and as toluene, DMF, acetonitrile, DME, THF, in benzene etc., at organic bases, as triethylamine, DBU, diisopropylethylamine etc., or mineral alkali, as under the existence of Na, NaH etc., with R
2oH reacts, and obtains 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN; 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN in the basic conditions, as under NaOH or salt of wormwood existence, with hydrogen peroxide oxidation, obtains 6-R
1-3-O-R
2-2-Zinamide;
Wherein R
1and R
2definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine or iodine.
The invention still further relates to the method preventing and/or treating virus infection associated diseases, described method comprises to individuality in need with compound, its pharmaceutically useful salt or the solvate described in any one of first aspect present invention preventing and/or treating significant quantity or pharmaceutical composition of the 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 EquineEncephalitis Virus), or yellow fever virus (Yellow Fever Virus).
Wherein virus infection associated diseases is such as influenza, hepatitis C, singapore hemorrhagic fever, hemorrhagic fever (such as 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 individuality in need can be such as Mammals, and as people or artiodactyl, described artiodactyl can be pig, ox or sheep etc.
Compound of the present invention or pharmaceutical composition can be used alone, or mix with tap water or mix with animal-feed, for artiodactyl, as the prevention and therapy 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 plays antivirus action by esterase or P450 enzymes metabolism in vivo, compared with proto-drug T1105 or T705, it is high that compound of Formula I of the present invention has bioavailability, the obviously advantage such as long action time in body.
Accompanying drawing explanation
Fig. 1 is compound 14,15,16,17 after mouse stomach administration the drug-time curve of T705 in body.
Fig. 2 is compound 1,2,3,4,5 after mouse stomach administration the drug-time curve (T1105 is oral under 0.0637mmol/10ml/kg dosage, does not detect T1105 in blood plasma) of T1105 in 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 for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturers suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
embodiment 1the preparation (method 1) of 3-(n-propyl oxygen base)-2-Zinamide (compound 1).
In drying, in there-necked flask with thermometer, prolong and drying tube, add anhydrous propyl alcohol 30mL, add sodium 146mg (6.34mmol), stirring at room temperature or be slightly heated to the completely dissolve of sodium grain, add the good 3-of purifying chloro-2-Zinamide 500mg (3.17mmol), be warming up to 80 DEG C, reaction 20min, after being cooled to room temperature, add glacial acetic acid 1mL, be evaporated to dry, after silica gel mixed sample, Flash chromatography column is separated (methylene chloride/methanol wash-out) and obtains target compound
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 2the preparation (method 2) of 3-(n-propyl oxygen base)-2-Zinamide (compound 1).
step 1the preparation of 3-(n-propyl oxygen base)-2-pyrazine formonitrile HCN
In drying, in 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) with anhydrous triethylamine (1.5ml, about 11.85mmol), be warming up to 80-120 – C and react 2 hours, after being cooled to room temperature, dilute with water, extraction into ethyl acetate, washing, sodium chloride solution is washed, be evaporated to dry, obtain crude product without separation, after drying, be directly used in next step reaction.
step 2the preparation of 3-(n-propyl oxygen base)-2-Zinamide (compound 1)
With in the there-necked flask of thermometer, add the dissolve with ethanol of 3-(n-propyl oxygen base)-2-pyrazine formonitrile HCN (980mg, about 6mmol) 60mL95%, ice-water bath is down to 5 – C, adds the H of 30%
2o
2with the NaOH aqueous solution of 6N, stirring reaction 2 hours under ice-water bath, with 1NHC adjust pH to neutral, under the condition of warm 45-50 – C outside, be evaporated to dry, Flash column chromatography (methylene chloride/methanol wash-out) after silica gel mixed sample, 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 3the preparation of 3-(sec.-propyl oxygen base)-2-Zinamide (compound 2)
Method, with embodiment 1, just replaces n-propyl alcohol with Virahol, 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 4the preparation of 3-(isobutyl-oxygen base)-2-Zinamide (compound 3)
Method, with embodiment 1, just replaces n-propyl alcohol with isopropylcarbinol, 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-Zinamide (compound 4)
Method, with embodiment 1, just replaces n-propyl alcohol with Pentyl alcohol, 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-Zinamide (compound 5)
Method, with embodiment 1, just replaces n-propyl alcohol with primary isoamyl alcohol, 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-Zinamide (compound 6)
Method, with embodiment 1, just replaces n-propyl alcohol with n-hexyl alcohol, 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-Zinamide (compound 7)
Method, with embodiment 1, just replaces n-propyl alcohol with hexalin, 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-Zinamide (compound 8)
Method, with embodiment 1, just replaces n-propyl alcohol with n-Octanol, 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 preparation of 3-[2-(oxyethyl group)-oxyethyl group]-2-Zinamide (compound 9)
Method, with embodiment 1, just replaces n-propyl alcohol with ethoxy ethanol, 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 preparation of 3-[2-(methoxyl group)-oxyethyl group]-2-Zinamide (compound 10)
Method, with embodiment 1, just replaces n-propyl alcohol with methyl cellosolve, 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 12the preparation of 3-(benzyl oxygen base)-2-Zinamide (compound 11)
Method, with embodiment 1, just replaces n-propyl alcohol with phenylcarbinol, 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-Zinamide (compound 12)
Method, with embodiment 1, just to replace n-propyl alcohol to methoxybenzyl, obtains title compound,
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 of 3-(p-methoxyphenyl oxygen base)-2-Zinamide (compound 13)
Method, with embodiment 1, just to replace n-propyl alcohol to mequinol, obtains title compound,
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, brs), 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-Zinamide (compound 14)
step 1the preparation of 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN
In drying, in there-necked flask with thermometer, prolong and drying tube, add dry toluene 10mL, add 3,6-bis-fluoro-pyrazine-2-formonitrile HCN (1000mg, 7.09mmol), stirring and dissolving, adds dehydrated alcohol (653mg, 14.18mmol) with anhydrous triethylamine (1.5ml, about 11.85mmol), be warming up to 80 – C and react 2 hours, after being cooled to room temperature, be evaporated to dry, after silica gel mixed sample, Flash chromatography column is separated (ethyl acetate/petroleum ether wash-out) and obtains target compound 1020mg, 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-Zinamide (compound 14)
With in the there-necked flask of thermometer, add 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN (1020mg, 6mmol) with the dissolve with ethanol of 60mL95%, ice-water bath is down to 5 – C, add the NaOH aqueous solution of H2O2 and 6N of 30%, stirring reaction 2 hours under ice-water bath, with 1NHC adjust pH to neutral, under the condition of warm 45-50 – C outside, be evaporated to dry, Flash column chromatography (methylene chloride/methanol wash-out) after silica gel mixed sample, 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-Zinamide (compound 14)
In drying, in there-necked flask with thermometer, prolong and drying tube, add dry toluene 5mL, add 3,6-bis-fluoro-pyrazine-2-methane amide (159mg, 1.13mmol), stirring and dissolving, adds dehydrated alcohol (92mg, 2mmol) with anhydrous triethylamine (202mg, 2mmol), be warming up to 80 – C and react 2 hours, after being cooled to room temperature, be evaporated to dry, after silica gel mixed sample, Flash chromatography column is separated (ethyl acetate/petroleum ether wash-out) and obtains target compound 105mg, is white solid
1hNMR and EIMS is with the product of embodiment 15.
embodiment 17the preparation of 6-fluoro-3-butyl oxygen base-2-Zinamide (compound 15).
step 1the preparation of 6-fluoro-3-butyl oxygen base-2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just replaces ethanol with butanols, 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-Zinamide
Method, with embodiment 15 step 2, just replaces 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN with 6-fluoro-3-butyl oxygen base-2-pyrazine formonitrile HCN, obtains 6-fluoro-3-butyl oxygen base-2-Zinamide.
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 the fluoro-3-benzyloxy of 6--2-Zinamide (compound 16).
step 1the preparation of the fluoro-3-benzyloxy of 6--2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just replaces ethanol with benzylalcohol, obtains the fluoro-3-benzyloxy of 6--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 the fluoro-3-benzyloxy of 6--2-Zinamide
Method, with embodiment 15 step 2, just replaces 6-fluoro-3-ethyl oxygen base-2-pyrazine formonitrile HCN with 6-fluoro-3-benzyloxy-2-pyrazine formonitrile HCN, obtains the fluoro-3-benzyloxy of 6--2-Zinamide.
1HNMR(CDCl
3)δ5.56(2H,s),7.35-7.50(5H,m),6.00(1H,brs),7.55(1H,brs),8.15(1H,d,J＝8.8Hz)；EIMS(m/e,100)247(M
+,15),230(22),91(100)。
embodiment 19the preparation of the fluoro-3-of 6-(to methoxy benzyloxy)-2-Zinamide (compound 17)
step 1the preparation of the fluoro-3-of 6-(to methoxy benzyloxy)-2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just replaces ethanol with p-methoxybenzyl alcohol, obtains the fluoro-3-of 6-(to 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 the fluoro-3-of 6-(to methoxy benzyloxy)-2-Zinamide
Method, with embodiment 15 step 2, just replaces the fluoro-3-oxyethyl group of 6--2-pyrazine formonitrile HCN with the fluoro-3-of 6-(to methoxy benzyloxy)-2-pyrazine formonitrile HCN, obtains the fluoro-3-of 6-(to methoxy benzyloxy)-2-Zinamide,
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 20the preparation of the fluoro-3-of 6-(n-hexyl oxygen base)-2-Zinamide (compound 18)
step 1the preparation of the fluoro-3-of 6-(n-hexyl oxygen base)-2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just to replace ethanol to n-hexyl alcohol, obtains the fluoro-3-of 6-(n-hexyl oxygen base)-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 2the preparation of the fluoro-3-of 6-(n-hexyl oxygen base)-2-Zinamide (compound 18)
Method, with embodiment 15 step 2, just replaces the fluoro-3-oxyethyl group of 6--2-pyrazine formonitrile HCN with the fluoro-3-of 6-(n-hexyl oxygen base)-2-pyrazine formonitrile HCN, obtains the fluoro-3-of 6-(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 21the preparation of the fluoro-3-of 6-(n-octyl oxygen base)-2-Zinamide (compound 19)
step 1the preparation of the fluoro-3-of 6-(n-octyl oxygen base)-2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just to replace ethanol to n-Octanol, obtains the fluoro-3-of 6-(n-octyl oxygen base)-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 2the preparation of the fluoro-3-of 6-(n-octyl oxygen base)-2-Zinamide (compound 19)
Method, with embodiment 15 step 2, just replaces the fluoro-3-oxyethyl group of 6--2-pyrazine formonitrile HCN with the fluoro-3-of 6-(n-octyl oxygen base)-2-pyrazine formonitrile HCN, obtains the fluoro-3-of 6-(n-octyl oxygen base)-2-Zinamide,
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 22the preparation of the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-2-Zinamide (compound 20)
step 1the preparation of the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just to replace ethanol to 3-methoxyl group benzylalcohol, obtains the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-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 2the preparation of the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-2-Zinamide (compound 20)
Method is with embodiment 15 step 2, just replace the fluoro-3-oxyethyl group of 6--2-pyrazine formonitrile HCN with the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-2-pyrazine formonitrile HCN, obtain the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-2-Zinamide
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 23the preparation of the fluoro-3-of 6-[(3-ethoxycarbonyl propyl) oxygen base]-2-Zinamide (compound 21)
step 1the preparation of the fluoro-3-of 6-[(3-ethoxycarbonyl propyl) oxygen base]-2-pyrazine formonitrile HCN
Method, with embodiment 15 step 1, just to replace ethanol to 3-oxyethyl group propyl alcohol, obtains the fluoro-3-of 6-[(3-ethoxycarbonyl propyl) 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 2the preparation of the fluoro-3-of 6-[(3-ethoxycarbonyl propyl) oxygen base]-2-Zinamide (compound 21)
Method is with embodiment 15 step 2, just replace the fluoro-3-oxyethyl group of 6--2-pyrazine formonitrile HCN with the fluoro-3-of 6-[(3-ethoxycarbonyl propyl) oxygen base]-2-pyrazine formonitrile HCN, obtain the fluoro-3-of 6-[(3-ethoxycarbonyl propyl) oxygen base]-2-Zinamide
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), are divided into 8 groups at random by body weight, often organize 3.By 0.0637mmol/10ml/kg dosage (10mg/10ml/kg is equivalent to for T705 or T1105) respectively oral administration gavage give test-compound.To take a blood sample 20 μ L in administration different time points eye socket, add mark acetonitrile solution in 20 μ L positively charged ions, mark acetonitrile solution in 20 μ L negatively charged ion, 40 μ L acetonitriles, vibration, the centrifugal 10min of 18000g, get supernatant LC/MS/MS sample introduction, measure the concentration of corresponding test-compound and T705 or T1105 respectively.
Table 1 is time dependent data of the Plasma Concentration of T705 in body after mouse stomach administration such as compound T705 and compound 14,15,16,17,18,19,20,21 grade.Fig. 1 is compound 14,15,16,17 after mouse stomach administration the drug-time curve of T705 in body.Display compound 16 obviously can extend the transformation period of T705.
Table 2 is compounds 1,2,3,4,5,6,7,8,9,10,11 after mouse stomach administration time dependent data of the Plasma Concentration of T1105 in body.。Fig. 2 is compound 1-5 drug-time curve of T1105 in body after mouse stomach administration.Result display compound 1-11 all can significantly improve the oral administration biaavailability of T1105, and (T1105 is oral gastric infusion under 0.0637mmol/10ml/kg dosage, in blood plasma, do not detect T1105, also illustrates that T1105 oral absorption is very poor simultaneously.
Time dependent data of the Plasma Concentration of T705 in body after mouse stomach administration such as table 1 compound T705 and compound 14,15,16,17,18,19,20,21 grade
Table 2 compound 1,2,3,4,5,6,7,8,9,10,11 after mouse stomach administration time dependent data of the Plasma Concentration of T1105 in 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 amendment 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 (14)
1. there is the compound of general formula I, its pharmaceutically useful salt,
Wherein
R
1represent hydrogen, halogen;
Work as R
1during for hydrogen, R
2be selected from: C
1-10alkyl; C
1-6the C that alkoxyl group replaces
1-6alkyl; C
3-6cycloalkyl; The C that phenyl replaces
1-6alkyl or the C replaced with the phenyl of substituted radical
1-6alkyl, described substituting group is selected from C
1-6alkoxyl group; The phenyl replaced, described substituting group is selected from C
1-6alkoxyl group; Wherein, R is worked as
2for C
1-10during alkyl, described C
1-10alkyl does not comprise methyl, ethyl, normal-butyl; Work as R
2for replace phenyl time, described substituting group does not comprise methoxyl group;
Work as R
1during for halogen, R
2be selected from: C
1-10alkyl, benzyl or with substituent benzyl, wherein, described C
1-10alkyl does not comprise methyl, and described substituting group is selected from C
1-6alkoxyl group.
2. compound according to claim 1, its pharmaceutically useful salt, it is selected from:
(1) 3-n-propyl oxygen base-2-Zinamide;
(2) 3-sec.-propyl oxygen base-2-Zinamide;
(3) 3-isobutyl-oxygen base-2-Zinamide;
(4) 3-n-pentyl oxygen base-2-Zinamide;
(5) 3-isopentyl oxygen base-2-Zinamide;
(6) 3-n-hexyl oxygen base-2-Zinamide;
(7) 3-cyclohexyl oxygen base-2-Zinamide;
(8) 3-n-octyl oxygen base-2-Zinamide;
(9) 3-[2-(oxyethyl group)-oxyethyl group]-2-Zinamide;
(10) 3-[2-(methoxyl group)-oxyethyl group]-2-Zinamide;
(11) 3-(benzyl oxygen base)-2-Zinamide;
(12) 3-(to methoxy-benzyl oxygen base)-2-Zinamide;
(14) 6-fluoro-3-ethyl oxygen base-2-Zinamide;
(15) 6-fluoro-3-normal-butyl oxygen base-2-Zinamide;
(16) 6-fluoro-3-benzyl oxygen base-2-Zinamide;
(17) the fluoro-3-of 6-[(to methoxy-benzyl)-oxygen base]-2-Zinamide;
(18) 6-fluoro-3-n-hexyl oxygen base-2-Zinamide;
(19) 6-fluoro-3-n-octyl oxygen base-2-Zinamide;
(20) the fluoro-3-of 6-(3-methoxy-benzyl oxygen base)-2-Zinamide.
3. pharmaceutical composition, it comprises compound, its pharmaceutically useful salt described in claim 1 or 2, and pharmaceutically acceptable carrier.
4. pharmaceutical composition according to claim 3, it can be made into following preparation: solid preparation, injection, external preparation, spray, liquid preparation or compound preparation.
5. purposes in preparation antiviral of the compound of claim 1 or 2, its pharmaceutically useful salt or preparing the purposes prevented and/or treated in the medicine of virus infection associated diseases.
6. the purposes of claim 5, wherein said virus is RNA viruses.
7. the purposes of claim 6, wherein said virus comprises: influenza virus, HCV virus, bunyavirus, sand fly virus, foot and mouth disease virus, west nile virus, arenavirus, western equine encephalitis virus, or yellow fever virus.
8. the purposes prevented and/or treated in the medicine of Mammals foot and mouth disease prepared by the compound of claim 1 or 2, its pharmaceutically useful salt.
9. the preparation method of the compound of claim 1 or 2, it comprises:
(i) 6-R
1-3-halo-2-Zinamide, in anhydrous aprotic organic solvent, under the existence of organic bases, with R
2oH reacts, and obtains 6-R
1-3-O-R
2-2-Zinamide;
Wherein R
1and R
2definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine, iodine; Or
(ii) 6-R
1-3-halo-2-pyrazine formonitrile HCN in anhydrous aprotic organic solvent, under the existence of organic bases or mineral alkali, with R
2oH reacts, and obtains 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN; 6-R
1-3-O-R
2-2-pyrazine formonitrile HCN in the basic conditions, with hydrogen peroxide oxidation, obtains 6-R
1-3-O-R
2-2-Zinamide;
Wherein R
1and R
2definition with claim 1, X is halogen, comprises fluorine, chlorine, bromine, iodine.
10. preparation method according to claim 9, wherein step (i) and (ii) described anhydrous aprotic organic solvent comprise toluene, DMF, acetonitrile, DME, THF or benzene.
11. preparation methods according to claim 9, wherein step (i) and (ii) described organic bases comprise triethylamine, DBU or diisopropylethylamine.
12. preparation methods according to claim 9, wherein the described mineral alkali of step (i) comprises salt of wormwood or cesium carbonate.
13. preparation methods according to claim 9, wherein step (ii) described mineral alkali comprises Na or NaH.
14. preparation methods according to claim 9, wherein step (ii) described alkaline condition be included in NaOH or salt of wormwood exist under alkaline condition.
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