CN1523028A - Novel phosphonate-nucleotide compound - Google Patents

Novel phosphonate-nucleotide compound Download PDF

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Publication number
CN1523028A
CN1523028A CNA03115445XA CN03115445A CN1523028A CN 1523028 A CN1523028 A CN 1523028A CN A03115445X A CNA03115445X A CN A03115445XA CN 03115445 A CN03115445 A CN 03115445A CN 1523028 A CN1523028 A CN 1523028A
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hex
pen
salt
salts
nucleotide
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Chinese (zh)
Inventor
田镇华
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SHANGHAI SHUMENG CHEMICAL SCI-TECH Co Ltd
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Individual
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Abstract

The present invention relates to a new phosphonate-nucleotide compounds and their salts, hydrates and their solvent compounds. Said invention provides their structure formulas. These compounds, the salts, hydrates, solvent compounds or preparations have the broad-spectrum and high antiviral activity, specially have effect for HBV infection resisted by lamivudine. They have good safety for body, at the same time have oral absorbability, and can be used as antiviral medicine for curing the diseases of hepatitis B, human immunologic deficiency syndrome and herpes, also can be used as antitumor medicine.

Description

A kind of novel phosphonate-nucleotide compound
The present invention relates to chemical field, especially a kind of novel phosphonate-nucleotide compound particularly has phosphonate-nucleotide compound, its esters, hydrate or its solvate antiviral activity, that be used as medicine, and their pharmaceutical composition.
At present, it is that one of human health threatens greatly that HBV infects, and with serious hepatic diseases necessary relation is arranged, and comprises liver cirrhosis and hepatocellular carcinoma.The whole world has 2,000,000,000 populations of surpassing to infect HBV, accounts for 1/3 of world's total population.Wherein, 300,000,000 5 thousand ten thousand people are slow virus carrier, and 1/4 the people of having an appointment dies from HBV and infects.For this reason, invent and a kind ofly have stronger antiviral activity and, be used for the treatment of HBV and infect and other disease, will make huge contribution for human beings'health to the medicine of Normocellular growth unrestraint effect.Infect though lamivudine (3TC) can be used to treat HBV, it has resistance and low seroconversion rate.And 9-(2-phosphono methoxyl group) ethyl adenine PMEA, 9-(2-phosphono methoxyl group) propyl group VITAMIN B4 PMPA, 9-(2-phosphono methoxyl group) ethyl-2, phosphonic acid ester-nucleotide compounds such as 6-diaminopurine PMDAP, because oral can not the absorption, for the performance drug effect reaches necessary Plasma Concentration, can only use non-oral administration modes such as vein and intramuscular injection.This patient for non-inpatient or need long-term treatment is difficult.
The objective of the invention is provides a kind of new phosphonate-nucleotide compound for overcoming the problems referred to above, and they have high antiviral activity, particularly the HBV to the lamivudine opposing infects effectively, they have good security to body, simultaneously, have very high oral absorption again.
Technical scheme provided by the present invention is: novel cpd comprises the phosphonate-nucleotide compound shown in the following general formula (I), its esters, hydrate or its solvate and contains the pharmaceutical composition of this compounds that they can be used as antiviral.
Figure A0311544500031
In the formula: R1, R2 can be H or alkyl, described alkyl can be the alkyl of C1-C6, as methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl etc., R1, R2 can be the same or different.X1, X2 can be respectively O, NH, S etc., and X1, X2 can be the same or different.
Phosphate nucleotide compound ' shown in the above-mentioned general formula (I) can form pharmaceutical salts.For example when acidic-group existed, this salt can be metal-salts such as lithium salts, sodium salt, sylvite, magnesium salts, calcium salt, amine salt such as ammonium salt, methylamine salt, dimethylamine salt, front three amine salt, dicyclohexyl amine salt; When basic group exists, can form inorganic acid salts such as hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt, or form as organic acid salts such as mesylate, benzene sulfonate, tosilate, acetate, propionic salt, tartrate, fumarate, maleate, malate, oxalate, succinate, Citrate trianion, benzoate, mandelate, cinnamate, lactic acid salts.
Phosphate nucleotide compound ' shown in the above-mentioned general formula (I) or its salt can exist with hydrate or solvate form thereof, and the solvent that forms solvate for example has methyl alcohol, ethanol, Virahol, acetone, ethyl acetate, methylene dichloride etc.
Product of the present invention has wide spectrum, high antiviral activity, as anti-hepatitis B virus HBV, immunodeficiency virus (human immunodeficiency virus HIV, simian immunodeficiency virus SIV, feline immunodeficiency virus FIV etc.), simplexvirus (hsv, varicella zoster virus, cytomegalovirus etc.), Lao Sheershi murine leukemia virus (R-MuLV), mouse cytomegalovirus (MCMV), poxvirus, adenovirus etc.Particularly the HBV to the lamivudine opposing infects effectively, and they have good security to body, simultaneously, have very high oral absorption again.They can be used as the antiviral of diseases such as treatment hepatitis B, human immune deficiency syndromes, bleb, also can be used as antitumor drug.
The specific examples of phosphate nucleotide compound ' of the present invention is listed in table-1.Me is a methyl in the table, and Et is an ethyl, and n-Pr is a n-propyl, and i-Pr is a sec.-propyl, and c-Pr is a cyclopropyl, n-Bu is a normal-butyl, and i-Bu is an isobutyl-, and s-Bu is a sec-butyl, and t-Bu is the tertiary butyl, n-Pen is a n-pentyl, and n-Hex is a n-hexyl, and o-represents the ortho position, and p-represents contraposition or the like.
Table-1
The compound sequence number ?R1 ?R2 ?X1 ?X2
?1 ?H ?H ?O ?O
?2 ?Me ?H ?O ?O
?3 ?Et ?H ?O ?O
?4 ?n-Pr ?H ?O ?O
?5 ?i-Pr ?H ?O ?O
?6 ?c-Pr ?H ?O ?O
?7 ?n-Bu ?H ?O ?O
?8 ?i-Bu ?H ?O ?O
?9 ?s-Bu ?H ?O ?O
?10 ?t-Bu ?H ?O ?O
?11 ?n-Pen ?H ?O ?O
?12 ?n-Hex ?H ?O ?O
?13 ?H ?Me ?O ?O
?14 ?Me ?Me ?O ?O
?15 ?Et ?Me ?O ?O
?16 ?n-Pr ?Me ?O ?O
?17 ?i-Pr ?Me ?O ?O
?18 ?c-Pr ?Me ?O ?O
?19 ?n-Bu ?Me ?O ?O
?20 ?i-Bu ?Me ?O ?O
?21 ?s-Bu ?Me ?O ?O
?22 ?t-Bu ?Me ?O ?O
?23 ?n-Pen ?Me ?O ?O
?24 ?n-Hex ?Me ?O ?O
?25 ?H ?Et ?O ?O
?26 ?Me ?Et ?O ?O
?27 ?Et ?Et ?O ?O
?28 ?n-Pr ?Et ?O ?O
?29 ?i-Pr ?Et ?O ?O
?30 ?c-Pr ?Et ?O ?O
?31 ?n-Bu ?Et ?O ?O
?32 ?i-Bu ?Et ?O ?O
?33 ?s-Bu ?Et ?O ?O
?34 ?t-Bu ?Et ?O ?O
?35 ?n-Pen ?Et ?O ?O
?36 ?n-Hex ?Et ?O ?O
?37 ?H ?n-Pr ?O ?O
?38 ?Me ?n-Pr ?O ?O
?39 ?Et ?n-Pr ?O ?O
?40 ?n-Pr ?n-Pr ?O ?O
?41 ?i-Pr ?n-Pr ?O ?O
?42 ?c-Pr ?n-Pr ?O ?O
?43 ?n-Bu ?n-Pr ?O ?O
?44 ?i-Bu ?n-Pr ?O ?O
?45 ?s-Bu ?n-Pr ?O ?O
?46 ?t-Bu ?n-Pr ?O ?O
?47 ?n-Pen ?n-Pr ?O ?O
?48 ?n-Hex ?n-Pr ?O ?O
?49 ?H ?i-Pr ?O ?O
?50 ?Me ?i-Pr ?O ?O
?51 ?Et ?i-Pr ?O ?O
?52 ?n-Pr ?i-Pr ?O ?O
?53 ?i-Pr ?i-Pr ?O ?O
?54 ?c-Pr ?i-Pr ?O ?O
?55 ?n-Bu ?i-Pr ?O ?O
?56 ?i-Bu ?i-Pr ?O ?O
?57 ?s-Bu ?i-Pr ?O ?O
?58 ?t-Bu ?i-Pr ?O ?O
?59 ?n-Pen ?i-Pr ?O ?O
?60 ?n-Hex ?i-Pr ?O ?O
?61 ?H ?c-Pr ?O ?O
?62 ?Me ?c-Pr ?O ?O
?63 ?Et ?c-Pr ?O ?O
?64 ?n-Pr ?c-Pr ?O ?O
?65 ?i-Pr ?c-Pr ?O ?O
?66 ?c-Pr ?c-Pr ?O ?O
?67 ?n-Bu ?c-Pr ?O ?O
?68 ?i-Bu ?c-Pr ?O ?O
?69 ?s-Bu ?c-Pr ?O ?O
?70 ?t-Bu ?c-Pr ?O ?O
?71 ?n-Pen ?c-Pr ?O ?O
?72 ?n-Hex ?c-Pr ?O ?O
?73 ?H ?n-Bu ?O ?O
?74 ?Me ?n-Bu ?O ?O
?75 ?Et ?n-Bu ?O ?O
?76 ?n-Pr ?n-Bu ?O ?O
?77 ?i-Pr ?n-Bu ?O ?O
?78 ?c-Pr ?n-Bu ?O ?O
?79 ?n-Bu ?n-Bu ?O ?O
?80 ?i-Bu ?n-Bu ?O ?O
?81 ?s-Bu ?n-Bu ?O ?O
?82 ?t-Bu ?n-Bu ?O ?O
?83 ?n-Pen ?n-Bu ?O ?O
?84 ?n-Hex ?n-Bu ?O ?O
?85 ?H ?i-Bu ?O ?O
?86 ?Me ?i-Bu ?O ?O
?87 ?Et ?i-Bu ?O ?O
?88 ?n-Pr ?i-Bu ?O ?O
?89 ?i-Pr ?i-Bu ?O ?O
?90 ?c-Pr ?i-Bu ?O ?O
?91 ?n-Bu ?i-Bu ?O ?O
?92 ?i-Bu ?i-Bu ?O ?O
?93 ?s-Bu ?i-Bu ?O ?O
?94 ?t-Bu ?i-Bu ?O ?O
?95 ?n-Pen ?i-Bu ?O ?O
?96 ?n-Hex ?i-Bu ?O ?O
?97 ?H ?s-Bu ?O ?O
?98 ?Me ?s-Bu ?O ?O
?99 ?Et ?s-Bu ?O ?O
?100 ?n-Pr ?s-Bu ?O ?O
?101 ?i-Pr ?s-Bu ?O ?O
?102 ?c-Pr ?s-Bu ?O ?O
?103 ?n-Bu ?s-Bu ?O ?O
?103 ?i-Bu ?s-Bu ?O ?O
?105 ?s-Bu ?s-Bu ?O ?O
?106 ?t-Bu ?s-Bu ?O ?O
?107 ?n-Pen ?s-Bu ?O ?O
?108 ?n-Hex ?s-Bu ?O ?O
?109 ?H ?t-Bu ?O ?O
?110 ?Me ?t-Bu ?O ?O
?111 ?Et ?t-Bu ?O ?O
?112 ?n-Pr ?t-Bu ?O ?O
?113 ?i-Pr ?t-Bu ?O ?O
?114 ?c-Pr ?t-Bu ?O ?O
?115 ?n-Bu ?t-Bu ?O ?O
?116 ?i-Bu ?t-Bu ?O ?O
?117 ?s-Bu ?t-Bu ?O ?O
?118 ?t-Bu ?t-Bu ?O ?O
?119 ?n-Pen ?t-Bu ?O ?O
?120 ?n-Hex ?t-Bu ?O ?O
?121 ?H ?n-Pen ?O ?O
??122 ??Me ??n-Pen ??O ??O
??123 ??Et ??n-Pen ??O ??O
??124 ??n-Pr ??n-Pen ??O ??O
??125 ??i-Pr ??n-Pen ??O ??O
??126 ??c-Pr ??n-Pen ??O ??O
??127 ??n-Bu ??n-Pen ??O ??O
??128 ??i-Bu ??n-Pen ??O ??O
??129 ??s-Bu ??n-Pen ??O ??O
??130 ??t-Bu ??n-Pen ??O ??O
??131 ??n-Pen ??n-Pen ??O ??O
??132 ??n-Hex ??n-Pen ??O ??O
??133 ??H ??n-Hex ??O ??O
??134 ??Me ??n-Hex ??O ??O
??135 ??Et ??n-Hex ??O ??O
??136 ??n-Pr ??n-Hex ??O ??O
??137 ??i-Pr ??n-Hex ??O ??O
??138 ??c-Pr ??n-Hex ??O ??O
??139 ??n-Bu ??n-Hex ??O ??O
??140 ??i-Bu ??n-Hex ??O ??O
??141 ??s-Bu ??n-Hex ??O ??O
??142 ??t-Bu ??n-Hex ??O ??O
??143 ??n-Pen ??n-Hex ??O ??O
??144 ??n-Hex ??n-Hex ??O ??O
??145 ??H ??H ??NH ??O
??146 ??Me ??H ??NH ??O
??147 ??Et ??H ??NH ??O
??148 ??n-Pr ??H ??NH ??O
??149 ??i-Pr ??H ??NH ??O
??150 ??c-Pr ??H ??NH ??O
??151 ??n-Bu ??H ??NH ??O
??152 ??i-Bu ??H ??NH ??O
??153 ??s-Bu ??H ??NH ??O
??154 ??t-Bu ??H ??NH ??O
??155 ??n-Pen ??H ??NH ??O
??156 ??n-Hex ??H ??NH ??O
??157 ??H ??Me ??NH ??O
??158 ??Me ??Me ??NH ??O
??159 ??Et ??Me ??NH ??O
??160 ??n-Pr ??Me ??NH ??O
??161 ??i-Pr ??Me ??NH ??O
??162 ??c-Pr ??Me ??NH ??O
??163 ??n-Bu ??Me ??NH ??O
??164 ??i-Bu ??Me ??NH ??O
??165 ??s-Bu ??Me ??NH ??O
??166 ??t-Bu ??Me ??NH ??O
??167 ??n-Pen ??Me ??NH ??O
??168 ??n-Hex ??Me ??NH ??O
??169 ??H ??Et ??NH ??O
?170 ??Me ??Et ??NH ?O
?171 ??Et ??Et ??NH ?O
?172 ??n-Pr ??Et ??NH ?O
?173 ??i-Pr ??Et ??NH ?O
?174 ??c-Pr ??Et ??NH ?O
?175 ??n-Bu ??Et ??NH ?O
?176 ??i-Bu ??Et ??NH ?O
?177 ??s-Bu ??Et ??NH ?O
?178 ??t-Bu ??Et ??NH ?O
?179 ??n-Pen ??Et ??NH ?O
?180 ??n-Hex ??Et ??NH ?O
?181 ??H ??n-Pr ??NH ?O
?182 ??Me ??n-Pr ??NH ?O
?183 ??Et ??n-Pr ??NH ?O
?184 ??n-Pr ??n-Pr ??NH ?O
?185 ??i-Pr ??n-Pr ??NH ?O
?186 ??c-Pr ??n-Pr ??NH ?O
?187 ??n-Bu ??n-Pr ??NH ?O
?188 ??i-Bu ??n-Pr ??NH ?O
?189 ??s-Bu ??n-Pr ??NH ?O
?190 ??t-Bu ??n-Pr ??NH ?O
?191 ??n-Pen ??n-Pr ??NH ?O
?192 ??n-Hex ??n-Pr ??NH ?O
?193 ??H ??i-Pr ??NH ?O
?194 ??Me ??i-Pr ??NH ?O
?195 ??Et ??i-Pr ??NH ?O
?196 ??n-Pr ??i-Pr ??NH ?O
?197 ??i-Pr ??i-Pr ??NH ?O
?198 ??c-Pr ??i-Pr ??NH ?O
?199 ??n-Bu ??i-Pr ??NH ?O
?200 ??i-Bu ??i-Pr ??NH ?O
?201 ??s-Bu ??i-Pr ??NH ?O
?202 ??t-Bu ??i-Pr ??NH ?O
?203 ??n-Pen ??i-Pr ??NH ?O
?204 ??n-Hex ??i-Pr ??NH ?O
?205 ??H ??c-Pr ??NH ?O
?206 ??Me ??c-Pr ??NH ?O
?207 ??Et ??c-Pr ??NH ?O
?208 ??n-Pr ??c-Pr ??NH ?O
?209 ??i-Pr ??c-Pr ??NH ?O
?210 ??c-Pr ??c-Pr ??NH ?O
?211 ??n-Bu ??c-Pr ??NH ?O
?212 ??i-Bu ??c-Pr ??NH ?O
?213 ??s-Bu ??c-Pr ??NH ?O
?214 ??t-Bu ??c-Pr ??NH ?O
?215 ??n-Pen ??c-Pr ??NH ?O
?216 ??n-Hex ??c-Pr ??NH ?O
?217 ??H ??n-Bu ??NH ?O
?218 ?Me ?n-Bu ?NH ?O
?219 ?Et ?n-Bu ?NH ?O
?220 ?n-Pr ?n-Bu ?NH ?O
?221 ?i-Pr ?n-Bu ?NH ?O
?222 ?c-Pr ?n-Bu ?NH ?O
?223 ?n-Bu ?n-Bu ?NH ?O
?224 ?i-Bu ?n-Bu ?NH ?O
?225 ?s-Bu ?n-Bu ?NH ?O
?226 ?t-Bu ?n-Bu ?NH ?O
?227 ?n-Pen ?n-Bu ?NH ?O
?228 ?n-Hex ?n-Bu ?NH ?O
?229 ?H ?i-Bu ?NH ?O
?230 ?Me ?i-Bu ?NH ?O
?231 ?Et ?i-Bu ?NH ?O
?232 ?n-Pr ?i-Bu ?NH ?O
?233 ?i-Pr ?i-Bu ?NH ?O
?234 ?c-Pr ?i-Bu ?NH ?O
?235 ?n-Bu ?i-Bu ?NH ?O
?236 ?i-Bu ?i-Bu ?NH ?O
?237 ?s-Bu ?i-Bu ?NH ?O
?238 ?t-Bu ?i-Bu ?NH ?O
?239 ?n-Pen ?i-Bu ?NH ?O
?240 ?n-Hex ?i-Bu ?NH ?O
?241 ?H ?s-Bu ?NH ?O
?242 ?Me ?s-Bu ?NH ?O
?243 ?Et ?s-Bu ?NH ?O
?244 ?n-Pr ?s-Bu ?NH ?O
?245 ?i-Pr ?s-Bu ?NH ?O
?246 ?c-Pr ?s-Bu ?NH ?O
?247 ?n-Bu ?s-Bu ?NH ?O
?248 ?i-Bu ?s-Bu ?NH ?O
?249 ?s-Bu ?s-Bu ?NH ?O
?250 ?t-Bu ?s-Bu ?NH ?O
?251 ?n-Pen ?s-Bu ?NH ?O
?252 ?n-Hex ?s-Bu ?NH ?O
?253 ?H ?t-Bu ?NH ?O
?254 ?Me ?t-Bu ?NH ?O
?255 ?Et ?t-Bu ?NH ?O
?256 ?n-Pr ?t-Bu ?NH ?O
?257 ?i-Pr ?t-Bu ?NH ?O
?258 ?c-Pr ?t-Bu ?NH ?O
?259 ?n-Bu ?t-Bu ?NH ?O
?260 ?i-Bu ?t-Bu ?NH ?O
?261 ?s-Bu ?t-Bu ?NH ?O
?262 ?t-Bu ?t-Bu ?NH ?O
?263 ?n-Pen ?t-Bu ?NH ?O
?264 ?n-Hex ?t-Bu ?NH ?O
?265 ?H ?n-Pen ?NH ?O
?266 ?Me ?n-Pen ?NH ?O
?267 ?Et ?n-Pen ?NH ?O
?268 ?n-Pr ?n-Pen ?NH O
?269 ?i-Pr ?n-Pen ?NH ?O
?270 ?c-Pr ?n-Pen ?NH ?O
?271 ?n-Bu ?n-Pen ?NH ?O
?272 ?i-Bu ?n-Pen ?NH ?O
?273 ?s-Bu ?n-Pen ?NH ?O
?274 ?t-Bu ?n-Pen ?NH ?O
?275 ?n-Pen ?n-Pen ?NH ?O
?276 ?n-Hex ?n-Pen ?NH ?O
?277 ?H ?n-Hex ?NH ?O
?278 ?Me ?n-Hex ?NH ?O
?279 ?Et ?n-Hex ?NH ?O
?280 ?n-Pr ?n-Hex ?NH ?O
?281 ?i-Pr ?n-Hex ?NH ?O
?282 ?c-Pr ?n-Hex ?NH ?O
?283 ?n-Bu ?n-Hex ?NH ?O
?284 ?i-Bu ?n-Hex ?NH ?O
?285 ?s-Bu ?n-Hex ?NH ?O
?286 ?t-Bu ?n-Hex ?NH ?O
?287 ?n-Pen ?n-Hex ?NH ?O
?288 ?n-Hex ?n-Hex ?NH ?O
?289 ?H ?H ?S ?O
?290 ?Me ?H ?S ?O
?291 ?Et ?H ?S ?O
?292 ?n-Pr ?H ?S ?O
?293 ?i-Pr ?H ?S ?O
?294 ?c-Pr ?H ?S ?O
?295 ?n-Bu ?H ?S ?O
?296 ?i-Bu ?H ?S ?O
?297 ?s-Bu ?H ?S ?O
?298 ?t-Bu ?H ?S ?O
?299 ?n-Pen ?H ?S ?O
?300 ?n-Hex ?H ?S ?O
?301 ?H ?Me ?S ?O
?302 ?Me ?Me ?S ?O
?303 ?Et ?Me ?S ?O
?304 ?n-Pr ?Me ?S ?O
?305 ?i-Pr ?Me ?S ?O
?306 ?c-Pr ?Me ?S ?O
?307 ?n-Bu ?Me ?S ?O
?308 ?i-Bu ?Me ?S ?O
?309 ?s-Bu ?Me ?S ?O
?310 ?t-Bu ?Me ?S ?O
?311 ?n-Pen ?Me ?S ?O
?312 ?n-Hex ?Me ?S ?O
?313 ?H ?Et ?S ?O
?314 ?Me ?Et ?S ?O
?315 ?Et ?Et ?S ?O
?316 ?n-Pr ?Et ?S ?O
?317 ?i-Pr ?Et ?S ?O
?318 ?c-Pr ?Et ?S ?O
?319 ?n-Bu ?Et ?S ?O
?320 ?i-Bu ?Et ?S ?O
?321 ?s-Bu ?Et ?S ?O
?322 ?t-Bu ?Et ?S ?O
?323 ?n-Pen ?Et ?S ?O
?324 ?n-Hex ?Et ?S ?O
?325 ?H ?n-Pr ?S ?O
?326 ?Me ?n-Pr ?S ?O
?327 ?Et ?n-Pr ?S ?O
?328 ?n-Pr ?n-Pr ?S ?O
?329 ?i-Pr ?n-Pr ?S ?O
?330 ?c-Pr ?n-Pr ?S ?O
?331 ?n-Bu ?n-Pr ?S ?O
?332 ?i-Bu ?n-Pr ?S ?O
?333 ?s-Bu ?n-Pr ?S ?O
?334 ?t-Bu ?n-Pr ?S ?O
?335 ?n-Pen ?n-Pr ?S ?O
?336 ?n-Hex ?n-Pr ?S ?O
?337 ?H ?i-Pr ?S ?O
?338 ?Me ?i-Pr ?S ?O
?339 ?Et ?i-Pr ?S ?O
?340 ?n-Pr ?i-Pr ?S ?O
?341 ?i-Pr ?i-Pr ?S ?O
?342 ?c-Pr ?i-Pr ?S ?O
?343 ?n-Bu ?i-Pr ?S ?O
?344 ?i-Bu ?i-Pr ?S ?O
?345 ?s-Bu ?i-Pr ?S ?O
?346 ?t-Bu ?i-Pr ?S ?O
?347 ?n-Pen ?i-Pr ?S ?O
?348 ?n-Hex ?i-Pr ?S ?O
?349 ?H ?c-Pr ?S ?O
?350 ?Me ?c-Pr ?S ?O
?351 ?Et ?c-Pr ?S ?O
?352 ?n-Pr ?c-Pr ?S ?O
?353 ?i-Pr ?c-Pr ?S ?O
?354 ?c-Pr ?c-Pr ?S ?O
?355 ?n-Bu ?c-Pr ?S ?O
?356 ?i-Bu ?c-Pr ?S ?O
?357 ?s-Bu ?c-Pr ?S ?O
?358 ?t-Bu ?c-Pr ?S ?O
?359 ?n-Pen ?c-Pr ?S ?O
?360 ?n-Hex ?c-Pr ?S ?O
?361 ?H ?n-Bu ?S ?O
?362 ?Me ?n-Bu ?S ?O
?363 ?Et ?n-Bu ?S ?O
?364 ?n-Pr ?n-Bu ?S ?O
?365 ?i-Pr ?n-Bu ?S ?O
?366 ?c-Pr ?n-Bu ?S ?O
?367 ?n-Bu ?n-Bu ?S ?O
?368 ?i-Bu ?n-Bu ?S ?O
?369 ?s-Bu ?n-Bu ?S ?O
?370 ?t-Bu ?n-Bu ?S ?O
?371 ?n-Pen ?n-Bu ?S ?O
?372 ?n-Hex ?n-Bu ?S ?O
?373 ?H ?i-Bu ?S ?O
?374 ?Me ?i-Bu ?S ?O
?375 ?Et ?i-Bu ?S ?O
?376 ?n-Pr ?i-Bu ?S ?O
?377 ?i-Pr ?i-Bu ?S ?O
?378 ?c-Pr ?i-Bu ?S ?O
?379 ?n-Bu ?i-Bu ?S ?O
?380 ?i-Bu ?i-Bu ?S ?O
?381 ?s-Bu ?i-Bu ?S ?O
?382 ?t-Bu ?i-Bu ?S ?O
?383 ?n-Pen ?i-Bu ?S ?O
?384 ?n-Hex ?i-Bu ?S ?O
?385 ?H ?s-Bu ?S ?O
?386 ?Me ?s-Bu ?S ?O
?387 ?Et ?s-Bu ?S ?O
?388 ?n-Pr ?s-Bu ?S ?O
?389 ?i-Pr ?s-Bu ?S ?O
?390 ?c-Pr ?s-Bu ?S ?O
?391 ?n-Bu ?s-Bu ?S ?O
?392 ?i-Bu ?s-Bu ?S ?O
?393 ?s-Bu ?s-Bu ?S ?O
?394 ?t-Bu ?s-Bu ?S ?O
?395 ?n-Pen ?s-Bu ?S ?O
?396 ?n-Hex ?s-Bu ?S ?O
?397 ?H ?t-Bu ?S ?O
?398 ?Me ?t-Bu ?S ?O
?399 ?Et ?t-Bu ?S ?O
?400 ?n-Pr ?t-Bu ?S ?O
?401 ?i-Pr ?t-Bu ?S ?O
?402 ?c-Pr ?t-Bu ?S ?O
?403 ?n-Bu ?t-Bu ?S ?O
?404 ?i-Bu ?t-Bu ?S ?O
?405 ?s-Bu ?t-Bu ?S ?O
?406 ?t-Bu ?t-Bu ?S ?O
?407 ?n-Pen ?t-Bu ?S ?O
?408 ?n-Hex ?t-Bu ?S ?O
?409 ?H ?n-Pen ?S ?O
?410 ?Me ?n-Pen ?S ?O
?411 ?Et ?n-Pen ?S ?O
?412 ?n-Pr ?n-Pen ?S ?O
?413 ?i-Pr ?n-Pen ?S ?O?????-
?414 ?c-Pr ?n-Pen ?S ?O
?415 ?n-Bu ?n-Pen ?S ?O
?416 ?i-Bu ?n-Pen ?S ?O
?417 ?s-Bu ?n-Pen ?S ?O
?418 ?t-Bu ?n-Pen ?S ?O
?419 ?n-Pen ?n-Pen ?S ?O
?420 ?n-Hex ?n-Pen ?S ?O
?421 ?H ?n-Hex ?S ?O
?422 ?Me ?n-Hex ?S ?O
?423 ?Et ?n-Hex ?S ?O
?424 ?n-Pr ?n-Hex ?S ?O
?425 ?i-Pr ?n-Hex ?S ?O
?426 ?c-Pr ?n-Hex ?S ?O
?427 ?n-Bu ?n-Hex ?S ?O
?428 ?i-Bu ?n-Hex ?S ?O
?429 ?s-Bu ?n-Hex ?S ?O
?430 ?t-Bu ?n-Hex ?S ?O
?431 ?n-Pen ?n-Hex ?S ?O
?432 ?n-Hex ?n-Hex ?S ?O
?433 ?H ?H ?O ?S
?434 ?Me ?H ?O ?S
?435 ?Et ?H ?O ?S
?436 ?n-Pr ?H ?O ?S
?437 ?i-Pr ?H ?O ?S
?438 ?c-Pr ?H ?O ?S
?439 ?n-Bu ?H ?O ?S
?440 ?i-Bu ?H ?O ?S
?441 ?s-Bu ?H ?O ?S
?442 ?t-Bu ?H ?O ?S
?443 ?n-Pen ?H ?O ?S
?444 ?n-Hex ?H ?O ?S
?445 ?H ?Me ?O ?S
?446 ?Me ?Me ?O ?S
?447 ?Et ?Me ?O ?S
?448 ?n-Pr ?Me ?O ?S
?449 ?i-Pr ?Me ?O ?S
?450 ?c-Pr ?Me ?O ?S
?451 ?n-Bu ?Me ?O ?S
?452 ?i-Bu ?Me ?O ?S
?453 ?s-Bu ?Me ?O ?S
?454 ?t-Bu ?Me ?O ?S
?455 ?n-Pen ?Me ?O ?S
?456 ?n-Hex ?Me ?O ?S
?457 ?H ?Et ?O ?S
????458 ?Me ?Et ?O ?S
????459 ?Et ?Et ?O ?S
????460 ?n-Pr ?Et ?O ?S
????461 ?i-Pr ?Et ?O ?S
????462 ?c-Pr ?Et ?O ?S
????463 ?n-Bu ?Et ?O ?S
????464 ?i-Bu ?Et ?O ?S
????465 ?s-Bu ?Et ?O ?S
????466 ?t-Bu ?Et ?O ?S
????467 ?n-Pen ?Et ?O ?S
????468 ?n-Hex ?Et ?O ?S
????469 ?H ?n-Pr ?O ?S
????470 ?Me ?n-Pr ?O ?S
????471 ?Et ?n-Pr ?O ?S
????472 ?n-Pr ?n-Pr ?O ?S
????473 ?i-Pr ?n-Pr ?O ?S
????474 ?c-Pr ?n-Pr ?O ?S
????475 ?n-Bu ?n-Pr ?O ?S
????476 ?i-Bu ?n-Pr ?O ?S
????477 ?s-Bu ?n-Pr ?O ?S
????478 ?t-Bu ?n-Pr ?O ?S
????479 ?n-Pen ?n-Pr ?O ?S
????480 ?n-Hex ?n-Pr ?O ?S
????481 ?H ?i-Pr ?O ?S
????482 ?Me ?i-Pr ?O ?S
????483 ?Et ?i-Pr ?O ?S
????484 ?n-Pr ?i-Pr ?O ?S
????485 ?i-Pr ?i-Pr ?O ?S
????486 ?c-Pr ?i-Pr ?O ?S
????487 ?n-Bu ?i-Pr ?O ?S
????488 ?i-Bu ?i-Pr ?O ?S
????489 ?s-Bu ?i-Pr ?O ?S
????490 ?t-Bu ?i-Pr ?O ?S
????491 ?n-Pen ?i-Pr ?O ?S
????492 ?n-Hex ?i-Pr ?O ?S
????493 ?H ?c-Pr ?O ?S
????494 ?Me ?c-Pr ?O ?S
????495 ?Et ?c-Pr ?O ?S
????496 ?n-Pr ?c-Pr ?O ?S
????497 ?i-Pr ?c-Pr ?O ?S
????498 ?c-Pr ?c-Pr ?O ?S
????499 ?n-Bu ?c-Pr ?O ?S
????500 ?i-Bu ?c-Pr ?O ?S
????501 ?s-Bu ?c-Pr ?O ?S
????502 ?t-Bu ?c-Pr ?O ?S
????503 ?n-Pen ?c-Pr ?O ?S
????504 ?n-Hex ?c-Pr ?O ?S
????505 ?H ?n-Bu ?O ?S
????506 ?Me ?n-Bu ?O ?S
????507 ?Et ?n-Bu ?O ?S
????508 ?n-Pr ?n-Bu ?O ?S
????509 ?i-Pr ?n-Bu ?O ?S
????510 ?c-Pr ?n-Bu ?O ?S
????511 ?n-Bu ?n-Bu ?O ?S
????512 ?i-Bu ?n-Bu ?O ?S
????513 ?s-Bu ?n-Bu ?O ?S
????514 ?t-Bu ?n-Bu ?O ?S
????515 ?n-Pen ?n-Bu ?O ?S
????516 ?n-Hex ?n-Bu ?O ?S
????517 ?H ?i-Bu ?O ?S
????518 ?Me ?i-Bu ?O ?S
????519 ?Et ?i-Bu ?O ?S
????520 ?n-Pr ?i-Bu ?O ?S
????521 ?i-Pr ?i-Bu ?O ?S
????522 ?c-Pr ?i-Bu ?O ?S
????523 ?n-Bu ?i-Bu ?O ?S
????524 ?i-Bu ?i-Bu ?O ?S
????525 ?s-Bu ?i-Bu ?O ?S
????526 ?t-Bu ?i-Bu ?O ?S
????527 ?n-Pen ?i-Bu ?O ?S
????528 ?n-Hex ?i-Bu ?O ?S
????529 ?H ?s-Bu ?O ?S
????530 ?Me ?s-Bu ?O ?S
????531 ?Et ?s-Bu ?O ?S
????532 ?n-Pr ?s-Bu ?O ?S
????533 ?i-Pr ?s-Bu ?O ?S
????534 ?c-Pr ?s-Bu ?O ?S
????535 ?n-Bu ?s-Bu ?O ?S
????536 ?i-Bu ?s-Bu ?O ?S
????537 ?s-Bu ?s-Bu ?O ?S
????538 ?t-Bu ?s-Bu ?O ?S
????539 ?n-Pen ?s-Bu ?O ?S
????540 ?n-Hex ?s-Bu ?O ?S
????541 ?H ?t-Bu ?O ?S
????542 ?Me ?t-Bu ?O ?S
????543 ?Et ?t-Bu ?O ?S
????544 ?n-Pr ?t-Bu ?O ?S
????545 ?i-Pr ?t-Bu ?O ?S
????546 ?c-Pr ?t-Bu ?O ?S
????547 ?n-Bu ?t-Bu ?O ?S
????548 ?i-Bu ?t-Bu ?O ?S
????549 ?s-Bu ?t-Bu ?O ?S
????550 ?t-Bu ?t-Bu ?O ?S
????551 ?n-Pen ?t-Bu ?O ?S
????552 ?n-Hex ?t-Bu ?O ?S
????553 ?H ?n-Pen ?O ?S
????554 ?Me ?n-Pen ?O ?S
????555 ?Et ?n-Pen ?O ?S
????556 ?n-Pr ?n-Pen ?O ?S
????557 ?i-Pr ?n-Pen ?O ?S
????558 ?c-Pr ?n-Pen ?O ?S
????559 ?n-Bu ?n-Pen ?O ?S
????560 ?i-Bu ?n-Pen ?O ?S
????561 ?s-Bu ?n-Pen ?O ?S
????562 ?t-Bu ?n-Pen ?O ?S
????563 ?n-Pen ?n-Pen ?O ?S
????564 ?n-Hex ?n-Pen ?O ?S
????565 ?H ?n-Hex ?O ?S
????566 ?Me ?n-Hex ?O ?S
????567 ?Et ?n-Hex ?O ?S
????568 ?n-Pr ?n-Hex ?O ?S
????569 ?i-Pr ?n-Hex ?O ?S
????570 ?c-Pr ?n-Hex ?O ?S
????571 ?n-Bu ?n-Hex ?O ?S
????572 ?i-Bu ?n-Hex ?O ?S
????573 ?s-Bu ?n-Hex ?O ?S
????574 ?t-Bu ?n-Hex ?O ?S
????575 ?n-Pen ?n-Hex ?O ?S
????576 ?n-Hex ?n-Hex ?O ?S
????577 ?H ?H ?NH ?S
????578 ?Me ?H ?NH ?S
????579 ?Et ?H ?NH ?S
????580 ?n-Pr ?H ?NH ?S
????581 ?i-Pr ?H ?NH ?S
????582 ?c-Pr ?H ?NH ?S
????583 ?n-Bu ?H ?NH ?S
????584 ?i-Bu ?H ?NH ?S
????585 ?s-Bu ?H ?NH ?S
????586 ?t-Bu ?H ?NH ?S
????587 ?n-Pen ?H ?NH ?S
????588 ?n-Hex ?H ?NH ?S
????589 ?H ?Me ?NH ?S
????590 ?Me ?Me ?NH ?S
????591 ?Et ?Me ?NH ?S
????592 ?n-Pr ?Me ?NH ?S
????593 ?i-Pr ?Me ?NH ?S
????594 ?c-Pr ?Me ?NH ?S
????595 ?n-Bu ?Me ?NH ?S
????596 ?i-Bu ?Me ?NH ?S
????597 ?s-Bu ?Me ?NH ?S
????598 ?t-Bu ?Me ?NH ?S
????599 ?n-Pen ?Me ?NH ?S
????600 ?n-Hex ?Me ?NH ?S
????601 ?H ?Et ?NH ?S
????602 ?Me ?Et ?NH ?S
????603 ?Et ?Et ?NH ?S
????604 ?n-Pr ?Et ?NH ?S
????605 ?i-Pr ?Et ?NH ?S
????606 ?c-Pr ?Et ?NH ?S
????607 ?n-Bu ?Et ?NH ?S
????608 ?i-Bu ?Et ?NH ?S
????609 ?s-Bu ?Et ?NH ?S
????610 ?t-Bu ?Et ?NH ?S
????611 ?n-Pen ?Et ?NH ?S
????612 ?n-Hex ?Et ?NH ?S
????613 ?H ?n-Pr ?NH ?S
????614 ?Me ?n-Pr ?NH ?S
????615 ?Et ?n-Pr ?NH ?S
????616 ?n-Pr ?n-Pr ?NH ?S
????617 ?i-Pr ?n-Pr ?NH ?S
????618 ?c-Pr ?n-Pr ?NH ?S
????619 ?n-Bu ?n-Pr ?NH ?S
????620 ?i-Bu ?n-Pr ?NH ?S
????621 ?s-Bu ?n-Pr ?NH ?S
????622 ?t-Bu ?n-Pr ?NH ?S
????623 ?n-Pen ?n-Pr ?NH ?S
????624 ?n-Hex ?n-Pr ?NH ?S
????625 ?H ?i-Pr ?NH ?S
????626 ?Me ?i-Pr ?NH ?S
????627 ?Et ?i-Pr ?NH ?S
????628 ?n-Pr ?i-Pr ?NH ?S
????629 ?i-Pr ?i-Pr ?NH ?S
????630 ?c-Pr ?i-Pr ?NH ?S
????631 ?n-Bu ?i-Pr ?NH ?S
????632 ?i-Bu ?i-Pr ?NH ?S
????633 ?s-Bu ?i-Pr ?NH ?S
????634 ?t-Bu ?i-Pr ?NH ?S
????635 ?n-Pen ?i-Pr ?NH ?S
????636 ?n-Hex ?i-Pr ?NH ?S
????637 ?H ?c-Pr ?NH ?S
????638 ?Me ?c-Pr ?NH ?S
????639 ?Et ?c-Pr ?NH ?S
????640 ?n-Pr ?c-Pr ?NH ?S
????641 ?i-Pr ?c-Pr ?NH ?S
????642 ?c-Pr ?c-Pr ?NH ?S
????643 ?n-Bu ?c-Pr ?NH ?S
????644 ?i-Bu ?c-Pr ?NH ?S
????645 ?s-Bu ?c-Pr ?NH ?S
????646 ?t-Bu ?c-Pr ?NH ?S
????647 ?n-Pen ?c-Pr ?NH ?S
????648 ?n-Hex ?c-Pr ?NH ?S
????649 ?H ?n-Bu ?NH ?S
????650 ?Me ?n-Bu ?NH ?S
????651 ?Et ?n-Bu ?NH ?S
????652 ?n-Pr ?n-Bu ?NH ?S
????653 ?i-Pr ?n-Bu ?NH ?S
????654 ?c-Pr ?n-Bu ?NH ?S
????655 ?n-Bu ?n-Bu ?NH ?S
????656 ?i-Bu ?n-Bu ?NH ?S
????657 ?s-Bu ?n-Bu ?NH ?S
????658 ?t-Bu ?n-Bu ?NH ?S
????659 ?n-Pen ?n-Bu ?NH ?S
????660 ?n-Hex ?n-Bu ?NH ?S
????661 ?H ?i-Bu ?NH ?S
????662 ?Me ?i-Bu ?NH ?S
????663 ?Et ?i-Bu ?NH ?S
????664 ?n-Pr ?i-Bu ?NH ?S
????665 ?i-Pr ?i-Bu ?NH ?S
????666 ?c-Pr ?i-Bu ?NH ?S
????667 ?n-Bu ?i-Bu ?NH ?S
????668 ?i-Bu ?i-Bu ?NH ?S
????669 ?s-Bu ?i-Bu ?NH ?S
????670 ?t-Bu ?i-Bu ?NH ?S
????671 ?n-Pen ?i-Bu ?NH ?S
????672 ?n-Hex ?i-Bu ?NH ?S
????673 ?H ?s-Bu ?NH ?S
????674 ?Me ?s-Bu ?NH ?S
????675 ?Et ?s-Bu ?NH ?S
????676 ?n-Pr ?s-Bu ?NH ?S
????677 ?i-Pr ?s-Bu ?NH ?S
????678 ?c-Pr ?s-Bu ?NH ?S
????679 ?n-Bu ?s-Bu ?NH ?S
????680 ?i-Bu ?s-Bu ?NH ?S
????681 ?s-Bu ?s-Bu ?NH ?S
????682 ?t-Bu ?s-Bu ?NH ?S
????683 ?n-Pen ?s-Bu ?NH ?S
????684 ?n-Hex ?s-Bu ?NH ?S
????685 ?H ?t-Bu ?NH ?S
????686 ?Me ?t-Bu ?NH ?S
????687 ?Et ?t-Bu ?NH ?S
????688 ?n-Pr ?t-Bu ?NH ?S
????689 ?i-Pr ?t-Bu ?NH ?S
????690 ?c-Pr ?t-Bu ?NH ?S
????691 ?n-Bu ?t-Bu ?NH ?S
????692 ?i-Bu ?t-Bu ?NH ?S
????693 ?s-Bu ?t-Bu ?NH ?S
????694 ?t-Bu ?t-Bu ?NH ?S
????695 ?n-Pen ?t-Bu ?NH ?S
????696 ?n-Hex ?t-Bu ?NH ?S
????697 ?H ?n-Pen ?NH ?S
????698 ?Me ?n-Pen ?NH ?S
????699 ?Et ?n-Pen ?NH ?S
????700 ?n-Pr ?n-Pen ?NH ?S
????701 ?i-Pr ?n-Pen ?NH ?S
????702 ?c-Pr ?n-Pen ?NH ?S
????703 ?n-Bu ?n-Pen ?NH ?S
????704 ?i-Bu ?n-Pen ?NH ?S
????705 ?s-Bu ?n-Pen ?NH ?S
????706 ?t-Bu ?n-Pen ?NH ?S
????707 ?n-Pen ?n-Pen ?NH ?S
????708 ?n-Hex ?n-Pen ?NH ?S
????709 ?H ?n-Hex ?NH ?S
????710 ?Me ?n-Hex ?NH ?S
????711 ?Et ?n-Hex ?NH ?S
????712 ?n-Pr ?n-Hex ?NH ?S
????713 ?i-Pr ?n-Hex ?NH ?S
????714 ?c-Pr ?n-Hex ?NH ?S
????715 ?n-Bu ?n-Hex ?NH ?S
????716 ?i-Bu ?n-Hex ?NH ?S
????717 ?s-Bu ?n-Hex ?NH ?S
????718 ?t-Bu ?n-Hex ?NH ?S
????719 ?n-Pen ?n-Hex ?NH ?S
????720 ?n-Hex ?n-Hex ?NH ?S
????721 ?H ?H ?S ?S
????722 ?Me ?H ?S ?S
????723 ?Et ?H ?S ?S
????724 ?n-Pr ?H ?S ?S
????725 ?i-Pr ?H ?S ?S
????726 ?c-Pr ?H ?S ?S
????727 ?n-Bu ?H ?S ?S
????728 ?i-Bu ?H ?S ?S
????729 ?s-Bu ?H ?S ?S
????730 ?t-Bu ?H ?S ?S
????731 ?n-Pen ?H ?S ?S
????732 ?n-Hex ?H ?S ?S
????733 ?H ?Me ?S ?S
????734 ?Me ?Me ?S ?S
????735 ?Et ?Me ?S ?S
????736 ?n-Pr ?Me ?S ?S
????737 ?i-Pr ?Me ?S ?S
????738 ?c-Pr ?Me ?S ?S
????739 ?n-Bu ?Me ?S ?S
????740 ?i-Bu ?Me ?S ?S
????741 ?s-Bu ?Me ?S ?S
????742 ?t-Bu ?Me ?S ?S
????743 ?n-Pen ?Me ?S ?S
????744 ?n-Hex ?Me ?S ?S
????745 ?H ?Et ?S ?S
????746 ?Me ?Et ?S ?S
????747 ?Et ?Et ?S ?S
????748 ?n-Pr ?Et ?S ?S
????749 ?i-Pr ?Et ?S ?S
????750 ?c-Pr ?Et ?S ?S
????751 ?n-Bu ?Et ?S ?S
????752 ?i-Bu ?Et ?S ?S
????753 ?s-Bu ?Et ?S ?S
????754 ?t-Bu ?Et ?S ?S
????755 ?n-Pen ?Et ?S ?S
????756 ?n-Hex ?Et ?S ?S
????757 ?H ?n-Pr ?S ?S
????758 ?Me ?n-Pr ?S ?S
????759 ?Et ?n-Pr ?S ?S
????760 ?n-Pr ?n-Pr ?S ?S
????761 ?i-Pr ?n-Pr ?S ?S
????762 ?c-Pr ?n-Pr ?S ?S
????763 ?n-Bu ?n-Pr ?S ?S
????764 ?i-Bu ?n-Pr ?S ?S
????765 ?s-Bu ?n-Pr ?S ?S
????766 ?t-Bu ?n-Pr ?S ?S
????767 ?n-Pen ?n-Pr ?S ?S
????768 ?n-Hex ?n-Pr ?S ?S
????769 ?H ?i-Pr ?S ?S
????770 ?Me ?i-Pr ?S ?S
????771 ?Et ?i-Pr ?S ?S
????772 ?n-Pr ?i-Pr ?S ?S
????773 ?i-Pr ?i-Pr ?S ?S
????774 ?c-Pr ?i-Pr ?S ?S
????775 ?n-Bu ?i-Pr ?S ?S
????776 ?i-Bu ?i-Pr ?S ?S
????777 ?s-Bu ?i-Pr ?S ?S
????778 ?t-Bu ?i-Pr ?S ?S
????779 ?n-Pen ?i-Pr ?S ?S
????780 ?n-Hex ?i-Pr ?S ?S
????781 ?H ?c-Pr ?S ?S
????782 ?Me ?c-Pr ?S ?S
????783 ?Et ?c-Pr ?S ?S
????784 ?n-Pr ?c-Pr ?S ?S
????785 ?i-Pr ?c-Pr ?S ?S
????786 ?c-Pr ?c-Pr ?S ?S
????787 ?n-Bu ?c-Pr ?S ?S
????788 ?i-Bu ?c-Pr ?S ?S
????789 ?s-Bu ?c-Pr ?S ?S
????790 ?t-Bu ?c-Pr ?S ?S
????791 ?n-Pen ?c-Pr ?S ?S
????792 ?n-Hex ?c-Pr ?S ?S
????793 ?H ?n-Bu ?S ?S
????794 ?Me ?n-Bu ?S ?S
????795 ?Et ?n-Bu ?S ?S
????796 ?n-Pr ?n-Bu ?S ?S
????797 ?i-Pr ?n-Bu ?S ?S
????798 ?c-Pr ?n-Bu ?S ?S
????799 ?n-Bu ?n-Bu ?S ?S
????800 ?i-Bu ?n-Bu ?S ?S
????801 ?s-Bu ?n-Bu ?S ?S
????802 ?t-Bu ?n-Bu ?S ?S
????803 ?n-Pen ?n-Bu ?S ?S
????804 ?n-Hex ?n-Bu ?S ?S
????805 ?H ?i-Bu ?S ?S
????806 ?Me ?i-Bu ?S ?S
????807 ?Et ?i-Bu ?S ?S
????808 ?n-Pr ?i-Bu ?S ?S
????809 ?i-Pr ?i-Bu ?S ?S
????810 ?c-Pr ?i-Bu ?S ?S
????811 ?n-Bu ?i-Bu ?S ?S
????812 ?i-Bu ?i-Bu ?S ?S
????813 ?s-Bu ?i-Bu ?S ?S
????814 ?t-Bu ?i-Bu ?S ?S
????815 ?n-Pen ?i-Bu ?S ?S
????816 ?n-Hex ?i-Bu ?S ?S
????817 ?H ?s-Bu ?S ?S
????818 ?Me ?s-Bu ?S ?S
????819 ?Et ?s-Bu ?S ?S
????820 ?n-Pr ?s-Bu ?S ?S
????821 ?i-Pr ?s-Bu ?S ?S
????822 ?c-Pr ?s-Bu ?S ?S
????823 ?n-Bu ?s-Bu ?S ?S
????824 ?i-Bu ?s-Bu ?S ?S
????825 ?s-Bu ?s-Bu ?S ?S
????826 ?t-Bu ?s-Bu ?S ?S
????827 ?n-Pen ?s-Bu ?S ?S
????828 ?n-Hex ?s-Bu ?S ?S
????829 ?H ?t-Bu ?S ?S
????830 ?Me ?t-Bu ?S ?S
????831 ?Et ?t-Bu ?S ?S
????832 ?n-Pr ?t-Bu ?S ?S
????833 ?i-Pr ?t-Bu ?S ?S
????834 ?c-Pr ?t-Bu ?S ?S
????835 ?n-Bu ?t-Bu ?S ?S
????836 ?i-Bu ?t-Bu ?S ?S
????837 ?s-Bu ?t-Bu ?S ?S
????838 ?t-Bu ?t-Bu ?S ?S
????839 ?n-Pen ?t-Bu S ?S
????840 ?n-Hex ?t-Bu ?S ?S
????841 ?H ?n-Pen ?S ?S
????842 ?Me ?n-Pen ?S ?S
????843 ?Et ?n-Pen ?S ?S
????844 ?n-Pr ?n-Pen ?S ?S
????845 ?i-Pr ?n-Pen ?S ?S
????846 ?c-Pr ?n-Pen ?S ?S
????847 ?n-Bu ?n-Pen ?S ?S
????848 ?i-Bu ?n-Pen ?S ?S
????849 ?s-Bu ?n-Pen ?S ?S
????850 ?t-Bu ?n-Pen ?S ?S
????851 ?n-Pen ?n-Pen ?S ?S
????852 ?n-Hex ?n-Pen ?S ?S
????853 ?H ?n-Hex ?S ?S
????854 ?Me ?n-Hex ?S ?S
????855 ?Et ?n-Hex ?S ?S
????856 ?n-Pr ?n-Hex ?S ?S
????857 ?i-Pr ?n-Hex ?S ?S
????858 ?c-Pr ?n-Hex ?S ?S
????859 ?n-Bu ?n-Hex ?S ?S
????860 ?i-Bu ?n-Hex ?S ?S
????861 ?s-Bu ?n-Hex ?S ?S
????862 ?t-Bu ?n-Hex ?S ?S
????863 ?n-Pen ?n-Hex ?S ?S
????864 ?n-Hex ?n-Hex ?S ?S
????865 ?H ?H ?O ?NH
????866 ?Me ?H ?O ?NH
????867 ?Et ?H ?O ?NH
????868 ?n-Pr ?H ?O ?NH
????869 ?i-Pr ?H ?O ?NH
????870 ?c-Pr ?H ?O ?NH
????871 ?n-Bu ?H ?O ?NH
????872 ?i-Bu ?H ?O ?NH
????873 ?s-Bu ?H ?O ?NH
????874 ?t-Bu ?H ?O ?NH
????875 ?n-Pen ?H ?O ?NH
????876 ?n-Hex ?H ?O ?NH
????877 ?H ?Me ?O ?NH
????878 ?Me ?Me ?O ?NH
????879 ?Et ?Me ?O ?NH
????880 ?n-Pr ?Me ?O ?NH
????881 ?i-Pr ?Me ?O ?NH
????882 ?c-Pr ?Me ?O ?NH
????883 ?n-Bu ?Me ?O ?NH
????884 ?i-Bu ?Me ?O ?NH
????885 ?s-Bu ?Me ?O ?NH
????886 ?t-Bu ?Me ?O ?NH
????887 ?n-Pen ?Me ?O ?NH
????888 ?n-Hex ?Me ?O ?NH
????889 ?H ?Et ?O ?NH
????890 ?Me ?Et ?O ?NH
????891 ?Et ?Et ?O ?NH
????892 ?n-Pr ?Et ?O ?NH
????893 ?i-Pr ?Et ?O ?NH
????894 ?c-Pr ?Et ?O ?NH
????895 ?n-Bu ?Et ?O ?NH
????896 ?i-Bu ?Et ?O ?NH
????897 ?s-Bu ?Et ?O ?NH
????898 ?t-Bu ?Et ?O ?NH
????899 ?n-Pen ?Et ?O ?NH
????900 ?n-Hex ?Et ?O ?NH
????901 ?H ?n-Pr ?O ?NH
????902 ?Me ?n-Pr ?O ?NH
????903 ?Et ?n-Pr ?O ?NH
????904 ?n-Pr ?n-Pr ?O ?NH
????905 ?i-Pr ?n-Pr ?O ?NH
????906 ?c-Pr ?n-Pr ?O ?NH
????907 ?n-Bu ?n-Pr ?O ?NH
????908 ?i-Bu ?n-Pr ?O ?NH
????909 ?s-Bu ?n-Pr ?O ?NH
????910 ?t-Bu ?n-Pr ?O ?NH
????911 ?n-Pen ?n-Pr ?O ?NH
????912 ?n-Hex ?n-Pr ?O ?NH
????913 ?H ?i-Pr ?O ?NH
????914 ?Me ?i-Pr ?O ?NH
????915 ?Et ?i-Pr ?O ?NH
????916 ?n-Pr ?i-Pr ?O ?NH
????917 ?i-Pr ?i-Pr ?O ?NH
????918 ?c-Pr ?i-Pr ?O ?NH
????919 ?n-Bu ?i-Pr ?O ?NH
????920 ?i-Bu ?i-Pr ?O ?NH
????921 ?s-Bu ?i-Pr ?O ?NH
????922 ?t-Bu ?i-Pr ?O ?NH
????923 ?n-Pen ?i-Pr ?O ?NH
????924 ?n-Hex ?i-Pr ?O ?NH
????925 ?H ?c-Pr ?O ?NH
????926 ?Me ?c-Pr ?O ?NH
????927 ?Et ?c-Pr ?O ?NH
????928 ?n-Pr ?c-Pr ?O ?NH
????929 ?i-Pr ?c-Pr ?O ?NH
????930 ?c-Pr ?c-Pr ?O ?NH
????931 ?n-Bu ?c-Pr ?O ?NH
????932 ?i-Bu ?c-Pr ?O ?NH
????933 ?s-Bu ?c-Pr ?O ?NH
????934 ?t-Bu ?c-Pr ?O ?NH
????935 ?n-Pen ?c-Pr ?O ?NH
????936 ?n-Hex ?c-Pr ?O ?NH
????937 ?H ?n-Bu ?O ?NH
????938 ?Me ?n-Bu ?O ?NH
????939 ?Et ?n-Bu ?O ?NH
????940 ?n-Pr ?n-Bu ?O ?NH
????941 ?i-Pr ?n-Bu ?O ?NH
????942 ?c-Pr ?n-Bu ?O ?NH
????943 ?n-Bu ?n-Bu ?O ?NH
????944 ?i-Bu ?n-Bu ?O ?NH
????945 ?s-Bu ?n-Bu ?O ?NH
????946 ?t-Bu ?n-Bu ?O ?NH
????947 ?n-Pen ?n-Bu ?O ?NH
????948 ?n-Hex ?n-Bu ?O ?NH
????949 ?H ?i-Bu ?O ?NH
????950 ?Me ?i-Bu ?O ?NH
????951 ?Et ?i-Bu ?O ?NH
????952 ?n-Pr ?i-Bu ?O ?NH
????953 ?i-Pr ?i-Bu ?O ?NH
????954 ?c-Pr ?i-Bu ?O ?NH
????955 ?n-Bu ?i-Bu ?O ?NH
????956 ?i-Bu ?i-Bu ?O ?NH
????957 ?s-Bu ?i-Bu ?O ?NH
????958 ?t-Bu ?i-Bu ?O ?NH
????959 ?n-Pen ?i-Bu ?O ?NH
????960 ?n-Hex ?i-Bu ?O ?NH
????961 ?H ?s-Bu ?O ?NH
????962 ?Me ?s-Bu ?O ?NH
????963 ?Et ?s-Bu ?O ?NH
????964 ?n-Pr ?s-Bu ?O ?NH
????965 ?i-Pr ?s-Bu ?O ?NH
????966 ?c-Pr ?s-Bu ?O ?NH
????967 ?n-Bu ?s-Bu ?O ?NH
????968 ?i-Bu ?s-Bu ?O ?NH
????969 ?s-Bu ?s-Bu ?O ?NH
????970 ?t-Bu ?s-Bu ?O ?NH
????971 ?n-Pen ?s-Bu ?O ?NH
????972 ?n-Hex ?s-Bu ?O ?NH
????973 ?H ?t-Bu ?O ?NH
????974 ?Me ?t-Bu ?O ?NH
????975 ?Et ?t-Bu ?O ?NH
????976 ?n-Pr ?t-Bu ?O ?NH
????977 ?i-Pr ?t-Bu ?O ?NH
????978 ?c-Pr ?t-Bu ?O ?NH
????979 ?n-Bu ?t-Bu ?O ?NH
????980 ?i-Bu ?t-Bu ?O ?NH
????981 ?s-Bu ?t-Bu ?O ?NH
????982 ?t-Bu ?t-Bu ?O ?NH
????983 ?n-Pen ?t-Bu ?O ?NH
????984 ?n-Hex ?t-Bu ?O ?NH
????985 ?H ?n-Pen ?O ?NH
????986 ?Me ?n-Pen ?O ?NH
????987 ?Et ?n-Pen ?O ?NH
????988 ?n-Pr ?n-Pen ?0 ?NH
????989 ?i-Pr ?n-Pen ?O ?NH
????990 ?c-Pr ?n-Pen ?O ?NH
????991 ?n-Bu ?n-Pen ?O ?NH
????992 ?i-Bu ?n-Pen ?O ?NH
????993 ?s-Bu ?n-Pen ?O ?NH
????994 ?t-Bu ?n-Pen ?O ?NH
????995 ?n-Pen ?n-Pen ?O ?NH
????996 ?n-Hex ?n-Pen ?O ?NH
????997 ?H ?n-Hex ?O ?NH
????998 ?Me ?n-Hex ?O ?NH
????999 ?Et ?n-Hex ?O ?NH
????1000 ?n-Pr ?n-Hex ?O ?NH
????1001 ?i-Pr ?n-Hex ?O ?NH
????1002 ?c-Pr ?n-Hex ?O ?NH
????1003 ?n-Bu ?n-Hex ?O ?NH
????1004 ?i-Bu ?n-Hex ?O ?NH
????1005 ?s-Bu ?n-Hex ?O ?NH
????1006 ?t-Bu ?n-Hex ?O ?NH
????1007 ?n-Pen ?n-Hex ?O ?NH
????1008 ?n-Hex ?n-Hex ?O ?NH
????1009 ?H ?H ?NH ?NH
????1010 ?Me ?H ?NH ?NH
????1011 ?Et ?H ?NH ?NH
????1012 ?n-Pr ?H ?NH ?NH
????1013 ?i-Pr ?H ?NH ?NH
????1014 ?c-Pr ?H ?NH ?NH
????1015 ?n-Bu ?H ?NH ?NH
????1016 ?i-Bu ?H ?NH ?NH
????1017 ?s-Bu ?H ?NH ?NH
????1018 ?t-Bu ?H ?NH ?NH
????1019 ?n-Pen ?H ?NH ?NH
????1020 ?n-Hex ?H ?NH ?NH
????1021 ?H ?Me ?NH ?NH
????1022 ?Me ?Me ?NH ?NH
????1023 ?Et ?Me ?NH ?NH
????1024 ?n-Pr ?Me ?NH ?NH
????1025 ?i-Pr ?Me ?NH ?NH
????1026 ?c-Pr ?Me ?NH ?NH
????1027 ?n-Bu ?Me ?NH ?NH
????1028 ?i-Bu ?Me ?NH ?NH
????1029 ?s-Bu ?Me ?NH ?NH
????1030 ?t-Bu ?Me ?NH ?NH
????1031 ?n-Pen ?Me ?NH ?NH
????1032 ?n-Hex ?Me ?NH ?NH
????1033 ?H ?Et ?NH ?NH
????1034 ?Me ?Et ?NH ?NH
????1035 ?Et ?Et ?NH ?NH
????1036 ?n-Pr ?Et ?NH ?NH
????1037 ?i-Pr ?Et ?NH ?NH
????1038 ?c-Pr ?Et ?NH ?NH
????1039 ?n-Bu ?Et ?NH ?NH
????1040 ?i-Bu ?Et ?NH ?NH
????1041 ?s-Bu ?Et ?NH ?NH
????1042 ?t-Bu ?Et ?NH ?NH
????1043 ?n-Pen ?Et ?NH ?NH
????1044 ?n-Hex ?Et ?NH ?NH
????1045 ?H ?n-Pr ?NH ?NH
????1046 ?Me ?n-Pr ?NH ?NH
????1047 ?Et ?n-Pr ?NH ?NH
????1048 ?n-Pr ?n-Pr ?NH ?NH
????1049 ?i-Pr ?n-Pr ?NH ?NH
????1050 ?c-Pr ?n-Pr ?NH ?NH
????1051 ?n-Bu ?n-Pr ?NH ?NH
????1052 ?i-Bu ?n-Pr ?NH ?NH
????1053 ?s-Bu ?n-Pr ?NH ?NH
????1054 ?t-Bu ?n-Pr ?NH ?NH
????1055 ?n-Pen ?n-Pr ?NH ?NH
????1056 ?n-Hex ?n-Pr ?NH ?NH
????1057 ?H ?i-Pr ?NH ?NH
????1058 ?Me ?i-Pr ?NH ?NH
????1059 ?Et ?i-Pr ?NH ?NH
????1060 ?n-Pr ?i-Pr ?NH ?NH
????1061 ?i-Pr ?i-Pr ?NH ?NH
????1062 ?c-Pr ?i-Pr ?NH ?NH
????1063 ?n-Bu ?i-Pr ?NH ?NH
????1064 ?i-Bu ?i-Pr ?NH ?NH
????1065 ?s-Bu ?i-Pr ?NH ?NH
????1066 ?t-Bu ?i-Pr ?NH ?NH
????1067 ?n-Pen ?i-Pr ?NH ?NH
????1068 ?n-Hex ?i-Pr ?NH ?NH
????1069 ?H ?c-Pr ?NH ?NH
????1070 ?Me ?c-Pr ?NH ?NH
????1071 ?Et ?c-Pr ?NH ?NH
????1072 ?n-Pr ?c-Pr ?NH ?NH
????1073 ?i-Pr ?c-Pr ?NH ?NH
????1074 ?c-Pr ?c-Pr ?NH ?NH
????1075 ?n-Bu ?c-Pr ?NH ?NH
????1076 ?i-Bu ?c-Pr ?NH ?NH
????1077 ?s-Bu ?c-Pr ?NH ?NH
????1078 ?t-Bu ?c-Pr ?NH ?NH
????1079 ?n-Pen ?c-Pr ?NH ?NH
????1080 ?n-Hex ?c-Pr ?NH ?NH
????1081 ?H ?n-Bu ?NH ?NH
????1082 ?Me ?n-Bu ?NH ?NH
????1083 ?Et ?n-Bu ?NH ?NH
????1084 ?n-Pr ?n-Bu ?NH ?NH
????1085 ?i-Pr ?n-Bu ?NH ?NH
????1086 ?c-Pr ?n-Bu ?NH ?NH
????1087 ?n-Bu ?n-Bu ?NH ?NH
????1088 ?i-Bu ?n-Bu ?NH ?NH
????1089 ?s-Bu ?n-Bu ?NH ?NH
????1090 ?t-Bu ?n-Bu ?NH ?NH
????1091 ?n-Pen ?n-Bu ?NH ?NH
????1092 ?n-Hex ?n-Bu ?NH ?NH
????1093 ?H ?i-Bu ?NH ?NH
????1094 ?Me ?i-Bu ?NH ?NH
????1095 ?Et ?i-Bu ?NH ?NH
????1096 ?n-Pr ?i-Bu ?NH ?NH
????1097 ?i-Pr ?i-Bu ?NH ?NH
????1098 ?c-Pr ?i-Bu ?NH ?NH
????1099 ?n-Bu ?i-Bu ?NH ?NH
????1100 ?i-Bu ?i-Bu ?NH ?NH
????1101 ?s-Bu ?i-Bu ?NH ?NH
????1102 ?t-Bu ?i-Bu ?NH ?NH
????1103 ?n-Pen ?i-Bu ?NH ?NH
????1104 ?n-Hex ?i-Bu ?NH ?NH
????1105 ?H ?s-Bu ?NH ?NH
????1106 ?Me ?s-Bu ?NH ?NH
????1107 ?Et ?s-Bu ?NH ?NH
????1108 ?n-Pr ?s-Bu ?NH ?NH
????1109 ?i-Pr ?s-Bu ?NH ?NH
????1110 ?c-Pr ?s-Bu ?NH ?NH
????1111 ?n-Bu ?s-Bu ?NH ?NH
????1112 ?i-Bu ?s-Bu ?NH ?NH
????1113 ?s-Bu ?s-Bu ?NH ?NH
????1114 ?t-Bu ?s-Bu ?NH ?NH
????1115 ?n-Pen ?s-Bu ?NH ?NH
????1116 ?n-Hex ?s-Bu ?NH ?NH
????1117 ?H ?t-Bu ?NH ?NH
????1118 ?Me ?t-Bu ?NH ?NH
????1119 ?Et ?t-Bu ?NH ?NH
????1120 ?n-Pr ?t-Bu ?NH ?NH
????1121 ?i-Pr ?t-Bu ?NH ?NH
????1122 ?c-Pr ?t-Bu ?NH ?NH
????1123 ?n-Bu ?t-Bu ?NH ?NH
????1124 ?i-Bu ?t-Bu ?NH ?NH
????1125 ?s-Bu ?t-Bu ?NH ?NH
????1126 ?t-Bu ?t-Bu ?NH ?NH
????1127 ?n-Pen ?t-Bu ?NH ?NH
????1128 ?n-Hex ?t-Bu ?NH ?NH
????1129 ?H ?n-Pen ?NH ?NH
????1130 ?Me ?n-Pen ?NH ?NH
????1131 ?Et ?n-Pen ?NH ?NH
????1132 ?n-Pr ?n-Pen ?NH ?NH
????1133 ?i-Pr ?n-Pen ?NH ?NH
????1134 ?c-Pr ?n-Pen ?NH ?NH
????1135 ?n-Bu ?n-Pen ?NH ?NH
????1136 ?i-Bu ?n-Pen ?NH ?NH
????1137 ?s-Bu ?n-Pen ?NH ?NH
????1138 ?t-Bu ?n-Pen ?NH ?NH
????1139 ?n-Pen ?n-Pen ?NH ?NH
????1140 ?n-Hex ?n-Pen ?NH ?NH
????1141 ?H ?n-Hex ?NH ?NH
????1142 ?Me ?n-Hex ?NH ?NH
????1143 ?Et ?n-Hex ?NH ?NH
????1144 ?n-Pr ?n-Hex ?NH ?NH
????1145 ?i-Pr ?n-Hex ?NH ?NH
????1146 ?c-Pr ?n-Hex ?NH ?NH
????1147 ?n-Bu ?n-Hex ?NH ?NH
????1148 ?i-Bu ?n-Hex ?NH ?NH
????1149 ?s-Bu ?n-Hex ?NH ?NH
????1150 ?t-Bu ?n-Hex ?NH ?NH
????1151 ?n-Pen ?n-Hex ?NH ?NH
????1152 ?n-Hex ?n-Hex ?NH ?NH
????1153 ?H ?H ?S ?NH
????1154 ?Me ?H ?S ?NH
????1155 ?Et ?H ?S ?NH
????1156 ?n-Pr ?H ?S ?NH
????1157 ?i-Pr ?H ?S ?NH
????1158 ?c-Pr ?H ?S ?NH
????1159 ?n-Bu ?H ?S ?NH
????1160 ?i-Bu ?H ?S ?NH
????1161 ?s-Bu ?H ?S ?NH
????1162 ?t-Bu ?H ?S ?NH
????1163 ?n-Pen ?H ?S ?NH
????1164 ?n-Hex ?H ?S ?NH
????1165 ?H ?Me ?S ?NH
????1166 ?Me ?Me ?S ?NH
????1167 ?Et ?Me ?S ?NH
????1168 ?n-Pr ?Me ?S ?NH
????1169 ?i-Pr ?Me ?S ?NH
????1170 ?c-Pr ?Me ?S ?NH
????1171 ?n-Bu ?Me ?S ?NH
????1172 ?i-Bu ?Me ?S ?NH
????1173 ?s-Bu ?Me ?S ?NH
????1174 ?t-Bu ?Me ?S ?NH
????1175 ?n-Pen ?Me ?S ?NH
????1176 ?n-Hex ?Me ?S ?NH
????1177 ?H ?Et ?S ?NH
????1178 ?Me ?Et ?S ?NH
????1179 ?Et ?Et ?S ?NH
????1180 ?n-Pr ?Et ?S ?NH
????1181 ?i-Pr ?Et ?S ?NH
????1182 ?c-Pr ?Et ?S ?NH
????1183 ?n-Bu ?Et ?S ?NH
????1184 ?i-Bu ?Et ?S ?NH
????1185 ?s-Bu ?Et ?S ?NH
????1186 ?t-Bu ?Et ?S ?NH
????1187 ?n-Pen ?Et ?S ?NH
????1188 ?n-Hex ?Et ?S ?NH
????1189 ?H ?n-Pr ?S ?NH
????1190 ?Me ?n-Pr ?S ?NH
????1191 ?Et ?n-Pr ?S ?NH
????1192 ?n-Pr ?n-Pr ?S ?NH
????1193 ?i-Pr ?n-Pr ?S ?NH
????1194 ?c-Pr ?n-Pr ?S ?NH
????1195 ?n-Bu ?n-Pr ?S ?NH
????1196 ?i-Bu ?n-Pr ?S ?NH
????1197 ?s-Bu ?n-Pr ?S ?NH
????1198 ?t-Bu ?n-Pr ?S ?NH
????1199 ?n-Pen ?n-Pr ?S ?NH
????1200 ?n-Hex ?n-Pr ?S ?NH
????1201 ?H ?i-Pr ?S ?NH
????1202 ?Me ?i-Pr ?S ?NH
????1203 ?Et ?i-Pr ?S ?NH
????1204 ?n-Pr ?i-Pr ?S ?NH
????1205 ?i-Pr ?i-Pr ?S ?NH
????1206 ?c-Pr ?i-Pr ?S ?NH
????1207 ?n-Bu ?i-Pr ?S ?NH
????1208 ?i-Bu ?i-Pr ?S ?NH
????1209 ?s-Bu ?i-Pr ?S ?NH
????1210 ?t-Bu ?i-Pr ?S ?NH
????1211 ?n-Pen ?i-Pr ?S ?NH
????1212 ?n-Hex ?i-Pr ?S ?NH
????1213 ?H ?c-Pr ?S ?NH
????1214 ?Me ?c-Pr ?S ?NH
????1215 ?Et ?c-Pr ?S ?NH
????1216 ?n-Pr ?c-Pr ?S ?NH
????1217 ?i-Pr ?c-Pr ?S ?NH
????1218 ?c-Pr ?c-Pr ?S ?NH
????1219 ?n-Bu ?c-Pr ?S ?NH
????1220 ?i-Bu ?c-Pr ?S ?NH
????1221 ?s-Bu ?c-Pr ?S ?NH
????1222 ?t-Bu ?c-Pr ?S ?NH
????1223 ?n-Pen ?c-Pr ?S ?NH
????1224 ?n-Hex ?c-Pr ?S ?NH
????1225 ?H ?n-Bu ?S ?NH
????1226 ?Me ?n-Bu ?S ?NH
????1227 ?Et ?n-Bu ?S ?NH
????1228 ?n-Pr ?n-Bu ?S ?NH
????1229 ?i-Pr ?n-Bu ?S ?NH
????1230 ?c-Pr ?n-Bu ?S ?NH
????1231 ?n-Bu ?n-Bu ?S ?NH
????1232 ?i-Bu ?n-Bu ?S ?NH
????1233 ?s-Bu ?n-Bu ?S ?NH
????1234 ?t-Bu ?n-Bu ?S ?NH
????1235 ?n-Pen ?n-Bu ?S ?NH
????1236 ?n-Hex ?n-Bu ?S ?NH
????1237 ?H ?i-Bu ?S ?NH
????1238 ?Me ?i-Bu ?S ?NH
????1239 ?Et ?i-Bu ?S ?NH
????1240 ?n-Pr ?i-Bu ?S ?NH
????1241 ?i-Pr ?i-Bu ?S ?NH
????1242 ?c-Pr ?i-Bu ?S ?NH
????1243 ?n-Bu ?i-Bu ?S ?NH
????1244 ?i-Bu ?i-Bu ?S ?NH
????1245 ?s-Bu ?i-Bu ?S ?NH
????1246 ?t-Bu ?i-Bu ?S ?NH
????1247 ?n-Pen ?i-Bu ?S ?NH
????1248 ?n-Hex ?i-Bu ?S ?NH
????1249 ?H ?s-Bu ?S ?NH
????1250 ?Me ?s-Bu ?S ?NH
????1251 ?Et ?s-Bu ?S ?NH
????1252 ?n-Pr ?s-Bu ?S ?NH
????1253 ?i-Pr ?s-Bu ?S ?NH
????1254 ?c-Pr ?s-Bu ?S ?NH
????1255 ?n-Bu ?s-Bu ?S ?NH
????1256 ?i-Bu ?s-Bu ?S ?NH
????1257 ?s-Bu ?s-Bu ?S ?NH
????1258 ?t-Bu ?s-Bu ?S ?NH
????1259 ?n-Pen ?s-Bu ?S ?NH
????1260 ?n-Hex ?s-Bu ?S ?NH
????1261 ?H ?t-Bu ?S ?NH
????1262 ?Me ?t-Bu ?S ?NH
????1263 ?Et ?t-Bu ?S ?NH
????1264 ?n-Pr ?t-Bu ?S ?NH
????1265 ?i-Pr ?t-Bu ?S ?NH
????1266 ?c-Pr ?t-Bu ?S ?NH
????1267 ?n-Bu ?t-Bu ?S ?NH
????1268 ?i-Bu ?t-Bu ?S ?NH
????1269 ?s-Bu ?t-Bu ?S ?NH
????1270 ?t-Bu ?t-Bu ?S ?NH
????1271 ?n-Pen ?t-Bu ?S ?NH
????1272 ?n-Hex ?t-Bu ?S ?NH
????1273 ?H ?n-Pen ?S ?NH
????1274 ?Me ?n-Pen ?S ?NH
????1275 ?Et ?n-Pen ?S ?NH
????1276 ?n-Pr ?n-Pen ?S ?NH
????1277 ?i-Pr ?n-Pen ?S ?NH
????1278 ?c-Pr ?n-Pen ?S ?NH
????1279 ?n-Bu ?n-Pen ?S ?NH
????1280 ?i-Bu ?n-Pen ?S ?NH
????1281 ?s-Bu ?n-Pen ?S ?NH
????1282 ?t-Bu ?n-Pen ?S ?NH
????1283 ?n-Pen ?n-Pen ?S ?NH
????1284 ?n-Hex ?n-Pen ?S ?NH
????1285 ?H ?n-Hex ?S ?NH
????1286 ?Me ?n-Hex ?S ?NH
????1287 ?Et ?n-Hex ?S ?NH
????1288 ?n-Pr ?n-Hex ?S ?NH
????1289 ?i-Pr ?n-Hex ?S ?NH
????1290 ?c-Pr ?n-Hex ?S ?NH
????1291 ?n-Bu ?n-Hex ?S ?NH
????1292 ?i-Bu ?n-Hex ?S ?NH
????1293 ?s-Bu ?n-Hex ?S ?NH
????1294 ?t-Bu ?n-Hex ?S ?NH
????1295 ?n-Pen ?n-Hex ?S ?NH
????1296 ?n-Hex ?n-Hex ?S ?NH
The synthetic method of the phosphate nucleotide compound ' of above-mentioned general formula (I) can be synthesized by following synthetic route of the present invention:
Figure A0311544500321
The source of the compound of general formula (II), (III), (VI) is unqualified, and they can be used as reagent and have bought, or synthesizes by known method.
The method of the compound of synthetic general formula (IV) is: general formula (II) and compound (III) in inert organic solvents, in the presence of basic catalyst, by the method that the adding condensing agent is sloughed a part water, are obtained the compound of general formula (IV).Effectively condensing agent can be selected triphen phosphorus-many methyl halides for use, triphen phosphorus-disulphide, phosphorous acid ester-pyridine-halogen, phosphorous acid ester-pyridine-mercury salt, dichloro oxidation Phenylphosphine, O, O-diethyl phosphinylidyne cyanogen, the diphenylphosphine acylazide, silicon tetrachloride, titanium tetrachloride, triethyl borate, boron trifluoride-ether, the two inferior acid amides (DCC) of dicyclohexyl carbon, N, the two imidazoles of N '-carbonyl, iodate-1-methyl-2-halogen pyridinium salt etc., organic solvent can be selected dimethyl sulfoxide (DMSO) for use, pyridine, acetonitrile, ether, dimethyl formamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, methylene dichloride, chloroform, benzene, toluene, dimethylbenzene etc., basic catalyst can be selected yellow soda ash for use, salt of wormwood, cesium carbonate, sodium hydride, potassium hydride KH, triethylamine, the diazabicyclo undecylene, N, N-dichloro hexyl-4-morpholine carboxylic acid etc.Temperature of reaction can be 20-200 ℃, preferred 50-150 ℃.Reaction times can be 0.5-72 hour, preferred 6-48 hour.Compound (II) and mol ratio (III) can be 0.5-3, preferred 1-2.The compound of the general formula that obtains (IV) can carry out separation and purification by separation and purification means commonly used such as extraction, precipitation, distillation, crystallization, chromatography etc. in case of necessity.Perhaps be directly used in next step reaction.
The method of the compound of synthetic logical formula V is: the compound and the acyl chloride reaction reagent react of general formula (IV) are formed the acyl chlorides that leads to formula V.Reaction can be carried out in the presence of inert solvent, does not perhaps add the direct chloride of inert solvent.Acyl chloride reaction reagent can be phosphorus trichloride, phosphorus pentachloride, sulfur oxychloride etc., as add inert solvent, can be dimethyl sulfoxide (DMSO), pyridine, acetonitrile, ether, dimethyl formamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, methylene dichloride, chloroform, benzene,toluene,xylene etc.Temperature of reaction can be 20-200 ℃, preferred 50-150 ℃.Reaction times can be 5min-24 hour, preferred 10min-12 hour.The compound of the logical formula V that obtains can carry out separation and purification by separation and purification means commonly used such as extraction, precipitation, distillation, crystallization, chromatography etc. in case of necessity.Perhaps be directly used in next step reaction.
The method of the compound of synthetic general formula (I) is: will lead to formula V and compound (VI) in inert organic solvents, and react in the presence of basic catalyst, and obtain the phosphate nucleotide compound ' of general formula of the present invention (I).Organic solvent can be selected dimethyl sulfoxide (DMSO), pyridine, acetonitrile, ether, dimethyl formamide, tetrahydrofuran (THF), 1-Methyl-2-Pyrrolidone, methylene dichloride, chloroform, benzene,toluene,xylene etc. for use, basic catalyst can be selected yellow soda ash, salt of wormwood, cesium carbonate, sodium hydride, potassium hydride KH, triethylamine, Trimethylamine 99, quinoline, pyridine, diazabicyclo undecylene, N for use, N-dichloro hexyl-4-morpholine carboxylic acid etc.Temperature of reaction can be-100-100 ℃, and preferred-50-50 ℃.Reaction times can be 0.5-24 hour, preferred 1-12 hour.Compound (V) and mol ratio (VI) can be 0.5-4, preferred 1-3.The phosphate nucleotide compound ' of the general formula that obtains at last (I) can obtain the phosphate nucleotide compound ' of the general formula (I) of purity＞90% at last by further separation and purification such as separation and purification means commonly used such as extraction, precipitation, distillation, crystallization, chromatographies.
The phosphate nucleotide compound ' of general formula of the present invention (I) can be used as antiviral, also can be used as antitumor drug.Virus Type as target spot does not have special qualification, and the specific examples of processed virus comprises hepatitis b virus hbv, hepatitis C virus, immunodeficiency virus (human immunodeficiency virus HIV, simian immunodeficiency virus SIV, feline immunodeficiency virus FIV etc.), simplexvirus (hsv, varicella zoster virus, cytomegalovirus etc.), Lao Sheershi murine leukemia virus (R-MuLV), mouse cytomegalovirus (MCMV), poxvirus, adenovirus etc.Preferably to human immunodeficiency virus HIV, hepatitis b virus hbv.
The compound of general formula of the present invention (I) can use separately as pharmaceuticals, also can form pharmaceutical composition with pharmaceutical carrier and uses, and also can form medicinal composition with other antiviral drug and use.They can be the various formulations that contain these compounds, as tablet, granule, micro mist agent, powder, dragee, emulsion, gelifying agent, paste, solution, sol, macromolecular solution agent, suspensoid, injection, capsule, pill, micropill, syrup, film, suppository, aerosol, sprays, drops, liposome, microballoon, preparation capable of permeating skin etc., also can be sustained-release preparation, targeting preparation etc.The available various administering mode administration of fitting is as oral, suction, injection, transdermal, cavity and mucosa delivery etc.
Pharmaceutical carrier is used for per os, through intestines, non-during, available various suitable organic or inorganic solid or liquid vehicles through intestines or local application.The used solid carrier of preparation solid dosage for example has lactose, sucrose, starch, talcum powder, Mierocrystalline cellulose, dextrin, kaolin, lime carbonate, agar, pectin, stearic acid, Magnesium Stearate, Yelkin TTS, sodium-chlor etc.The used liquid vehicle of liquid dosage form for oral use for example has glycerine, peanut oil, polyvinylpyrrolidone, sweet oil, ethanol, phenylcarbinol, propylene glycol, physiological saline, water etc., preparation during preparation except that above-mentioned carrier, also can add auxiliary material, for example wetting agent, suspension agent, sweetener, spices, pigment or sanitas.And liquid dosage form is when placing in the capsule, and capsule will be with adsorbable material as making with gelatin.Solvent that para-oral injection is used or suspension agent can be used for example water, propylene glycol, polyoxyethylene glycol, phenylcarbinol, ethyl oleate, Yelkin TTS etc.Above-mentioned various preparation can prepare according to a conventional method.
In various pharmaceutical dosage forms, oral administration is because medication is simple, thereby application is the most general, and kind and quantity account for first of the various formulations.Because compound of the present invention has very high oral absorption, so just meeting the requirement of oral administration.
Clinical consumption, becoming the human oral The compounds of this invention generally is 1-500mg every day, is preferably 5-100mg, according to age, the state of an illness, symptom, the whether suitably increase and decrease with other medicine is simultaneously taken 1 time or be divided into 2 times or repeatedly perhaps interval medication every day.
Below the present invention is specifically described with the embodiment form, but the present invention is not limited to following embodiment.
Embodiment 1: o.3 synthetic of compound N in the table one
In reactor, add 9-(2-phosphono methoxyethyl) VITAMIN B4 (PMEA) 10g, phenol 7g, triethylamine 5g and tetrahydrofuran (THF) 30g, reflux.Add N then, the two imidazoles 15g of N '-carbonyl.Continued back flow reaction 24 hours.Reaction solution is cooled to 25 ℃.Under reduced pressure reaction solution is condensed into filemot soup compound, adds water 18g then, and to regulate pH value with 25% NaOH solution be 11.Suspended solids is removed by the 1.5g diatomite filtration, then uses the 3g water wash.Mix filtrate and use ethyl acetate extraction.Water is adjusted to PH3.1 with 37% HCl solution, and 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 precipitation is filtered separation, and washs with methyl alcohol 10g.Product is pulp in 40g methyl alcohol, is filtered separation then, uses the 6g methanol wash again, and drying under reduced pressure obtains 9-(the 2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 (6.4g, productive rate 50%) of white solid.
In reactor, add 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 9g, DMF30g.Keep adding thionyl chloride 6g under mixture temperature＜50 ℃.With mixture heating up, back flow reaction 2 hours.Volatile matter 12g is collected in distillation under normal pressure.Resistates is cooled to 25 ℃, with the dilution of 40g methylene dichloride, and is chilled to-10 ℃.Methylene dichloride (35g) solution that adds ethyl lactate 7g then.Then add triethylamine 88g down at-10-0 ℃.Reaction mixture is heated to room temperature and with the dihydrogen phosphoric acid sodium solution of 10% concentration washing three times, consumption 20g at every turn.Organic solution 20g anhydrous sodium sulfate drying, filtration, and use the 30g eluent methylene chloride, under reduced pressure be condensed into an oily matter.20g acetone is added in the oily matter.Acetone soln is carried out separation and purification by column chromatography (230 to 400 silica gel 60).Chromatography column carries out wash-out with 500g acetone.Product behind the purifying under reduced pressure is condensed into oily.Add acetonitrile 20g in oily matter, mixture under reduced pressure concentrates.Add the 70g acetonitrile again, solution is cooled to 0-5 ℃ of 20h.Solid is filtered to be removed.Filtrate under reduced pressure concentrates and obtains pure compound table one NO.3 (5.8g, productive rate 50%).
Embodiment 2: o.5 synthetic of compound N in the table one
According to the same method of embodiment 1, in reactor, add 9-(2-phosphono methoxyethyl) VITAMIN B4 (PMEA) 10g, phenol 7g, triethylamine 5g and tetrahydrofuran (THF) 30g, reflux.Add N then, the two imidazoles 15g of N '-carbonyl.Continued back flow reaction 24 hours.Reaction solution is cooled to 25 ℃.Under reduced pressure reaction solution is condensed into filemot soup compound, adds water 18g then, and to regulate pH value with 25% NaOH solution be 11.Suspended solids is removed by the 1.5g diatomite filtration, then uses the 3g water wash.Mix filtrate and use ethyl acetate extraction.Water is adjusted to PH3.1 with 37% HCl solution, and 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 precipitation is filtered separation, and washs with methyl alcohol 10g.Product is pulp in 40g methyl alcohol, is filtered separation then, uses the 6g methanol wash again, and drying under reduced pressure obtains 9-(the 2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 (6.4g, productive rate 50%) of white solid.
In reactor, add 9-(2-benzene phosphine oxide acyl methoxyethyl) VITAMIN B4 9g, DMF30g.Keep adding thionyl chloride 6g under mixture temperature＜50 ℃.With mixture heating up, back flow reaction 2 hours.Volatile matter 12g is collected in distillation under normal pressure.Resistates is cooled to 25 ℃, with the dilution of 40g methylene dichloride, and is chilled to-10 ℃.Methylene dichloride (35g) solution that adds isopropyl lactate 7.8g then.Then add triethylamine 8g down at-10-0 ℃.Reaction mixture is heated to room temperature and with the dihydrogen phosphoric acid sodium solution of 10% concentration washing three times, consumption 20g at every turn.Organic solution 20g anhydrous sodium sulfate drying, filtration, and use the 30g eluent methylene chloride, under reduced pressure be condensed into an oily matter.20g acetone is added in the oily matter.Acetone soln is carried out separation and purification by column chromatography (230 to 400 silica gel 60).Chromatography column carries out wash-out with 500g acetone.Product behind the purifying under reduced pressure is condensed into oily.Add acetonitrile 20g in oily matter, mixture under reduced pressure concentrates.Add the 70g acetonitrile again, solution is cooled to 0-5 ℃ of 20h.Solid is filtered to be removed.Filtrate under reduced pressure concentrates and obtains pure compound table one NO.5 (6.0g, productive rate 50%).
Test example 1: anti-HBV experiment in vitro research
Utilize the human hepatoma cell strain Hep G2 2.2.15 cell of hepatitis b virus hbv DNA transfection, the external anti-HBV effect (HBV DNA quantitatively adopts fluorescence quantitative PCR method) of detection of drugs.With the cytotoxicity of tetramethyl-azo azoles salt (MTT) colorimetric analysis detection of drugs, the result is as follows:
Classes of compounds HBV-DNA50% synthesizes inhibition concentration (μ M) 50% cytotoxicity concentration (μ M)
?No.3 ????0.8 ????＞500
?No.5 ????0.8 ????＞500
?PMEA ????5.4 ????＞500
In a word, phosphonate-nucleotide compound of the present invention has good antiviral activity and lower toxicity, and oral absorption is good, and it will become effective medicine.

Claims (5)

1, a kind of novel phosphonic acid ester-nucleotide compound is characterized in that their structural formula is:
Figure A031154450002C1
In the formula: R1, R2 are respectively H or alkyl, described alkyl be C1-C6 alkyl promptly: methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl etc.; X1, X2 are respectively O, NH, S etc.
2, a kind of novel phosphonic acid ester-nucleotide compound according to claim 1, it is characterized in that its salt is: metal-salts such as lithium salts, sodium salt, sylvite, magnesium salts, calcium salt, inorganic acid salts such as amine salt, hydrochloride, hydrobromate, vitriol, nitrate, phosphoric acid salt such as ammonium salt, methylamine salt, dimethylamine salt, front three amine salt, dicyclohexyl amine salt; Or organic acid salt such as mesylate, benzene sulfonate, tosilate, acetate, propionic salt, tartrate, fumarate, maleate, malate, oxalate, succinate, Citrate trianion, benzoate, mandelate, cinnamate, lactic acid salt.
3, according to claim 1 and 2 described a kind of novel phosphonic acid ester-nucleotide compounds, it is characterized in that itself and its salt can be made into tablet, granule, micro mist agent, powder, dragee, emulsion, gelifying agent, paste, suspension agent, injection, capsule, syrup, film, sprays, liposome, microballoon, preparation capable of permeating skin, also can be made into sustained-release preparation, targeting preparation etc.
4, contain the pharmaceutical composition that right requires arbitrary compound and pharmaceutical carrier among the 1-3.
5, contain the antiviral that right requires arbitrary compound among the 1-3.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2908133A1 (en) * 2006-11-08 2008-05-09 Centre Nat Rech Scient NOVEL NUCLEOTIDE ANALOGUES AS ANTIVIRAL PRECURSOR MOLECULES
CN100415757C (en) * 2004-09-07 2008-09-03 天津大学 Acyclic nucleoside phosphonate compound containing nitrogen-oxygen bond, preparation method and application thereof
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
CN112979705A (en) * 2019-12-18 2021-06-18 华创合成制药股份有限公司 Nucleotide analogue compound and salt thereof, preparation method and pharmaceutical application thereof
CN117402189A (en) * 2018-01-10 2024-01-16 广东集宝医药技术有限公司 Aminophosphorus (phosphine) acid acetal and phosphorus (phosphine) acid acetal compounds

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100415757C (en) * 2004-09-07 2008-09-03 天津大学 Acyclic nucleoside phosphonate compound containing nitrogen-oxygen bond, preparation method and application thereof
FR2908133A1 (en) * 2006-11-08 2008-05-09 Centre Nat Rech Scient NOVEL NUCLEOTIDE ANALOGUES AS ANTIVIRAL PRECURSOR MOLECULES
WO2008056264A3 (en) * 2006-11-08 2008-10-30 Ct Nat De Rech Scient Cnrs Novel nucleotide analogues as percursor molecules for antivirals
US8884011B2 (en) 2006-11-08 2014-11-11 Centre National De La Recherche Scientifique-Cnrs Nucleotide analogues as precursor molecules for antivirals
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
CN117402189A (en) * 2018-01-10 2024-01-16 广东集宝医药技术有限公司 Aminophosphorus (phosphine) acid acetal and phosphorus (phosphine) acid acetal compounds
CN112979705A (en) * 2019-12-18 2021-06-18 华创合成制药股份有限公司 Nucleotide analogue compound and salt thereof, preparation method and pharmaceutical application thereof
CN112979705B (en) * 2019-12-18 2024-01-26 华创合成制药股份有限公司 Nucleotide analog compounds and salts thereof, preparation methods and pharmaceutical uses thereof

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