CN1223648A - Novel thiophene derivatives and drug compositions containing the same - Google Patents

Novel thiophene derivatives and drug compositions containing the same Download PDF

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CN1223648A
CN1223648A CN 97195963 CN97195963A CN1223648A CN 1223648 A CN1223648 A CN 1223648A CN 97195963 CN97195963 CN 97195963 CN 97195963 A CN97195963 A CN 97195963A CN 1223648 A CN1223648 A CN 1223648A
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hydrogen
azatropylidene
methyl
thienyl
title compound
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木村武德
村上猛
大森淳弥
森田琢磨
塚本绅一
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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Abstract

The present invention relates to thiophene derivatives of general formula (I) and pharmaceutically acceptable salts thereof. These compounds act as an anti-PCP agonist, thus being useful as psychotropic or antischizophrenic agents and so on. In said formula R1 is -A1-X1-R3; R2 is -A2-X2-R4 or nil; B is a four- to ten-membered nitrogenous cycloalkyl or a five- or six-membered nitrogenous unsaturated heterocycle; Ar is aryl or heteroaryl; A1, A2 and A3 are each independently a bond or lower alkylene; X1 and X2 are each independently a bond, -O-, -S- or the like; and R3 and R4 are each independently hydrogen, cyclic imido, lower alkyl, cycloalkyl, aryl or aralkyl, with the provisos that when Ar is a thiazole ring, at least either of A1 and A2 is lower alkylene and that when Ar is a benzene ring, compounds wherein one of R1 and R2 is methyl or halogeno and the other thereof is hydrogen are excepted.

Description

Novel thiophene derivant and medical composition thereof
Technical field
The present invention relates to medicine, particularly have the salt that allows on the thiophene derivant of novelty of anti-PCR (phencyclidine) effect or its pharmacopedics, and be the medicine of the anti-PCR effect of having of effective constituent with this derivative.
Background technology
As everyone knows, PCR can bring out and the similar mental symptom of schizoid each symptom [Am.J.Psychiat., 135,1081 (1987) Am.J.Phsychiat., 148,1301 (1991)] that comprises recessive symptom.On the other hand, if take PCR, then can bring out various abnormal behaviours to animal.Can think the medicine that can specificity suppresses the animal anomaly behavior (anti-PCR effect) that PCR brought out from the above-mentioned fact, as the schizoid medicine of people also useful [neural spiritual pharmacology, 15 (10), 651 (1993), BehavBrainRes, 74,45 (1996)].And, because PCR has nmda receptor blocking effect [J.Pharm.Exp.Thera., 238,938 (1986), Br.J.Pharmacol., 79,565 (1982)], so above-mentioned have the medicine of anti-PCR effect as weaken the memory that the disease that causes is a senile dementia because of nmda receptor function.The therapeutical agent of abnormal behaviour such as disturbance in cognition, delirium also useful [J.Neurochem., 54 (2), 526 (1990), LifeScience, 55 (25/26), 2147 (1994)].
In the past, mainly used dopamine receptor-blocking agent as schizoid medicine.But the Dopamine HCL blocker is not only to the poor effect of recessive symptom, but also has the problem [T.I.P.S., 13,116 (1992)] that side effects such as extrapyramidal symptoms occur.
Corresponding to this, specific anti-PCR medicine can improve the schizoid recessive symptom of using the Dopamine HCL blocker not prove effective, and it also has the advantage that does not cause the side effect of Dopamine HCL blocker sample.
At first, the thiophene derivant that present inventors have found to have the novelty of nitrogenous cycloalkyl low-grade alkyl has anti-PCR effect, this report to some extent in WO94/225450 communique or WO95/29910 communique.
In addition, in open the clear 62-192379 of communique number of Japanese Patent, put down in writing the compound that following general formula is represented,
(specific definition is with reference to above-mentioned communique)
Because used substituent difference is sometimes for having the thiophene derivant of nitrogenous cycloalkyl and thiazolyl.And, in open the clear 61-18178 of communique number of Japanese Patent, also put down in writing same compound.These two communiques have reported that also above-claimed cpd all has oxygen lack resistant function, anti-forgetful effect and angst resistance effect, and are also useful as the therapeutical agent or the antianxiety agent of dementia.But, more do not mention anti-PCR effect.
In addition, Journal ofthe Chemical Society, Perkin Transactions Pt.l:OrganicChemistry, 22,2355 (1976) have put down in writing the synthetic method of the compound that following general formula represents,
(specific definition is with reference to above-mentioned document)
But also show no sign of prompting or disclose anti-PCR effect.
The thiophene derivant of the novelty that logical formula I of the present invention is represented does not comprise the compound of open communique of aforementioned Japanese patent and document record, and, its structure also with the former open communique in the world of inventors in the compound that discloses obviously different.
The announcement of invention
Present inventors have carried out conscientiously research back discovery to the compound that has good anti-PCR effect specifically, have the salt that allows on the thiophene derivant of nitrogenous cycloalkyl low-grade alkyl (or nitrogenous unsaturated heterocycle) and aromatic ring or hetero-aromatic ring or its pharmacopedics and have good anti-PCR effect, thereby finished the present invention.
That is the salt that allows on the thiophene derivant of the novelty represented for logical formula I of the present invention or its pharmacopedics.
Figure A9719596300052
(symbol has following implication in the formula:
R 1: formula-A 1-X 1-R 3,
R 2: formula-A 2-X 2-R 4Or do not exist,
B ring: 1) 4～10 yuan of nitrogenous cycloalkyl rings or
2) 5～6 yuan of nitrogenous unsaturated heterocycles,
The Ar ring: can have substituent aromatic ring or comprise 1～4 heteroatomic 5～6 yuan of hetero-aromatic ring or 8～10 yuan of dicyclo class hetero-aromatic rings that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom more than a kind or 2 kinds,
A 1, A 2And A 3: identical or different key or low-grade alkylidene,
X 1And X 2: identical or different key, formula-O-,-S-,-NR 5-,
Figure A9719596300061
Or-C ≡ C-,
R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13: be hydrogen atom or low alkyl group identical or differently,
R 3And R 4: be hydrogen atom identical or differently, can have substituent substituent low alkyl group, cycloalkyl, the aryl or aralkyl of can maybe can having respectively with the cyclic imide base of phenyl ring condensation,
But, when the Ar ring is thiazole ring, A 1And A 2In any be low-grade alkylidene, in addition, Ar ring is during for phenyl ring, R 1And R 2In any be methyl or halogen, another is for except the situation of hydrogen atom)
Another object of the present invention provides the medical composition of being made up of the carrier that allows on salt that allows on above-mentioned thiophene derivant (I) or its pharmacopedics and the pharmacopedics.And this medical composition is the medicine with anti-PCR effect.
Be preferably, above-mentioned medicine with anti-PCR effect is psychotropic drug or antischizophrinic thing.And above-mentioned anti-PCR drugs with function is the therapeutical agent that nmda receptor function weakens associated diseases, i.e. dementia remedies, improve dull-witted with medicine, the therapeutical agent of children's's hyponea and/or the therapeutical agent of autism of abnormal behaviour.
The feature of salt on chemical structure that allows on thiophene derivant or its pharmacopedics shown in the logical formula I of the present invention is by the thiophene derivant of nitrogenous cycloalkyl low-grade alkyl (or low alkyl group of nitrogenous unsaturated heterocycle base replacement) and aromatic ring or hetero-aromatic ring replacement, and the feature on its pharmacology is also to improve the schizoid recessive symptom of using dopamine receptor-blocking agent not prove effective.
The salt that allows on thiophene derivant shown in the logical formula I or its pharmacopedics was not all put down in writing in any aforementioned open communique and document, was to have in the above-mentioned open communique etc. fully the not compounds of the new effect of record.
That is, The compounds of this invention (I) is at Ar ring substituents R 1And R 2Definition on, clearly removed the compound of putting down in writing in aforementioned open communique and the document.
Below, The compounds of this invention is elaborated.
There is no particular limitation for " rudimentary " speech of using when general formula of the present invention is defined, and the expression carbonatoms is the carbochain of 1～6 straight or branched.
So, " low alkyl group " can enumerate methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, 1-methyl butyl, 2-methyl butyl, 1,2-dimethyl propyl, hexyl or isohexyl particularly.
A 1, A 2And A 3" low-grade alkylidene " of expression can exemplify methylene radical, ethylidene, methyl methylene radical, propylidene, methyl ethylidene, butylidene, methyl propylidene, pentylidene or hexylidene particularly, is preferably carbonatoms and is 1～4 alkylidene group.A 3" low-grade alkylidene " of expression comprises above-mentioned group, and wherein best is methylene radical.
R 3And R 4" cycloalkyl " of expression is meant 3～8 yuan of monocycle alkyl, specifically comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group etc., is preferably cyclohexyl.
" aryl " is meant isocyclic aryl, specifically comprises benzene, biphenyl, naphthalene, anthracene or phenanthrene etc., is preferably phenyl.
" aralkyl " is meant that any hydrogen atom of aforementioned " low alkyl group " is replaced by phenyl or naphthyl and the group that obtains, specifically comprise phenmethyl, styroyl, hydrocinnamyl, methylbenzene ethyl, benzene butyl, methylbenzene propyl group, ethylbenzene ethyl, dimethyl benzene ethyl, benzene amyl group, methylbenzene butyl, benzene hexyl, methylbenzene amyl group, menaphthyl, naphthalene ethyl, naphthalene propyl group, naphthalene butyl, naphthalene amyl group or naphthalene hexyl etc., be preferably phenmethyl.
Be preferably " 4～10 yuan of nitrogenous cycloalkyl rings " in " 1) 4～10 yuan of nitrogenous cycloalkyl rings or 2) 5～6 yuan of nitrogenous unsaturated heterocycles " of B ring expression." 4～10 yuan of nitrogenous cycloalkyl rings " specifically is meant azetidine, tetramethyleneimine, piperidines, six hydrogen azatropylidenes, octahydro azocine, octahydro azonine or decahydro azecine etc., and wherein best is six hydrogen azatropylidenes." 5～6 yuan of nitrogenous unsaturated heterocycles " is meant and comprises 1～4 nitrogen-atoms as heteroatomic 5～6 yuan of unsaturated rings, specifically comprise pyrroles, imidazoles, triazole, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, pyrazine, triazine etc., is preferably imidazoles.
Specifically comprise the pyrroles " comprise respectively more than a kind or 2 kinds and be selected from nitrogen-atoms; 1～4 heteroatomic 5～6 yuan of hetero-aromatic ring or 8～10 yuan of bicyclic ring system hetero-aromatic rings of Sauerstoffatom and sulphur atom " of Ar ring expression, imidazoles, triazole, furans oxazole isoxazole oxadiazole, thiophene, thiazole, isothiazole, thiadiazoles, pyridine, pyridazine, pyrimidine, pyrazine, triazine, indoles, isoindole, benzoglyoxaline, benzotriazole, cumarone benzoxazole, benzoisoxazole Ben Bing oxadiazole, thionaphthene, benzothiazole, benzisothiazole, diazosulfide, quinoline, isoquinoline 99.9, the benzo pyridazine, the benzo pyrimidine, benzopyrazines, phentriazine, imidazopyridine, imidazopyrimidine, Triazolopyridazines etc., be preferably triazole oxadiazole, thiazole, thiadiazoles, imidazopyridine, imidazopyrimidine, Triazolopyridazines, best is that triazole is with oxadiazole.
R 3And R 4" can with the cyclic imide base of phenyl ring condensation " of expression specifically comprises succinimido, glutaryl imino-, phthalimido etc.
R 3And R 4" substituting group " in expression " can have and substituently can maybe can have substituent low alkyl group respectively with the cyclic imide base of phenyl ring condensation; cycloalkyl; aryl or aralkyl " specifically comprises halogen atom; hydroxyl; lower alkoxy; acyloxy; carbamoyloxy; one or the two elementary alkyl amido methanoyl; amino; one or two elementary alkyl amido; amido; carbamyl amino; one or the two elementary alkyl amido formamido group; carboxyl; elementary alkoxy carbonyl; formamyl; one or the two elementary alkyl amido formyl radical; cyano group; nitros etc. are preferably halogen atom; nitro; hydroxyl and lower alkoxy.
" halogen atom " is meant fluorine atom, chlorine atom, bromine atoms and iodine atom, is preferably fluorine atom and chlorine atom.
" lower alkoxy " is meant that carbonatoms is 1～6 straight or branched alkoxyl group, specifically comprise methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyl oxygen, uncle's pentyloxy etc., be preferably methoxyl group.
" acyl group " in " acyloxy " or " amido " is meant low-grade alkane acidyl or aroyl, specifically comprises formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, pivaloyl, caproyl, tertiary butyl ethanoyl, benzoyl, toluyl, methoxybenzoyl base and naphthalene carbonyl etc.
The compounds of this invention (I) also can carry out addition reaction and salify with acid.The salt that forms with acid comprises the acid salt that forms with mineral acid such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid or organic acids such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, citric acid, tartrate, carbonic acid, picric acid, methylsulfonic acid, ethyl sulfonic acid or L-glutamic acid.
Also can form salt, the additive salt that forms with organic basess such as mineral alkali such as lithium, sodium, potassium, magnesium, calcium or aluminium or methylamine, ethamine, thanomins for example, or the salt or the ammonium salt that form with basic aminoacidss such as Methionin or ornithines with alkali.
In addition, because The compounds of this invention comprises chiral carbon atom sometimes, so there is optically active isomer based on this chiral carbon atom.And, when 2 above chiral carbon atoms are arranged, also there is non-corresponding isomer.The present invention includes these mixture of isomers and monomer.
The isolated in form of various solvates such as The compounds of this invention (I) or its salt can also hydrates, ethanol compound or polymorphic material is come out, and The compounds of this invention comprises these hydrates, solvate and polymorphic material.
Being preferably the B ring in the The compounds of this invention (I) is the compound of 4～10 yuan of nitrogenous cycloalkyl rings, and good especially compound is that the B ring is the compound and/or the A of six hydrogen azatropylidenes 3Be the compound of methylene radical, better compound is the compound of Ar ring for triazole, oxadiazole, thiazole, thiadiazoles, imidazopyridine, imidazopyrimidine or Triazolopyridazines, and best compound is that Ar is the compound of triazole Huo oxadiazole.
Special ideal compound is 5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-3-phthaloyl sub-aminoethyl-1,2,4-oxadiazole, 5-amino-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the salt that allows on 4-triazole or its pharmacopedics.
More than, the The compounds of this invention among the application is illustrated, they all are included in the The compounds of this invention.
The preparation method
Utilization adopts various suitable synthetic methods can make the salt that allows on The compounds of this invention (I) and the pharmacopedics thereof based on the basic framework of the salt that allows on The compounds of this invention (I) and the pharmacopedics thereof or the feature of substituting group kind.Here on technology of preparing effectively means be as required, amino in the The compounds of this invention etc. to be replaced by the functional group that suitable protecting group can easily change amino groups into.These protecting groups also have the protecting group of being put down in writing in " Protective Groups in OrganicSyntheses " that for example Green and Wuts write the 2nd edition except aforesaid amino protecting group, according to different reaction conditionss, can suitably select for use.In addition, the above-mentioned protecting group functional group in addition that can easily change nitro, amino groups into also can use with protecting group the samely.
Below, the preparation method of representative The compounds of this invention is enumerated.
The preparation method 1
Figure A9719596300091
(in the formula, B ring and A 3As previously mentioned, R 14Be low alkyl group, R 15Be low alkyl group amino or that have protected hydroxyl.This moment, spendable protecting group comprised acetal radicals such as silyls such as phenmethyl, diphenyl-methyl, trityl, aroyl, low-grade alkane acidyl, t-butyldimethylsilyl, THP trtrahydropyranyl etc.)
Ester cpds and the reaction of amidoxime compound that logical formula II is represented just can make The compounds of this invention (Ia).
This reaction can in the presence of alkali such as diisopropylaminoethyl lithium, two (trimethyl silyl) lithium amide, sodium hydride, be carried out under cooling-reflux condition in organic solvents such as tetrahydrofuran (THF), ether, diox.
R 15Deprotection reaction during for protected hydroxyl can carry out according to common method; for example; phenmethyl class protecting group can utilize reduction, oxidation or under acidic conditions hydrolysis remove; acyl group class protecting group can be removed under acidity or alkaline condition in hydrolysis; the silyl protecting group can be removed with fluorion, and the acetals protecting group can utilize acidic conditions to remove.
Figure A9719596300092
(in the formula, B ring and A 3As previously mentioned, X represents halogen atom.)
In addition, ester cpds and the reaction of amidoxime compound that the halo acyl compounds of representing with general formula (II ') replaces logical formula II to represent also can make The compounds of this invention.At this moment, reaction can in the presence of organic basess such as triethylamine, diisopropylethylamine, at room temperature be carried out in tetrahydrofuran (THF), diox, chloroform, methylene dichloride, benzene, toluene equal solvent.
The preparation method 2
Figure A9719596300102
Figure A9719596300103
Figure A9719596300104
Figure A9719596300105
(in the formula, B ring and A 3As previously mentioned, but Y represents leaving groups such as halogen atom, tolysulfonyl oxygen base, methoxyl group, succinimide oxygen base, R 16And R 18Expression can have the identical or different protected amino or the low alkyl group or the aralkyl of hydroxyl, R 17The expression low alkyl group.The protecting group here as previously mentioned.)
Nitrile compound and sodium alkoxide reaction that logical formula III is represented obtain cyano amidine derivative (IV) with the cyanamide reaction then, make (IV) and oxammonium hydrochloride reaction again; Or making (III) and hydrazine and N, dinethylformamide reacts; Or make (III) and oxammonium hydrochloride reaction obtain amidoxime derivative (V), make (V) and ester cpds or anhydride reaction again; Or make the reaction of (III) and hydrogen sulfide obtain thioamide derivatives (VI), and make (VI) and ketone derivatives reaction again, just can make The compounds of this invention (I b～e).
Can to the reflux condition, carry out in room temperature with the reaction of sodium alkoxide, can under organic solvents such as tetrahydrofuran (THF), diox or condition of no solvent, carry out with the reaction of cyanamide.Can use tetrahydrofuran (THF), diox, methyl alcohol, ethanol equal solvent with the reaction of azanol, in the presence of organic basess such as triethylamine, diisopropylethylamine or mineral alkalis such as sodium hydroxide, potassium hydroxide, to the reflux condition, carry out in room temperature.Can use DMF, tetrahydrofuran (THF), diox equal solvent with the reaction of hydrazine, under the reflux condition, carry out.Can use tetrahydrofuran (THF), diox, chloroform, methylene dichloride, benzene, toluene equal solvent with the reaction of ester, carboxylic acid halides or acid anhydrides, in the presence of mineral alkalis such as organic basess such as triethylamine, diisopropylethylamine or sodium hydride or under the neutrallty condition, to the reflux condition, carry out ice-cooled.Can use pyridine, tetrahydrofuran (THF), diox equal solvent with the reaction of hydrogen sulfide, in the presence of organic basess such as triethylamine, diisopropylethylamine, carry out.Can use methyl alcohol, ethanol equal solvent with the reaction of ketone compound, to the reflux condition, carry out in room temperature.
The preparation method 3
Figure A9719596300111
Figure A9719596300112
Figure A9719596300113
Figure A9719596300114
Figure A9719596300121
Figure A9719596300122
Figure A9719596300123
(in the formula, B ring and A 3As previously mentioned, R 19And R 22Represent low alkyl group or aralkyl, R identical or differently 20Expression hydrogen atom or low alkyl group, R 21And R 23The expression low alkyl group.)
Make the hydrazide compound and the sulfuric acid S-methyl-isothiourea of general formula (VII) expression, cyanamide, after various lsothiocyanates, Tetrafluoroboric acid carbonyl lower alkoxy-2-methyl azomethine or imido-ester or imido-ester react than compound, cyclisation; Or the reaction of (VII) and bromine cyanic acid, just can make The compounds of this invention (If～j).
With the reaction of sulfuric acid S-methylthiourea or cyanamide can methyl alcohol, ethanol etc. carries out to the reflux condition in room temperature for solvent, also can use mineral alkalis such as sodium hydroxide and potassium hydroxide in the reaction.Can use methyl alcohol, ethanol, THF, diox, ether, methylene dichloride equal solvent with the reaction of lsothiocyanates.Carry out to the reflux condition in room temperature.Can use THF, diox, ether, methylene dichloride equal solvent with the reaction of Tetrafluoroboric acid carbonyl lower alkoxy-2-methyl azomethine or imidate compound, in the presence of organic basess such as triethylamine, diisopropylethylamine, carry out.Cyclization can use methyl alcohol, ethanol equal solvent or not use solvent, under neutrallty condition, or under acidic conditionss such as the vitriol oil, acetate, toluenesulphonic acids, trifluoroacetic acid, ammonium chloride, or under alkaline conditions such as sodium hydroxide, potassium hydroxide, to reflux, carry out in room temperature.
And, the halo acyl compounds of aforementioned formula (II ') expression and aminoguanidine are reacted, be intermediate with the compound of general formula (VIII), also can make The compounds of this invention (If).
The preparation method 4
Figure A9719596300131
(in the formula, B ring and A 3As previously mentioned.)
Make the carboxylic acid cpd activation of general formula (XII) expression, make itself and cyanamide reaction obtain compound (X IV) again, make (X IV) and azanol reaction then, just can make The compounds of this invention (Ib).
Activation can change halogenide, acid anhydrides or succinimide ester into according to common method.The reaction of the acid derivative that is activated (X III) and cyanamide can be used organic solvents such as tetrahydrofuran (THF), diox, chloroform, methylene dichloride, benzene, toluene, carries out in the presence of mineral alkalis such as organic bases such as triethylamine, diisopropylethylamine or sodium hydride.Can carry out according to preparation method 2 condition with the reaction of azanol.
The preparation method 5
Figure A9719596300135
(in the formula, B ring and A 3As previously mentioned, R 23And R 24The expression low alkyl group.)
Make the amide derivatives and the N of general formula (X V) expression, dinethylformamide methylal and cyanamide reaction obtain compound (X VI), make (X VI) and hydroxylamine-o-sulfonic acid or hydrazine compound reaction then, just can make The compounds of this invention (Ik and Ii).
With N, the reaction of dinethylformamide methylal can DMF be that solvent carries out to heating condition in room temperature.Can in organic solvents such as methyl alcohol, ethanol, in the presence of organic basess such as pyridine, triethylamine, diisopropylethylamine, to the reflux condition, carry out with the reaction of hydroxylamine-o-sulfonic acid in room temperature.With the reaction of hydrazine compound can acetate etc. organic acid be solvent, carry out to the reflux condition in room temperature.
The preparation method 6
Figure A9719596300141
Figure A9719596300142
(in the formula, B ring and A 3As previously mentioned, R 25Expression low alkyl group or aralkyl.)
Make the acetyl derivative and the aminotriazole reaction of general formula (X VII) expression,, make (X IX) cyclisation of gained again, just can make The compounds of this invention (Im) then with tert.-butoxy two (dimethylamino) methane reaction.
The dehydration reaction of aminotriazole can be used benzene or toluene equal solvent, under acidic conditionss such as acetate, toluenesulphonic acids, trifluoroacetic acid, carries out to the reflux condition in room temperature.Cyclization can carry out according to preparation method 3 condition.
The preparation method 7
Figure A9719596300143
Figure A9719596300144
(in the formula, B ring, A 3With Y as previously mentioned, R 26Expression low alkyl group or aralkyl, Z represents CH or N, n represents 3～9.)
Make ketone compound and the 2-aminopyridine or the reaction of 2-aminopyrimidine of general formula (XX) expression, remove phthaloyl then, form cyclammonium, just can make The compounds of this invention (In).
Can use methyl alcohol, ethanol equal solvent with the reaction of 2-aminopyridine or 2-aminopyrimidine, to the reflux condition, carry out in room temperature.The deprotection reaction of phthaloyl can carry out according to common method.For example, adopt the method for having used pyridazine, methylamine etc.The reaction that forms cyclammonium can be adopted the alkylated reaction of amine according to a conventional method.For example, use propyl alcohol, butanols, tetrahydrofuran (THF), diox equal solvent, in the presence of mineral alkalis such as salt of wormwood, to the reflux condition, carry out with the dihalo alkylene in room temperature.For the carrying out that promotes to react, can add potassiumiodide etc.
The preparation method 8 (in the formula, B ring, A 3, Ar, R 1, R 2As previously mentioned.)
After making the thiophene compound metallization of general formula (XX III) expression, itself and iodide are reacted, just can make The compounds of this invention (Io).
This reaction can be used hexane, tetrahydrofuran (THF), ether and toluene equal solvent, in the presence of two (triphenyl phosphine) nickel of chlorination, diisobutylaluminium hydride, n-Butyl Lithium and zinc chloride, carries out to room temperature at-80 ℃.
The The compounds of this invention (I) that is made to preparation method 8 by preparation method 1 has various substituting groups, it is modified also can make The compounds of this invention.For example, according to common method, can carry out modifications such as amidation, urethane, ureaization to having amino substituent compound; Or, the compound with ester group or carboxyl substituent is carried out amidation restore into modifications such as alcohol according to common method.According to common method, can carry out esterification, carbonic acid esterification, urethane etc. to the hydroxyl of group with hydroxyl.And, make hydroxyl and phthalic imidine carry out the Mitsunobu reaction, slough phthaloyl according to preparation method 7 condition then, just can make hydroxyl change amino into.
The The compounds of this invention that more than makes can free form, the form of its salt, its hydrate, its solvate or polymorphic material separation and purification in addition, and the salt of compound (I) can make according to the salt-forming reaction of routine.
Conventional chemical operation such as separation and purification can adopt extraction, concentrates, distillation, crystallization, filtration, recrystallization, various chromatography.
By selecting suitable starting compound or utilizing physical properties difference between isomer, separable various isomer.For example, by selecting suitable raw material or utilizing the racemize Split Method (for example, general and the alkali with opticity form the method for optical resolution of diastereomeric salt etc.) of racemic compound can make the pure isomer of stereochemistry.
The possibility of utilizing on the industry
Because The compounds of this invention (I) has special anti-PCR effect, can improve weakening of nmda receptor function, so, based on this, as psychotropic drug, the antischizophrinic thing, the antidementia agent of treatment degenerative brain disorder, the medicine that improves the medicine of the abnormal behaviours such as delirium follow dementia and/or children's's hyponea and autism is of great use.
Utilize following test method can confirm the anti-PCR effect of The compounds of this invention (I).
Anti-PCR effect test
Experimental technique
(body weight 200～300g) subcutaneous injection PCR (3mg/kg) are after 30 minutes, with its porose plank device of packing into (HBA, hole board apparatus) to give Wistar male rat (n=8).Subcutaneous injection compound (10mg/kg) under test in 15 minutes behind injection PCR.HBA is that 16 diameters are arranged is the hole of 4cm in the bottom, and the wall of high 20cm is arranged on every side, all is the shedding motion [Psychopharmacology, 52,271 (1977)] of 40cm in length and breadth.
Measure amount of exercise (number of times (Locomotion) that moves in the bottom that is divided into 9 parts) and the exploratory behavior (head stretches into the number of times (Dipping) in the hole) of the rat among the HBA after 5 minutes.In addition, with subcutaneous injection the Wistar male rat (n=8) of PCR (3mg/kg) be control group.
This pharmacological testing shows that the phenomenon that amount of exercise increases and exploratory behavior reduces that The compounds of this invention causes PCR has the antagonistic action (with Mann-Whitney U-test, comparing with control group) (following table) of statistical significance.
Table 1
Embodiment 34 Amount of exercise increases 10mg/kg·sc ????(P＜0.01)
Exploratory behavior reduces 10mg/kg·sc ????(P＜0.05)
The carrier, vehicle and other additives that use common preparation to use, can with contain The compounds of this invention more than a kind or 2 kinds (I) or its salt be the preparation of effective constituent make tablet, lozenge, pulvis, microgranules, granule, capsule, pill, per os with solution (comprising syrup), injection, inhalation, suppository, through skin with solution, ointment, through skin with patch, through mucous membrane with patch (for example applicator oral cavity in), through mucous membrane with solution (for example intranasal solution) but etc. per os or without for oral use.
The peroral administration solids composition of the present invention can be used tablet, pulvis, granule etc.Active substance and at least a kind of inert diluent more than a kind or a kind have been mixed in these solids compositions, as lactose, mannitol, glucose, hydroxypropylcellulose, Microcrystalline Cellulose, starch, polyvinylpyrrolidone, silicoaluminate magnesium.According to conventional methods, also can comprise the additive beyond the inert diluent in the composition, as disintegrating agents such as lubricant such as Magnesium Stearate and glycolic cellulose calcium, stablizers such as lactose, solubilizing agent and solubility promoters such as L-glutamic acid or aspartic acid.If necessary, also can carry out dressing in gastric solubilities such as tablet or pill external application sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or enteric film.
Peroral administration liquid composition comprises opacifying agent, solution, suspensoid, syrup and the elixir etc. that allow on the pharmaceutics, wherein comprises inert diluent commonly used, as Purified Water, ethanol etc.Except inert diluent, also can comprise auxiliary agents such as solubilizing agent and solubility promoter, wetting agent, suspension agent in this composition, and sweeting agent, correctives, perfume compound and sanitas.
Para-oral injection comprises sterile aqueous or non-aqueous solution agent, suspensoid, opacifying agent.The thinner of aqueous solution agent and suspensoid comprises distilled water for injection and physiological saline.The thinner of water-insoluble solution and suspensoid comprises propylene glycol, polyoxyethylene glycol, olive wet goods vegetables oil, alcohols such as ethanol, tween 80 (trade(brand)name) etc.Also can comprise additives such as isotonic agent, sanitas, lubricant, emulsifying agent, dispersion agent, stablizer (for example lactose), solubilizing agent and solubility promoter in these compositions.They can pass through the bacteriological filtration membrane filtration, are used antiseptic-germicide or reach the asepticize purpose by irradiation.Also they can be made aseptic solid composite, be used after with sterilized water or aseptic injection before use with dissolution with solvents.
The clinical administration amount of The compounds of this invention can suitably be selected according to the different works of patient's situations such as symptom, body weight, age, sex and route of administration.Usually per day for adults 0.1～1000mg/kg during oral administration is preferably 1～200mg, and general every day of the 0.1～100mg that is grown up during intravenous injection is preferably 0.3～30mg, but single administration or divide 2～4 administrations.
The optimum regime that carries out an invention
Below disclose prescription example and embodiment, the present invention is described in more detail.But the present invention is not limited to these embodiment.
Prescription example (tablet)
Form the 20mg tablet
The compounds of this invention 20mg
Lactose 75
W-Gum 16
Hydroxypropylcellulose 4.5
Calcium carboxymethylcellulose 8.8
Magnesium Stearate 0.7
Add up to 120mg
The 20mg tablet
With this compound of 100g, 375g lactose, 80g W-Gum uniform mixing, spray into 10% hydroxypropyl cellulose solution 225g with the fluidized granulation coating device then therein, carry out granulation.After the drying, crossing 20 mesh sieves, add 19g calcium carboxymethylcellulose and 3.5g Magnesium Stearate then therein, mix, use Rotarytabletpress, is the tablet of 120mg with every of the drift extrusion of 7mm * 8.4R.
Embodiment 1
1-[5-(3-benzyl-1,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
With 535mg (2.0mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl]-carboxylic acid, ethyl ester and 360mg (2.4mmol) 2-phenyl acetyl amidoxime be dissolved in the 20ml tetrahydrofuran (THF), add 120mg (3.0mmol) sodium hydride under the room temperature, reflux 2 hours.After filtering insolubles, decompression is concentrated filtrate down.Add entry then in residue, use ethyl acetate extraction, organic layer is used anhydrous magnesium sulfate drying after with the saturated common salt water washing.Boil off solvent under the decompression, the residue obtained silica gel column chromatography of using obtains the free type title compound of 343mg with chloroform-methanol (80: 1) wash-out.This free type compound of 960mg (2.72mmol) is dissolved in the 30ml ethyl acetate, drips 4N HCl/AcOEt 0.7ml (2.8mmol) then, the acetonitrile recrystallization is used in the crystallization that leaching is separated out, and obtains the 690mg title compound.
Fusing point: 189～192 ℃
1H-NMR(δppm,DMSO-d 6)
1.53-1.59(2H,m),1.65-1.67(2H,m),1.82-1.85(4H,m),3.02-3.08(2H,m),3.41(1H,br),4.15(2H,s),4.64(2H,d,J=5.5Hz),7.27(1H,m),7.34(4H,br),7.63(1H,d,J=3.7Hz),7.97(1H,d,J=3.7Hz),11.36(1H,br)
Embodiment 2
1-[5-(3-styroyl-1,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
Raw material is 1.34g (5.0mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl]-carboxylic acid, ethyl ester and 985mg (6.0mmol) 3-phenyl propionyl amidoxime, operation similarly to Example 1 obtains the 650mg title compound.
Fusing point: 180～182 ℃
1H-NMR(δppm,DMSO-d 6)
1.56-1.60(2H,m),1.66-1.68(2H,m),1.84(4H,br),3.03-3.09(6H,m),4.66(2H,d,J=4.9Hz),7.21(1H,m),7.26-7.30(4H,m),7.64(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.24(1H,br)
Embodiment 3
1-[5-[3-(3-hydrocinnamyl)-1,2,4-oxadiazole-5-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
Raw material is 1.34g (5.0mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl]-carboxylic acid, ethyl ester and 1.07g (6.0mmol) 4-phenyl butyryl amidoxime, operation similarly to Example 1 obtains the 560mg title compound.
Fusing point: 174～176 ℃ (acetonitrile)
1H-NMR(δppm,DMSO-d 6)
1.55-1.60(2H,m),1.64-1.67(2H,m),1.83(4H,br),1.98-2.04(2H,m),2.66-2.69(2H,m),2.74-2.77(2H,m),3.05-3.09(2H,m),4.66(2H,d,J=5.5Hz),7.18-7.31(5H,m),7.62(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.07(1H,br)
Embodiment 4
1) methyl 5-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-3-tetrahydro-pyran oxy methyl isophthalic acid, 2, the 4-oxadiazole
Raw material is 8.0g (29.9mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl]-carboxylic acid, ethyl ester and 6.3g (35.9mmol) 2-(tetrahydro-pyran oxy) acetyl amidoxime, operation similarly to Example 1 obtains the 4.4g title compound.
1H-NMR(δppm,DMSO～d 6)
1.55-1.90(10H,m),2.60-2.70(4H,m),3.30-3.73(3H,m),3.85～4.23(4H,m),4.70(1H,d,J=13.4Hz),4.80-4.96(3H,m),6.95(1H,d,J=3.7Hz),7.75(1H,d,J=3.7Hz)
2) methyl 5-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2,4-oxadiazole-3-methyl alcohol
1) drip 1N HCl75ml (75mmol) among the ethanolic soln 80m1 of gained compound 6.23g (16.74mmol), stirred 4 hours under the room temperature.The concentrating under reduced pressure reaction solution adds 1NNaOH80ml in residue obtained then, uses ethyl acetate extraction, organic layer saturated common salt water washing.Use the anhydrous magnesium sulfate drying organic layer again, then, the pressure reducing and steaming solvent, the residue obtained silica gel column chromatography of using with chloroform-methanol (75: 1) wash-out, obtains the 3.76g title compound.
Fusing point: 79～81 ℃ (isopropyl ether)
1H-NMR(δppm,DMSO-d 6)
1.58-1.78(9H,m),2.68-2.70(4H,m),3.88(2H,m),3.88(2H,s),4.83(2H,s),6.96(1H,d,J=3.7Hz),7.75(1H,d,J=3.7Hz)
Embodiment 5
1-[5-(3-benzyloxymethyl-1,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
In 0 ℃ argon gas stream, in the tetrahydrofuran (THF) suspension 10ml of 118mg (2.94mmol) sodium hydride, drip 820mg (2.8mmol) embodiment 4-2) the tetrahydrofuran solution 20ml of compound, stirred 15 minutes.Add 0.35ml (2.94mmol) bromotoluene and 10mg tetrabutylammonium iodide, in stirring at room 16 hours.Add water then in reaction solution, use ethyl acetate extraction, organic layer is used anhydrous magnesium sulfate drying after using the saturated common salt water washing.The pressure reducing and steaming solvent, the residue obtained silica gel column chromatography of using with chloroform-methanol (80: 1) wash-out, obtains free type title compound 580mg.Add 4N HCl/AcOEt 0.3ml then, acetonitrile-re-crystallizing in ethyl acetate is used in the crystallization that leaching is separated out again, obtains the 467mg title compound.
Fusing point: 166～168 ℃
1H-NMR(δppm,DMSO-d 6)
1.55-1.60(2H,m),1.65-1.67(2H,m),1.84(4H,br),3.04-3.12(2H,m),4.63(2H,s),4.67-4.69(2H,m),4.71(2H,s),7.33(1H,m),7.37(5H,m),7.65(1H,d,J=3.7Hz),8.03(1H,d,J=3.7Hz),11.21(1H,br)
Embodiment 6
Phenylformic acid [5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-2-thienyl]-1,2,4-oxadiazole-3-yl] methyl esters 1.0 oxalate
With 450mg (1.53mmol) embodiment 4～2) compound be dissolved in the 30ml methylene dichloride, add 0.32ml (2.3mmol) triethylamine, 0.21ml (1.84mmol) Benzoyl chloride then, one evening of stirring at room.After the washing of reaction solution process, the organic layer anhydrous magnesium sulfate drying.Behind the pressure reducing and steaming solvent, the residue obtained silica gel column chromatography of using with chloroform-methanol (75: 1) wash-out, obtains the free type title compound of 550mg.The above-mentioned free type compound of 180mg (0.453mmol) is dissolved in the 5ml methyl alcohol, adds the methanol solution 5ml of 40mg (0.44mmol) oxalic acid then, in stirring at room 10 minutes, the pressure reducing and steaming solvent, then, in residue obtained, add small amount of methanol, ether, make it crystallization.The leaching crystallization, drying obtains the 166mg title compound.
Fusing point: 120～121 ℃
1H-NMR(δppm,DMSO-d 6)
8.03-8.01(2H,m),7.97(1H,d,J=3.7Hz),7.72(1H,m),7.59-7.56(2H,m),7.34(1H,d,J=3.7Hz),5.56(2H,s),4.28(2H,s),2.93(4H,brs),1.70(4H,brs),1.59(4H,brs)
Embodiment 7
N-benzylamino formic acid [5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-2-thienyl]-1,2,4-oxadiazole-3-yl] methyl esters 1.0 oxalate
With 480mg (1.64mmol) embodiment 4)-2 compound is dissolved in 10ml N, in the dinethylformamide, drip the N of 162mg (1.64mmol) cuprous chloride and 229mg (1.72mmol) benzyl mustard oil then, dinethylformamide solution 5ml is one evening of stirring at room.The concentrating under reduced pressure reaction solution is dissolved in chloroform with residue, and dried over mgso is used in washing again.The pressure reducing and steaming solvent, refining residue obtained with silica gel column chromatography, obtain the free type title compound of 690mg.Get above-mentioned free type compound of 520mg and 104mg oxalic acid, operation is carried out to reactant salt similarly to Example 6, obtains the 398mg title compound.
Fusing point: 129～130 ℃
1H-NMR(δppm,DMSO-d 6)
8.05(1H,t),7.94(1H,d),7.32-7.22(6H,m),5.23(2H,s),4.26-4.22(4H,m),2.92(4H,br),1.70(4H,brs),1.59(4H,brs)
Embodiment 8
1-[5-(3-aminomethyl-1,2,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene 2 hydrochlorides
Under ice-cooled, at 2.0g (6.82mmol) embodiment 4-2) the tetrahydrofuran solution 50ml of compound in add 1.1g (7.5mmol) phthalic imidine, 1.97g (7.5mmol) triphenyl phosphine and 1.31g (7.5mmol) diethylazodicarboxylate, stirred 2 hours under the room temperature.The concentrating under reduced pressure reaction solution is dissolved in the 50ml ethanol residue obtained, drips 3.3ml (68.2mmol) hydrazine-hydrate then, stirs 2 hours under the room temperature.The concentrating under reduced pressure reaction solution adds 1N HCl in residue obtained, make it become acidity after, clean with chloroform.Then, in water layer, add the 4N aqueous sodium hydroxide solution, make it change alkalescence into after, use ethyl acetate extraction, organic layer with saturated aqueous common salt clean after, use anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, the residue obtained silica gel column chromatography of using obtain the free type title compound of 1.86g with chloroform-methanol (30: 1) wash-out.In the free type compound of 400mg, add 1N HCl then, make its salify, use the Virahol recrystallization again, obtain the 362mg title compound.
Fusing point: 230～232 ℃
1H-NMR(δppm,DMSO-d 6)
1.59-1.66(4H,m),1.85(4H,m),3.08(2H,br),4.31(2H,s),4.67(2H,s),7.68(1H,d,J=3.7Hz),8.05(1H,d,J=3.7Hz),8.92(3H,br),11.79(1H,br)
Embodiment 9
1-benzyl-3-[[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] methyl] urea
The free type compound of 770mg (2.63mmol) embodiment 8 is dissolved among the 20ml DMF, adds the DMF solution 5ml of 369mg (2.77mmol) benzyl mustard oil, in stirring at room 1 hour.With the reaction solution concentrating under reduced pressure, make the residue obtained chloroform that is dissolved in, after the washing, use anhydrous magnesium sulfate drying.Boil off solvent, the residue obtained silica gel column chromatography of using obtains the 1.0g title compound with chloroform-methanol (50: 1) wash-out.
Fusing point: 101～103 ℃
1H-NMR(δppm,CDCl 3)
7.70(1H,d,J=3.7Hz),7.31-7.26(5H,m),6.95(1H.d.J=3.7Hz),5.10(2H,m),4.57(2H,d,J=5.7Hz),4.42(2H,d,J=7.5Hz),3.88(2H,s),2.71(4H,m),1.64(8H,brs)
Embodiment 10
N-[[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] methyl] benzamide 1.0 fumarates
The free type compound of 585mg (2.0mmol) embodiment 8 is dissolved in the 20ml methylene dichloride, adds 0.6ml (4.0mmol) triethylamine, 0.28ml (2.4mmol) Benzoyl chloride and 4-DMAP (catalyzer) then, in stirring at room 19 hours.Reaction solution is used anhydrous magnesium sulfate drying through after washing.Boil off solvent, the residue obtained silica gel column chromatography of using obtains the free type title compound of 510mg with chloroform-methanol (80: 1) wash-out.In the free type compound of 490mg (1.24mmol), add 140mg (1.2mmol) fumaric acid, make its salify, obtain the 348mg title compound.
Fusing point: 79～81 ℃
1H-NMR(δppm,DMSO-d 6)
9.22(1H,t),7.91-7.85(3H,m),7.58-7.48(3H,m),7.16(1H,d),6.92(2H,s),4.62(2H,d),3.91(2H,s),2.67-2.64(4H,m),1.57(8H,brs)
Embodiment 11
A) methyl N-benzyl-5-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2,4-oxadiazole-3-base methylamine 2 hydrochlorides
B) N, N-dibenzyl-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-base methylamine 2 hydrochlorides
At 1 of the free type compound of 1.52g (5.2mmol) embodiment 8, drip 0.53ml (5.2mmol) phenyl aldehyde among the 2-dichloroethane solution 55ml, after 2.5 hours, drip 31.44g (6.76mmol) NaBH (OAc) and 0.6ml acetate in stirring at room again, in room temperature restir 2 days.In reaction solution, add strong aqua then, divide and get organic layer, use anhydrous magnesium sulfate drying.Boil off solvent, the residue obtained silica gel column chromatography of using obtains the b of free type with chloroform-methanol (100: 1～80: 1) wash-out) 359mg, a) 980mg of free type.Use 4N HCl/AcOEt salify then, obtain title compound b) 330mg, a) 1036mg.
a) 1H-NMR(δppm,DMSO-d 6)
11.84(1H,br),10.42(2H,br),8.06(1H,d),7.70(1H,d),7.61-7.59(2H,m),7.45-7.25(3H,m),4.68(2H,brs),4.42(2H,brs),4.30(2H,brs),3.33(2H,br),3.08(2H,br),1.99-1.89(4H,m),1.67(4H,br),1.58(4H,br)
MS(FAB,Pos,m/z)383(M ++1)
b) 1H-NMR(δppm,DMSO-d 6)
11.64(1H,br),8.04(1H,d),7.70(1H,d),7.55(4H,br),7.43-7.39(6H,m),4.68(2H,d),4.11(4H,br),3.33(2H,m),3.11-3.05(2H,m),1.91-1.85(4H,m),1.69-1.65(4H,m),1.61-1.55(4H,m)
MS(FAB,Pos,m/z)473(M ++1)
Embodiment 12
1) methyl 3-t-butyldimethylsilyloxy base ethyl-5-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2, the 4-oxadiazole
Use 12.0g (44.9mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl] carboxylic acid, ethyl ester and 12.7g (58.3mmol) 3-t-butyldimethylsilyloxy base propionyl amidoxime, operate equally with embodiment, obtain the 9.62g title compound.
1H-NMR(δppm,CDCl 3)
0.04(6H,s),0.86(9H,s),1.63-1.70(8H,m),2.69(4H,m),2.99(2H,t,J=6.8Hz),3.87(2H,s),4.04(2H,t,J=6.8Hz),6.94(1H,d,J=3.9Hz),7.71(1H,d,J=3.9Hz)
2) methyl 5-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2,4-oxadiazole-3-ethylate hydrochlorate
Ice-cooled down, at 9.97g (25.2mmol) 1) drip 28.4ml (28.4mmol) tetrabutylammonium (1.0M, THF solution) among the tetrahydrofuran solution 250ml of gained compound, under same temperature, stirred 1 hour.Concentration of reaction solution adds 1N HCl in residue obtained, make it become acidity after, clean with chloroform.In water layer, add 4N NaOH then, after making the reaction solution alkalize, use ethyl acetate extraction, organic layer is cleaned with saturated aqueous common salt, uses anhydrous magnesium sulfate drying again, boils off solvent, obtain free type title compound 7.27g (quantitatively), make wherein 950mg (3.09mmol) salify with 4N HCl/AcOEt then, use the acetonitrile recrystallization again, obtain the 639mg title compound.
Fusing point: 229～231 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-1.78(4H,m),1.83(4H,br),2.87-2.90(2H,m),3.05-3.09(2H,m),3.78-3.80(2H,m),4.66-4.68(2H,m),7.62(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.06(1H,br)
Embodiment 13
1-[5-[3-(2-benzyloxy ethyl)-1,2,4-oxadiazole-5-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
Use 1.34g (5.0mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl] carboxylic acid, ethyl ester and 1.8g (9.28mmol) 3-benzyloxy propionyl amidoxime, operation similarly to Example 1, the title compound of the free type of acquisition 850mg.
Fusing point: 145～147 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-1.75(4H,m),1.84(4H,m),3.04-3.10(4H,m),3.82-3.85(2H,m),4.51(2H,s),4.66-4.68(2H,m),7.20-7.38(5H,m),7.64(1H,d,J=3.7Hz),7.98(1H,d,J=3.7Hz),11.28(1H,br)
Embodiment 14
1-[5-[3-(2-ethoxyethyl group)-1,2,4-oxadiazole-5-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
Use 1.07g (4.0mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl] carboxylic acid, ethyl ester and 0.8g (6.0mmol) 3-ethoxy-c amidoxime, operation similarly to Example 1 obtains the 507mg title compound.
Fusing point: 149～151 ℃
1H-NMR(δppm,DMSO-d 6)
11.1(1H,br),7.99(1H,d),7.63(1H,d),4.67(2H,s),3.77(2H,t),3.47-3.43(2H,m),3.38-3.35(4H,m),2.99(2H,t),1.84(4H,m),1.67-1.64(2H,m),1.60-1.55(2H,m),1.08(3H,t)
Embodiment 15
1-[5-(3-vinyl-1,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
At 615mg (2.0mmol) embodiment 12-2) the tetrahydrofuran solution 25ml of free type compound in add 418mg (3.0mmol) 4-nitrophenols, 786mg (3.0mmol) triphenyl phosphine and 0.48ml (3.0mmol) diethylazodicarboxylate, stir an evening under the room temperature.Concentration of reaction solution, residue obtained refining with silica gel column chromatography, the title compound of the free type of acquisition 260mg.Make its salify with 4N HCl/AcOEt then, obtain the 191mg title compound.
Fusing point: 173～174 ℃
1H-NMR(δppm,DMSO-d 6)
11.07(1H,br),8.03(1H,d,J=3.7Hz),7.64(1H,d,J=3.7Hz),6.85(1H,m),6.40(1H,m),5.94(1H,m),4.68(2H,s),3.39-3.34(4H,br),1.84(4H,br),1.67-1.64(2H,m),1.61-1.57(2H,m)
Embodiment 16
Phenylformic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 6 is by 450mg (1.46mmol) embodiment 12-2) free type compound, obtain the free type title compound of 580mg.Make wherein 541mg (1.31mmol) salify with 112.5mg (1.25mmol) oxalic acid, obtain the 384mg title compound.
Fusing point: 121-123 ℃
1H-NMR(δppm,DMSO-d 6)
7.96-7.90(3H,m),7.60(1H,m),7.52(2H,t,J=7.9Hz),7.32(1H,br),4.65(2H,t,J=6.1Hz),4.25(2H,br),3.26(2H,t,J=6.1Hz),2.92(4H,brs),1.69(4H,brs),1.59(4H,brs)
Embodiment 17
4-methoxybenzoic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethoxal salt
Operation similarly to Example 6 is by 307mg (1.0mmol) embodiment 12-2) free type compound and 205mg (1.2mmol) 4-methoxy benzoyl chloride, obtain the 444mg title compound.
Fusing point: 131～132 ℃
1H-NMR(δppm,DMSO-d 6)
7.91(1H,d),7.88-7.86(2H,m),7.31(1H,d),7.04-7.02(2H,m),4.60(2H,t),4.25(2H,br),3.82(3H,s),3.24(2H,t),2.92(4H,br),1.69(4H,br),1.59(4H,br)
Embodiment 18
4-fluorobenzoic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethoxal salt
Operation similarly to Example 6 is by 307mg (1.0mmol) embodiment 12-2) free type compound and 0.14ml (1.2mmol) 4-fluorobenzoyl chloride, obtain the 438mg title compound.
Fusing point: 96～97 ℃
1H-NMR(δppm,DMSO-d 6)
8.01-7.98(2H,m),7.91(1H,d),7.38-7.33(3H,m),4.64(2H,t),4.28(2H,br),3.26(2H,t),2.94(4H,br),1.70(4H,br),1.59(4H,br)
Embodiment 19
4-nitrobenzoic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethoxal salt
Operation similarly to Example 6 is by 307mg (1.0mmol) embodiment 12-2) free type compound and 4-nitrobenzoyl chloride, obtain the 439mg title compound.
Fusing point: 67～69 ℃
1H-NMR(δppm,CDCl 3)
8.40-8.10(4H,m),7.72(1H,d,J=3.7Hz),6.96(1H,d,J=3.7Hz),4.79(2H,t,J=6.4Hz),3.80(2H,s),3.27(2H,t,J=6.4Hz),2.70(4H,br),1.64(8H,br)
Embodiment 20
Hexahydrobenzoic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester
Operation similarly to Example 6 is by 307mg (1.0mmol) embodiment 12-2) free type compound and 0.16ml (1.2mmol) hexanaphthene carbonyl chloride, obtain the 409mg title compound.
Fusing point: 41～42 ℃
1H-NMR(δppm,CDCl 3)
7.72(1H,d),6.95(1H,d),4.48(2H,t),3.88(2H,s),3.10(2H,t),2.69(2H,t),2.70-2.68(4H,m),2.29(1H,m),1.90-1.86(2H,m),1.75-1.61(10H,m),1.47-1.37(2H,m),1.31-1.16(4H,m)
Embodiment 21
Acetate 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 6 is by 615mg (2.0mmol) embodiment 12-2) free type compound and 0.38ml (4.0mmol) acetic anhydride, obtain the 330mg title compound.
Fusing point: 105～106 ℃
1H-NMR(δppm,DMSO-d 6)
7.85(1H,d,J=3.7Hz),7.16(1H,d,J=3.7Hz),6.62(2H,s),4.38(2H,t,J=6.1Hz),3.93(2H,s),3.09(2H,t,J=6.1Hz),3.69-3.67(4H,m),1.99(3H,s),1.61-1.59(8H,m)
Embodiment 22
1-[5-(3-methyl isophthalic acid, 2,4-oxadiazole-5-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene
Operation similarly to Example 1 is by 570mg (7.70mmol) acetyl amidoxime and 1.03g (3.85mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl] carboxylic acid, ethyl ester, obtain the 280mg title compound.
Fusing point: 45～46 ℃
1H-NMR(δppm,CDCl 3)
7.71(1H,d),6.95(1H,d),3.88(2H,s),2.70-2.64(4H,m),2.43(3H,s),1.64(8H,brs)
Embodiment 23
N-benzylamino formic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester
Operation similarly to Example 7 is by 610mg (1.98mmol) embodiment 12-2) free type compound and 278mg (2.08mmol) benzyl mustard oil, obtain the free type title compound of 570mg.Make wherein 560mg salify with the 141mg fumaric acid then, obtain the 366mg title compound.
Fusing point: 138～139 ℃
1H-NMR(δppm,DMSO-d 6)
7.84(1H,d,J=3.7Hz),7.72(1H,t),7.30-7.16(5H,m),6.62(2H,s),4.36(2H,t,J=6.1Hz),4.15(2H,d,J=6.1Hz),3.93(2H,s),3.07(2H,t,J=6.1Hz),2.68-2.66(4H,m),1.61-1.58(8H,m)
Embodiment 24
N-ethyl carbamic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 330mg (1.07mmol) embodiment 12-2) free type compound and 82mg (1.15mmol) ethyl isocyanate, obtain the 198mg title compound.
Fusing point: 112～113 ℃
1H-NMR(δppm,DMSO-d 6)
7.92(1H,d),7.33(1H,d),7.12(1H,br),4.31(2H,t),4.27(2H,br),3.05(2H,t),3.00-2.93(6H,m),1.70(4H,br),1.59(4H,br),0.98(3H,t)
Embodiment 25
N-(2-chloroethyl) carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 0.15ml (1.65mmol) isocyanic acid 2-chloroethene ester, obtain the 437mg title compound.
Fusing point: 71～72 ℃
1H-NMR(δppm,DMSO-d 6)
7.92(1H,d),7.45(1H,t),7.34(1H,d),4.35(2H,t),4.29(2H,br),3.56(2H,t),3.29-3.24(2H,m),3.07(2H,t),2.94(4H,br),1.71(4H,br),1.59(4H,br)
Embodiment 26
N-butyl carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 0.19ml (1.65mmol) n-butyl isocyanate, obtain the 573mg title compound.
Fusing point: 109～110 ℃
1H-NMR(δppm,DMSO-d 6)
7.93(1H,d),7.37(1H,d),7.13(1H,t),4.34-4.30(4H,m),3.06(2H,t),2.99(4H,m),2.94-2.91(2H,m),1.72(4H,br),1.59(4H,br),1.36-1.30(2H,m),1.26-1.20(2H,m),0.86(3H,t)
Embodiment 27
N-tertiary butyl carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 0.19ml (1.65mmol) tert-butyl isocyanate, obtain the 378mg title compound.
Fusing point: 140～141 ℃
1H-NMR(δppm,DMSO-d 6)
7.92(1H,d),7.34(1H,d),6.90(1H,br),4.29-4.27(4H,m),3.04(2H,t),2.95(4H,br),1.71(4H,br),1.59(4H,br),1.18(9H,s)
Embodiment 28
N-cyclohexyl carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 0.25ml (1.95mmol) NSC 87419, obtain the 363mg title compound.
Fusing point: 78～79 ℃
1H-NMR(δppm,DMSO-d 6)
7.92(1H,d),7.35(1H,d),7.08(1H,d),4.31(2H,t),3.38(1H,m),3.21(1H,br),3.05(2H,t),2.96(4H,br),1.71(6H,br),1.59(6H,br),1.22-1.06(6H,m)
Embodiment 29
N-phenylcarbamic acid 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 232mg (1.95mmol) phenylcarbimide, obtain the 515mg title compound.
Fusing point: 68～70 ℃
1H-NMR(δppm,DMSO-d 6)
7.73(1H,d),7.37-7.27(3H,m),7.05(1H,m),6.96(1H,d),6.66(1H,br),4.60(2H,t),3.88(2H,br),3.16(2H,t),2.70-2.68(4H,m),1.65(8H,m)
Embodiment 30
N-(4-nitrophenyl) carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 320mg (1.95mmol) isocyanic acid 4-nitro phenyl ester, obtain the 604mg title compound.
Fusing point: 73～74 ℃
1H-NMR(δppm,DMSO-d 6)
8.29-8.26(2H,m),8.22-8.19(2H,m),7.54(1H,m),6.96(1H,d),4.79(2H,t),3.88(2H,br),3.28(2H,t),2.70-2.68(4H,m),1.66-1.63(8H,m)
Embodiment 31
N-(4-p-methoxy-phenyl) carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 291mg (1.95mmol) isocyanic acid 4-methoxyl group phenyl ester, obtain the 652mg title compound.
Fusing point: 83～84 ℃
1H-NMR(δppm,DMSO-d 6)
9.45(1H,br),7.93(1H,d),7.36-7.33(3H,m),6.86-6.82(2H,m),4.45(2H,t),4.27(2H,br),3.69(3H,s),3.15(2H,t),2.93(4H,br),1.70(4H,br),1.59(4H,br)
Embodiment 32
N-(4-fluorophenyl) carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 267mg (1.95mmol) isocyanic acid 4-fluorobenzene ester, obtain the 465mg title compound.
Fusing point: 93～94 ℃
1H-NMR(δppm,DMSO-d 6)
9.70(1H,br),7.93(1H,d),7.46-7.42(2H,m),7.34(1H,d),7.10(2H,t),4.47(2H,t),4.30(2H,br),3.16(2H,t),2.96-2.94(4H,m),1.70(4H,br),1.59(4H,br)
Embodiment 33
N-(2-nitrophenyl) carboxylamine 2-[5-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl ester 1.0 oxalate
Operation similarly to Example 7 is by 462mg (1.5mmol) embodiment 12-2) free type compound and 271mg (1.65mmol) isocyanic acid 2-nitro phenyl ester, obtain the 440mg title compound.
Fusing point: 88～89 ℃
1H-NMR(δppm,DMSO-d 6)
9.87(1H,br),7.96-7.93(2H,m),7.69-7.61(2H,m),7.35-7.30(2H,m),4.47(2H,t),4.31(2H,br),2.96(2H,br),1.71(4H,br),1.59(1H,br)
Embodiment 34
N-[2-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl] phthalimide hydrochloride
Under the room temperature, at 5.0g (16.27mmol) embodiment 12-2) the anhydrous tetrahydrofuran solution 100ml of free type compound in add 3.59g (24.4mmol) phthalic imidine, 3.84ml (24.4mmol) diethylazodicarboxylate and 6.39g (24.4mmol) triphenyl phosphine, stirred 10 hours under the room temperature.Concentrating under reduced pressure reaction solution then, residue obtained with silica gel column chromatography with ethyl acetate-normal hexane (1: 1) wash-out, obtain the mixture that 8.9g contains free type title compound.After this solid substance pulverizing, add 1N HCl, make it become acidity, add ethyl acetate again and stirred 1 hour, the crystallization that leaching is separated out obtains the 5.344g crude product.With acetonitrile wherein 1.10g is carried out recrystallization at last, obtain the 724mg title compound.
Fusing point: 181～182 ℃
1H-NMR(δppm,DMSO-d 6)
11.13(1H,br),7.94(1H,d),7.90-7.83(4H,m),7.63(1H,d),6.66(2H,d),3.97(2H,t),3.36(4H,m),3.13(2H,t),1.84(4H,m),1.67-1.55(4H,m)
Embodiment 35
1) N alpha-cyano-2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carbonyl amidine
In the methanol solution 210ml of 7.5g (34.04mmol) 2-cyano group-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl] thiophene, add 3.68g (68.08mmol) sodium methylate, under argon atmosphere, stirring at room 24 hours.Add 3.9ml (68.08mmol) acetate and 2.15g (51.06mmol) cyanamide then in reaction solution, restir is 24 hours under the room temperature.Concentration of reaction solution adds chloroform-methanol (20: 1) in residue obtained, after the washing, use anhydrous magnesium sulfate drying.Boil off solvent, the residue obtained silica gel column chromatography of using obtains the 2.62g title compound with chloroform-methanol (50: 1～10: 1) wash-out.
1H-NMR(δppm,DMSO-d 6)
9.02(1H,br),8.49(1H,br),7.84(1H,d),7.01(1H,d),3.80(2H,s),2.59(4H,br),1.56(8H,brs)
2) 1-[5-(3-amino-1,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene
With 2.62g (9.99mmol) 1) the gained compound is dissolved in 55ml tetrahydrofuran (THF) and the 11ml methyl alcohol, adds 1.41g (19.98mmol) oxammonium hydrochloride and 4.23ml (29.97mmol) triethylamine then, reflux 21 hours.The concentrating under reduced pressure reaction solution adds chloroform-methanol (10: 1) in residue obtained, after the washing, use anhydrous magnesium sulfate drying.After boiling off solvent, the residue obtained silica gel column chromatography of using obtains the 2.58g title compound with chloroform-methanol (75: 1) wash-out.
Fusing point: 135～136 ℃
1H-NMR(δppm,DMSO-d 6)
7.68(1H,d),7.09(1H,d),6.35(2H,s),3.87(2H,s),2.65-2.63(4H,brs),1.58(8H,brs)
Embodiment 36
1-[5-(4-amino-4H-1,2,4-triazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
2.0g (9.08mmol) 2-cyano group-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl] thiophene is dissolved in 13.5mlN, in the dinethylformamide, adds 13.5ml hydrazine-hydrate then, reflux 5 hours.After being cooled to room temperature, in reaction solution impouring frozen water, the crystallization that leaching is separated out after the washing, in a dry evening under 70 ℃ of reduced pressure, obtains the 1.97g title compound.With ethyl acetate wherein 560mg is carried out recrystallization at last, obtain 335mg purpose product.
Fusing point: 104～105 ℃
1H-NMR(δppm,DMSO-d 6)
8.44(1H,s),7.72(1H,d),7.00(1H,d),6.34(2H,s),3.83(2H,s),2.64-2.62(4H,m),1.57(8H,brs)
Embodiment 37
1) 4-benzyl imino--3-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2, the 4-triazole
In the methanol solution 10ml of 831mg (3.0mmol) embodiment 36 compounds, add 0.31ml (3.0mmol) phenyl aldehyde, stirred 4 hours under the room temperature.Add 827mg (3.9mmol) NaBH (OAc) 3 and 0.35ml acetate down in reaction solution ice-cooled then, at room temperature restir is 9 days.Reaction solution is used anhydrous magnesium sulfate drying after using saturated sodium bicarbonate aqueous solution and saturated common salt water washing.After boiling off solvent, the residue obtained silica gel column chromatography of using obtains the 600mg title compound with chloroform-methanol (25: 1) wash-out.
1H-NMR(δppm,CDCl 3)
8.63(2H,d),7.95(2H,d),7.84(1H,d),7.61-7.53(3H,m),6.95(1H,d),3.89(2H,s),2.71-2.69(4H,m),1.68-1.62(8H,m)
2) 1-[5-(4-benzylamino-4H-1,2,4-triazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
Ice-cooled down, at 354mg (0.969mmol) 1) add 58mg (1.5mmol) sodium borohydride among the ethanolic soln 20ml of gained compound, stirred 24 hours under the room temperature.Behind the concentration of reaction solution, in residue, add chloroform and ammoniacal liquor, divide and get organic layer, use anhydrous magnesium sulfate drying.After boiling off solvent, the residue obtained silica gel column chromatography of using obtains the 353mg title compound with chloroform-methanol-ammoniacal liquor (100: 10: 1) wash-out.
Fusing point: 79～81 ℃
1H-NMR(δppm,DMSO-d 6)
8.61(1H,s),7.67(1H,d),7.37-7.27(5H,m),7.19(1H,t),6.99(1H,d),4.22(2H,d),3.84(2H,s),2.65-2.62(4H,m),1.59(8H,brs)
Embodiment 38
1) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid amidino groups hydrazides
The NaOH that in 11.0g (43.4mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, adds 6.07g (21.7mmol) sulfuric acid S-methyl-isothiourea and 43.5ml (43.5mmol) 1N, in reaction mixture, add methyl alcohol (about 130ml) and become homogeneous solution until it, then, stirred 10 days under the room temperature, behind the elimination insolubles, concentrated solvent, the residue obtained silica gel column chromatography of directly using with chloroform-methanol-ammoniacal liquor (40: 10: 1) wash-out, is obtained the 7.32g title compound.
1H-NMR(δppm,DMSO-d 6)
10.37(1H,br),7.13(1H,d),6.76(1H,d),6.73(4H,br),3.71(2H,s),2.59-2.57(4H,m),1.56(8H,brs)
2) 1-[5-(5-amino-1H-1,2,4-triazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
With 7.32g (24.8mmol) 1) the ethanolic soln 80ml reflux of gained compound 8 days.Concentration of reaction solution, the residue obtained silica gel column chromatography of using obtains the 5.98g title compound with chloroform-methanol-ammoniacal liquor (100: 10: 1～40: 10: 1) wash-out.With the 25ml acetonitrile wherein 1.5g is carried out recrystallization, obtain 1.26g purpose product.
Fusing point: 160～161 ℃
1H-NMR(δppm,DMSO-d 6)
11.95(1H,brs),7.20(1H,brs),6.86(1H,brs),6.04(2H,brs),3.76(2H,s),2.61-2.59(4H,m),1.56(8H,brs)
Embodiment 39
5-amino-N-benzyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl]-1H-1,2,4-triazole-1-methane amide
At the N of 690mg (2.49mmol) embodiment 38 compounds, add the N of 331mg (2.49mmol) benzyl mustard oil among the dinethylformamide solution 75ml, dinethylformamide solution 5ml stirred 2 hours under the room temperature.Concentration of reaction solution with the residue obtained chloroform that is dissolved in, after the washing, is used anhydrous magnesium sulfate drying.Then, boil off solvent, the residue obtained silica gel column chromatography of using obtains the 1.07g title compound with chloroform-methanol (75: 1) wash-out.Add an amount of ether therein, make its crystallization, use ethyl acetate-normal hexane recrystallization again, obtain purpose compound 564mg.
Fusing point: 130～131 ℃
1H-NMR(δppm,DMSO-d 6)
7.45(1H,d,J=3.7Hz),7.40-7.31(5H,m),7.24(1H,t),6.84(1H,d,J=3.7Hz),6.27(2H,brs),4.57(2H,d,J=6.1Hz),3.83(2H,s),2.68-2.66(4H,m),1.65-1.60(8H,m)
Embodiment 40
1) ethyl-N 1-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-2-thiophene ketone group]-N 2-オ キ サ ミ De ラ ゾ ネ-ト
Add 7.4ml (52.5mmol) triethylamine, reflux 36 hours among the anhydrous methylene chloride solution 150ml of カ Le ボ ェ ト キ シ-S-メ チ Le チ オ ホ Le system イ ミ ジ ウ system テ ト ラ Off Le オ ロ ボ レ-ト (30.86mmol) and 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides 6.33g (25.0mmol).After the reaction solution washing, use anhydrous magnesium sulfate drying.Boil off solvent, make with extra care residue obtained, obtain the 5.70g title compound with silica gel column chromatography.
1H-NMR(δppm,CDCl 3)
11.45(1H,br),8.10(1H,d),6.94(1H,d),6.12(2H,br),4.38(2H,m),3.87(2H,s),2.66(4H,m),1.62(8H,br),1.45(3H,t)
2) methyl 3-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1H-1,2,4-triazole-5-carboxylic acid, ethyl ester
With 1) in gained compound 352mg (1.0mmol) be dissolved in the 5ml acetate reflux 3 hours.The concentrating under reduced pressure reaction solution adds ammoniacal liquor and chloroform in residue obtained, divide and get organic layer, behind anhydrous magnesium sulfate drying, boils off solvent.With silica gel column chromatography residue is made with extra care at last, obtained the 248mg title compound.
1H-NMR(δppm,CDCl 3)
7.51(1H,d),6.85(1H,d),4.45-4.29(2H,m),3.96(2H,brs),2.81(4H,br),1.61(8H,br),1.33(3H,t)
MS(FAB,Pos,m/z)335(M ++1)
Embodiment 41
5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2,4-triazole-3-methyl alcohol
Under ice-cooled, the anhydrous tetrahydrofuran solution 20ml of Dropwise 5 02mg (1.5mmol) embodiment 40 compounds in the anhydrous tetrahydro furan suspension 5ml of 85.4mg (2.25mmol) lithium aluminium hydride stirred 4 hours under same temperature.Add sodium sulfate 10 hydrates then in reaction mixture, behind the elimination insolubles, boil off solvent, the residue obtained silica gel column chromatography of using obtains the 312mg title compound with chloroform-methanol (10: 1) wash-out.
Fusing point: 159～161 ℃
1H-NMR(δppm,DMSO-d 6)
13.89(1H,br),7.37(1H,d),6.93(1H,d),5.62(1H,br),4.57(2H,d),3.81(2H,s),2.63-2.60(4H,m),1.57(8H,brs)
Embodiment 42
1-[5-(5-methyl isophthalic acid H-1,2,4-triazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene 2 hydrochlorides
In the ethanolic soln 5ml of 1.01g (4.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, add 2.8ml (20mmol) triethylamine and 2.48g (20mmol) ethylenemine acid ethyl ester hydrochloride salt, stirred 21 hours under the room temperature.In this solution, add 1.2g ammonium chloride, stirred 4 hours in 80 ℃.Concentration of reaction solution adds 28% ammoniacal liquor and chloroform in residue obtained, divide and get organic layer, uses anhydrous magnesium sulfate drying.Boil off solvent, the residue obtained silica gel column chromatography of using obtains the free type title compound of 814mg with chloroform-methanol (80: 1) wash-out.Make its salify with 4N HCl/ ethyl acetate at last, obtain the 593mg title compound.
Fusing point: 161～163 ℃
1H-NMR(δppm,DMSO-d 6)
11.06(1H,br),7.59(1H,d),7.45(1H,d),4.56-4.55(2H,d),3.38-3.33(2H,m),3.10-3.02(2H,m),2.39(3H,s),1.85-1.83(4H,m),1.68-1.63(2H,m),1.60-1.54(2H,m)
Embodiment 43
1-[5-(5-amino-1,3,4-oxadiazole-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene
In the ethanolic soln 250ml of 5.43g (21.43mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, add 2.5g (23.57mmol) cyano group bromine, stir under the room temperature after 2 hours, stirred 7 hours in 50 ℃.The concentrating under reduced pressure reaction solution adds saturated sodium bicarbonate aqueous solution and chloroform in residue obtained, after branch is got organic layer, use the saturated common salt water washing, use anhydrous magnesium sulfate drying then, boil off solvent, the residue obtained re-crystallizing in ethyl acetate of using obtains the 2.43g title compound.
Fusing point: 232-234 ℃
1H-NMR(δppm,DMSO-d 6)
7.33(1H,d),7.23(2H,s),7.00(1H,d),3.83(2H,s),2.63-2.61(4H,m),1.57(8H,brs)
Embodiment 44
1-benzyl-3-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,3,4-oxadiazole-2-yl] urea
In the pyridine solution 20ml of 278mg (1.0mmol) embodiment 43 compounds, add 0.14ml (1.1mmol) benzyl mustard oil, stirred 24 hours under the room temperature.The concentrating under reduced pressure reaction solution, the residue obtained silica gel column chromatography of using obtains the 406mg title compound with chloroform-methanol (50: 1) wash-out.
Fusing point: 184～185 ℃
1H-NMR(δppm,DMSO-d 6)
10.96(1H,br),7.97(1H,t),7.48(1H,d,J=3.7Hz),7.37-7.24(5H,m),7.07(1H,d,J=3.7Hz),4.41(2H,d,J=5.7Hz),3.86(2H,s),2.64(4H,brs),1.58(8H,brs)
Embodiment 45
1) methyl 4-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1-benzyl thiosemicarbazide
Drip the ethanolic soln 5ml of 928mg (6.22mol) benzyl isothiocyanide in the ethanolic soln 15ml of 1.5g (5.92mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, stir under the room temperature after 2 hours, reheat refluxed 1 hour.Cool off reaction solution with frozen water, the crystallization that leaching is separated out, behind cold ethanol thorough washing, drying under reduced pressure obtains the 2.19g title compound.
1H-NMR(δppm,DMSO-d 6)
8.06(1H,t),7.94(1H,d),7.32-7.22(6H,m),5.23(2H,s),4.26-4.22(4H,m),2.92(4H,brs),1.70(4H,brs),1.59(4H,brs)
2) 1-[5-(5-amino-1,3,4-thiadiazoles-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene
Ice-cooled down, 1) add the 6ml vitriol oil among the gained compound 806mg (2.0mmol), at room temperature stirred again 3 hours after 1 hour in stirring under this temperature.With in the reaction solution impouring ice, add the 5N aqueous sodium hydroxide solution again and make it change alkalescence into then, use ethyl acetate extraction.Organic layer with anhydrous magnesium sulfate drying after, boil off solvent, again with ethyl acetate-normal hexane to the residue obtained recrystallization that carries out, obtain the 482mg title compound.
Fusing point: 156～157 ℃
1H-NMR(δppm,CDCl 3)
7.17(1H,d,J=3.9Hz),6.83(1H,d,J=3.9Hz),5.44(2H,brs),3.83(2H,s),2.69-2.66(4H,m),1.65-1.62(8H,m)
Embodiment 46
1-benzyl-3-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,3,4-thiadiazoles-2-yl] urea
At embodiment 45-2) the N of compound 342mg (1.16mmol), drip the N of 132mg (1.16mmol) benzyl mustard oil among the dinethylformamide solution 25ml, dinethylformamide solution 5ml stirred 22 hours under the room temperature.The concentrating under reduced pressure reaction solution adds chloroform and water in residue obtained then, divides and gets organic layer, uses anhydrous magnesium sulfate drying, boils off solvent, and the residue obtained silica gel column chromatography of using obtains the 399mg title compound with chloroform-methanol (40: 1～25: 1) wash-out.
Fusing point: 232-233 ℃
1H-NMR(δppm,DMSO-d 6)
11.13(1H,br),7.41(1H,d,J=3.7Hz),7.36-7.25(5H,m),7.16(1H,brs),6.98(1H,d,J=3.7Hz),4.37(2H,d,J=6.1Hz),3.82(2H,s),2.64-2.62(4H,m),1.58(8H,br)
Embodiment 47
N-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,3,4-thiadiazoles-2-yl] benzamide
Use 350mg (1.19mmol) embodiment 45-2) compound, 0.33ml (2.38mmol) triethylamine and 0.18mg (1.55mol) Benzoyl chloride, and the 4-N of catalytic amount, the N-dimethyl aminopyridine, operation similarly to Example 10 obtains the 396mg title compound.
Fusing point: 219～221 ℃
1H-NMR(δppm,DMSO-d 6)
13.04(1H,br),8.14(2H,d),7.66(1H,d),7.59-7.56(3H,m),7.04(1H,d),3.88(2H,s),2.68-2.66(4H,m),1.60(8H,m)
Embodiment 48
1-[5-(5-benzylamino-1,3,4-thiadiazoles-2-yl)-2 thenyls] six hydrogen-1H-azatropylidene
At 1.08g (3.67mmol) embodiment 45-2) compound 1, drip 0.37ml (3.67mmol) phenyl aldehyde among the 2-dichloroethane solution 100ml, stir under the room temperature after 90 minutes, add 1.02g (7.34mmol) NaBH (OAC) 3And 0.42ml (7.34mmol) acetate, restir is 51 hours under the room temperature.Use saturated sodium bicarbonate aqueous solution and saturated common salt water washing then successively, use anhydrous magnesium sulfate drying again, the pressure reducing and steaming solvent is made with extra care residue obtained with silica gel column chromatography, obtains the 270mg title compound.
Fusing point: 165～166 ℃
1H-NMR(δppm,DMSO-d 6)
8.40(1H,t),7.38-7.26(5H,m),7.22(1H,d,J=3.7Hz),6.93(1H,d,J=3.7Hz),4.52(2H,d,J=5.5Hz),3.79(2H,s),2.62-2.60(4H,m),1.57(8H,br)
Embodiment 49
1-[5-(5-ethylamino-1,3,4-thiadiazoles-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene
Operate equally with embodiment 45,, obtain the 820mg title compound by 760mg (3.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides and 288mg (3.3mmol) ethyl mustard oil.
Fusing point: 112～114 ℃
1H-NMR(δppm,DMSO-d 6)
7.88(1H,t),7.22(1H,d),6.93(1H,d),3.80(2H,s),3.34-3.29(2H,s),2.63-2.61(4H,m),1.57(8H,br),1.20(3H,t)
Embodiment 50
1-ethyl-3-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,3,4-thiadiazoles-2-yl] urea
Operate equally with embodiment 46, by 200mg (0.68mmol) embodiment 45-2) compound and 51mg (0.72mmol) ethyl isocyanate obtain the 220mg title compound.
Fusing point: 203～204 ℃
1H-NMR(δppm,DMSO-d 6)
10.99(1H,brs),7.41(1H,d,J=3.7Hz).6.98(1H,d,J=3.7Hz),6.62(1H,brs),3.82(2H,s),3.21-3.15(2H,m),2.64-2.62(4H,m),1.58(8H,brs),1.08(3H,t,J=6.7Hz)
Embodiment 51
N-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,3,4-thiadiazoles-2-yl] ethanamide
Operate equally with embodiment 47, by 350mg (1.19mmol) embodiment 45-2) compound and 0.15ml diacetyl oxide obtain the 380mg title compound.
Fusing point: 248～249 ℃
1H-NMR(δppm,DMSO-d 6)
12.61(1H,br),7.52(1H,d,J=3.7Hz),7.0(1H,d,J=3.7Hz),3.83(2H,s),3.64-3.62(4H,m),2.21(3H,s),1.58(8H,brs)
Embodiment 52
1) methyl 5-[(six hydrogen-1H-azatropylidene-1-yl)]-thiophene-5-N-methoxyl group-N-methylformamide
The hydrochloride of 8.0g (29.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid is suspended in the 300ml tetrahydrofuran (THF), at room temperature add 10.1ml (72.5mmol) triethylamine, 4.12g (30.46mmol) hydroxybenzotriazole and 8.34g (43.5mmol) WSCDHCl then, stirred 1 hour.Add 3.51g (36.0mmol) N again, O-dimethyl hydroxylamine hydrochloride and 8.36ml (60.0mmol) triethylamine stirs an evening.Then in reaction solution, add ethyl acetate and water, divide and get organic layer, use anhydrous magnesium sulfate drying.Boil off solvent, the residue obtained silica gel column chromatography of using obtains the 7.51g title compound with chloroform-methanol (80: 1) wash-out.
1H-NMR(δppm,CDCl 3)
1.63(8H,brs),2.68(4H,m),3.35(3H,s),3.84(3H,s),3.85(2H,s),6.89(1H,d,J=3.7Hz),7.80(1H,d,J=3.7Hz)
2) methyl 2-ethanoyl-5-[(six hydrogen-1H-azatropylidene-1-yl)]-thiophene
Under argon gas stream, in 0 ℃, at 9.51g (33.86mmol) 1) drip 39.0ml (40.4mmol) lithium methide (diethyl ether solution of 1.04M) among the anhydrous tetrahydrofuran solution 70ml of gained compound, after stirring 30 minutes under the same temperature, in room temperature restir 3 hours.In reaction solution, add entry and ethyl acetate then, divide and get organic layer, use anhydrous magnesium sulfate drying.The pressure reducing and steaming solvent, the residue obtained silica gel column chromatography of using obtains the 7.10g title compound with chloroform-methanol (80: 1) wash-out.
1H-NMR(δppm,CDCl 3)
7.55(1H,d),6.91(1H,d),3.83(2H,d),2.67-2.55(4H,m),2.52(3H,s),1.62(8H,br)
3) (E)-and N-[1-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl] ethylidene]-4H-1,2,4-triazole-4-amine
2) add 1.93g (22.95mmol) 4-amino-1 among the toluene solution 50ml of gained compound 1.19g (5.0mmol), 2, the tosic acid of 4-triazole and catalytic amount, in its Dean Stark pipe of packing into, 1 week of reflux, use saturated sodium bicarbonate aqueous solution and saturated aqueous common salt washing reaction liquid successively then, use anhydrous magnesium sulfate drying again, the pressure reducing and steaming solvent obtains the 1.28g title compound.
1H-NMR(δppm,CDCl 3)
8.21(2H,s),7.48(1H,d,J=4.0Hz),7.94(1H,d,J=4.0Hz),3.85(2H,s),2.69-2.65(4H,m),2.35(3H,s),1.64(8H,br)
4) (E, E)-N-[3-dimethylamino-1-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-2-propylidene-4H-1,2,4-triazole-4-amine
At 1.23g (4.05mmol) 3) drip 2.76ml (13.38mmol) tertiary butyl two (dimethylamino) methane (Bradereck ' s reagent) among the tetrahydrofuran solution 50ml of gained compound, then in argon atmosphere, in stirring at room 48 hours.The concentrating under reduced pressure reaction solution obtains the 1.38g title compound.
1H-NMR(δppm,CDCl 3)
8.23(2H,s),7.3-6.90(3H,m),4.74(1H,d),3.86(2H,s),2.89(6H,s),2.70-2.64(4H,m),1.63(8H,br)
5) methyl 6-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2,4-triazolo [4,3-b] pyridazine
With 717mg (2.0mmol) 4) the gained compound is dissolved in 20ml acetate, reflux 4 hours.The concentrating under reduced pressure reaction solution adds saturated sodium bicarbonate aqueous solution and chloroform in residue obtained then, divides and gets organic layer, after the saturated common salt water washing, uses anhydrous magnesium sulfate drying.Then, boil off solvent, the residue obtained silica gel column chromatography of using obtains the 690mg title compound with acetone-toluene (2: 1) wash-out.With ethyl acetate-isopropyl ether it is carried out recrystallization again, obtain 174 purpose products.
Fusing point: 101～102 ℃
1H-NMR(δppm,CDCl 3)
9.06(1H,s),8.09(1H,d),7.54(1H,d),7.49(1H,d),6.96(1H,d),3.88(2H,s),2.73-2.70(4H,m),1.68-1.59(8H,m)
Embodiment 53
1) N, N-dimethyl-N '-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-2-thienyl] carbonamidine
With 3.72g (15.65mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl] thiophene-2-carboxamide derivatives is dissolved in 30mlN, and dinethylformamide adds 3.4ml (25.6mmol) N then, and the dinethylformamide dimethyl-acetal stirred 4 hours in 80 ℃.Then concentration of reaction solution under reduced pressure is dissolved in the chloroform residue obtained, after the washing, uses anhydrous magnesium sulfate drying.Boil off solvent, obtain the 3.82g title compound.
1H-NMR(δppm,CDCl 3)
8.58(1H,s),7.73(1H,d),6.88(1H,d),3.85(2H,s),3.19(6H,s),2.71-2.62(4H,s),1.62(8H,brs)
2) 1-[5-(1,2,4-oxadiazole-5-yl)-2-thenyl] six hydrogen-1H-azatropylidene 1.0 oxalate
At 1.91g (7.25mmol) 1) add 0.9ml (11.0mmol) pyridine and 1.64g (14.5mmol) azanol O-sulphonate among the methanol solution 20ml of gained compound, 1 evening of stirring at room.Concentration of reaction solution under reduced pressure adds 10%K in residue obtained under ice-cooled then 2CO 3, then use chloroform extraction, use saturated common salt water washing organic layer again, use anhydrous magnesium sulfate drying.Pressure reducing and steaming solvent, the residue obtained silica gel column chromatography of using obtain the free type title compound of 42mg with chloroform-methanol (100: 1～80: 1) wash-out.Above-mentioned free type compound 40mg is dissolved in 5ml methyl alcohol and the 2ml chloroform, adds the methanol solution that contains 13mg oxalic acid then, decompression concentrates down, makes residue obtained crystallization with methyl alcohol and ether at last, obtains the 33mg title compound.
Fusing point: 131～132 ℃
1H-NMR(δppm,DMSO-d 6)
9.48(1H,br),7.37(1H,d),7.19(1H,d),4.51(2H,s),3.14(1H,br),3.10(1H,br),1.80(2H,m),1.60(4H,m)
Embodiment 54
1-[5-(1H-1,2,4-triazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
At 440mg (1.5mmol) embodiment 53-1) drip 0.15ml (3.0mmol) hydrazine-hydrate among the acetic acid solution 3.5ml of gained compound, stirred 120 hours under the room temperature, continue to stir 4 hours at 80 ℃ then.Then, the concentrating under reduced pressure reaction solution adds 28% ammoniacal liquor and chloroform in residue obtained, divide and get organic layer, uses anhydrous magnesium sulfate drying again.The pressure reducing and steaming solvent to the residue obtained recrystallization that carries out, obtains the 99mg title compound with ethyl acetate.
Fusing point: 129～130 ℃
1H-NMR(δppm,DMSO-d 6)
9.11(1H,s),7.42(1H,d),6.95(1H,d),3.80(2H,s),2.63-2.61(4H,m),1.57(8H,brs)
Embodiment 55
1) methyl 5-[(six hydrogen-1H-azatropylidene-1-yl)]-2-thiophene amidoxime
In the ethanolic soln 500ml of 70g 2-cyano group-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl] thiophene, add the 19g oxammonium hydrochloride,, stirred 5 hours in 80 ℃ of heating.Behind the concentration of reaction solution, add the 500ml saturated sodium bicarbonate aqueous solution, use the 300ml chloroform extraction again 3 times.Merge organic layer, and, use anhydrous sodium sulfate drying, with silica gel column chromatography the residue through drying under reduced pressure is made with extra care then, obtain the 51g title compound with after the saturated common salt water washing.
1H-NMR(δppm,CDCl 3)
1.61(8H,s),2.50-2.80(4H,m),3.82(2H,s),4.56(2H,br),6.82(1H,d),7.10(1H,d),7.27(1H,br)
2) methyl 3-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2,4-oxadiazole-5-carboxylic acid, ethyl ester hydrochloride
Ice-cooled down, at 831mg embodiment 55-1) the chloroformic solution 20ml of compound in add 0.5ml triethylamine and 0.4ml chloro glyoxylic acid ethyl ester after, heat to 40 ℃, stirred 3 hours.Adding the 50ml saturated sodium bicarbonate aqueous solution then in reaction solution extracts, organic layer with anhydrous sodium sulfate drying after, concentrating under reduced pressure, then make with extra care residue obtained with silica gel column chromatography, add 4N hydrochloric acid-ethyl acetate solution again, the crystallization that filtration is separated out obtains the 370mg title compound.
Fusing point: 178～179 ℃
1H-NMR(δppm,DMSO-d 6)
1.37(3H,t),1.50-1.90(8H,m),3.05-3.20(2H,m),3.35-3.50(2H,m),4.46(2H,q),4.67(2H,d),7.53(1H,d),7.91(1H,d),10.05(1H,br)
Embodiment 56
1) 1-[5-(5-t-butyldimethylsilyloxy ylmethyl-1,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
At 2.1g embodiment 55-1) the tetrahydrofuran solution 50ml of compound in add the 220mg sodium hydride, after 1 hour, add 1.8g2-t-butyldimethylsilyloxy guanidine-acetic acid ethyl ester in stirring at room again, be heated to 60 ℃, stirred 3 hours.In reaction solution, add the 200ml saturated aqueous common salt then, use the 100ml ethyl acetate extraction again 3 times, merge organic layer, after the saturated common salt water washing, use anhydrous sodium sulfate drying, concentrating under reduced pressure, with silica gel column chromatography residue is made with extra care at last, obtained the 1.1g title compound.
1H-NMR(δppm,CDCl 3)
0.03(6H,s),0.78(9H,s),1.04-1.60(8H,m),2.40-2.60(4H,m),3.70(2H,s),4.78(2H,s),6.75(1H,d),7.46(1H,d)
2) 1-[5-(5-hydroxymethyl-1,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
At 1.1g1-[5-(5-t-butyldimethylsilyloxy ylmethyl-1,2,4-oxadiazole-3-yl)-add 1.0N tetrabutylammonium-tetrahydrofuran solution 4.0ml, stirring at room 2 hours among the tetrahydrofuran solution 10ml of 2-thenyl 1 six hydrogen-1H-azatropylidene.The concentrating under reduced pressure reaction solution with the refining residue of silica gel column chromatography, adds 4N hydrochloric acid-ethyl acetate solution then, filters the crystallization of separating out, and obtains the 680mg title compound.
Fusing point: 171～172 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-1.75(4H,m),1.75-1.90(4H,s),3.00-3.20(2H,m),3.30-3.45(2H,m),4.63(2H,d),4.79(2H,s),6.11(1H,br),7.55(1H,d),7.79(1H,d),10.74(1H,br)
Embodiment 57
1) 1-[5-(5-tert-butoxycarbonyl aminomethyl-1,2,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
Use 1.7g 5-(six hydrogen-1H-azatropylidene-1-yl) methyl]-2-thiophene amidoxime and 2.0gN-tert-butoxycarbonyl glycine ethyl ester, adopt and embodiment 56-1) same method, the 1.1g title compound obtained.
1H-NMR(δppm,CDCl 3)
1.47(9H,s),1.63(8H,br),2.50-2.80(4H,s),3.86(2H,d),4.58(2H,d),5.20(1H,br),6.91(1H,d),7.61(1H,d)
2) 1-[5-(5-aminomethyl-1,2,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene 2 hydrochlorides 1/2 hydrate
With 1.1g1-[5-(5-tert-butoxycarbonyl aminomethyl-1,2,2,4-oxadiazole-3-yl)-and the 2-thenyl] six hydrogen-1H-azatropylidene is dissolved in 4N hydrochloric acid-1, among the 4-dioxane solution 30ml, stirred 30 minutes under the room temperature, the concentrating under reduced pressure reaction solution, the residue re-crystallizing in ethyl acetate obtains the 966mg title compound.
Fusing point: 203～204 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-1.75(4H,br),1.85(4H,s),3.00-3.20(2H,br),3.30-3.50(2H,br),4.58(2H,s),4.63(2H,s),7.58(1H,d),7.81(1H,d),8.94(3H,br),11.22(1H,br)
Embodiment 58
2-[3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxazole-5-yl] ethyl acetate hydrochloride
At 2.0g5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-add the 3.6g diethyl malonate among the toluene solution 100ml of thiophene-2-amidoxime, be heated to 100 ℃, stir an evening.Behind the concentrating under reduced pressure reaction solution, residue is refining with silica gel column chromatography, adds 4N hydrochloric acid-ethyl acetate solution then, with alcohol-ether the precipitation that generates is carried out recrystallization again, obtains the 1.6g title compound.(yield 53%)
Fusing point: 122～123 ℃
1H-NMR(δppm,CDCl 3)
1.22(3H,t),1.50-1.70(4H,m),1.75-1.90(4H,m),3.00-3.15(2H,m),3.30-3.45(2H,m),4.17(2H,q),4.37(2H,s),4.65(2H,d),7.53(1H,d),7.81(1H,d),10.34(1H,br)
Embodiment 59
1-[5-(5-hydroxyethyl-1,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
Under ice-cooled, at 1.5g 2-[3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,2,4-oxazole-5-yl] add the 650mg sodium borohydride among the THF solution 40ml of ethyl acetate free alkali, add 27ml methyl alcohol while stirring, last about 1 hour, restir 1 hour.Still ice-cooled following, adding 1N hydrochloric acid is non-foaming until solution in reaction solution, adds the 100ml saturated sodium bicarbonate aqueous solution again, uses 50ml chloroform extraction 3 times.Merge organic layer, after the saturated common salt water washing, use anhydrous sodium sulfate drying, concentrating under reduced pressure, recycle silicon glue column chromatography is made with extra care residue, then adds 4N hydrochloric acid-ethyl acetate solution, ethanol-re-crystallizing in ethyl acetate is used in the crystallization that filtration is separated out again, obtains the 725mg title compound.
Fusing point: 186～187 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-1.70(4H,m),1.75-1.90(4H,m),3.00-3.20(4H,m),3.30-3.40(2H,m),3.85(2H,t),4.65(2H,d),7.51(1H,d),7.78(1H,d),10.27(1H,br)
Embodiment 60
1) 1-[5-(5-tert-butoxycarbonyl amino-ethyl-1,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene 2 hydrochlorides
Use 2.9g 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-2-thiophene amidoxime and 2.0gN-tert-butoxycarbonyl-Beta-alanine methyl esters, adopt the method same with embodiment 56, obtain the 1.2g title compound.
1H-NMR(δppm,CDCl 3)
1.44(9H,s),1.63(8H,s),2.55-2.80(4H,m),3.11(2H,t),3.60(2H,t),3.86(2H,s),5.15(1H,br),6.91(1H,d),7.61(1H,d)
2) 1-[5-(5-amino-ethyl-1,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
Use 1.1g1-[5-(5-tert-butoxycarbonyl amino-ethyl-1,2,4-oxadiazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene, adopt and embodiment 57-2) same method goes protecting group, obtains the 1.1g title compound.
Fusing point: 210～211 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-1.75(4H,m),1.84(4H,s),2.40-2.60(2H,t),3.10-3.20(2H,t),3.40-3.50(4H,m),4.63(2H,d),7.56(1H,d),7.80(1H,d),8.15(3H,br),11.00(1H,br)
Embodiment 61
1) methyl 5-[(six hydrogen-1H-azatropylidene-1-yl)]-2-thiophene thioamides
In the pyridine solution 50ml of 4.6g1-(5-cyano group-2-thenyl) six hydrogen-1H-azatropylidene, add the 3ml triethylamine, import hydrogen sulfide under the room temperature while stirring, each a small amount of, last 2 hours.The concentrating under reduced pressure reaction solution adds the 50ml saturated sodium bicarbonate aqueous solution in residue, use 50ml chloroform extraction 3 times.Merge organic layer, after the saturated common salt water washing, use anhydrous sodium sulfate drying.Concentrating under reduced pressure, residue is refining with silica gel column chromatography, obtains the 4.3g title compound.
1H-NMR(δppm,DMSO-d 6)
1.56(8H,s),2.45-2.75(4H,m),3.74(2H,s),6.94(1H,d),7.54(1H,d),9.30(1H,br),9.47(1H,br)
2) 1-[5-(4-methylthiazol-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene 2 hydrochlorides
At 2.0g5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-add the 730mg acetone dichloride among the ethanolic soln 30ml of 2-thiophene thioamides, 80 ℃ of one evenings of heated and stirred.With after the reaction solution cooling, dripping hydrochloric acid is adjusted into 1 with pH value with ice, concentrating under reduced pressure then, residue acetonitrile recrystallization, acquisition 1.6g title compound.
Fusing point: 187～190 ℃
1H-NMR(δppm,DMSO-d 6)
1.50-2.00(8H,m),2.38(3H,s),3.00-3.20(2H,m),3.35-3.45(2H,m),4.54(2H,s),7.32(1H,s),7.46(1H,d),7.58(1H,d),7.70(1H,br),11.36(1H,br)
Embodiment 62
1) 2-[5-phthalimidomethyl-2-thienyl] imidazo [1,2-a] pyridine
5-acetyl bromide-2-(phthalimidomethyl) thiophene (0.80g) and 2-aminopyridine (0.23g) are dissolved in the dehydrated alcohol (50ml) reflux 6 hours.The crystallization that leaching generates is with silica gel column chromatography (chloroform: methyl alcohol=100: 1) make with extra care, obtain the 0.38g title compound.
1H-NMR(δppm,DMSO-d 6)
8.48(1H,d),8.24(1H,s),7.90(4H,s),6.79-7.56(5H,s),4.95(2H,s)
2) methyl 2-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl] imidazo [1,2-a] pyridine hydrochloride
Making 2-[5-phthalimidomethyl-2-thienyl] imidazo [1,2-a] pyridine (0.38g) and hydrazine hydrate (0.058g) be dissolved in the mixing solutions of methyl alcohol (10ml) and chloroform (5ml), one evening of reflux.Filtering reacting liquid is after filtrate concentrates, with silica gel column chromatography (chloroform: methyl alcohol=4: 1) make with extra care, obtain 0.14g amino methyl thiophene intermediate.In propyl carbinol (10ml), add above-mentioned intermediate (0.14g), 1,6-dibromo-hexane (0.16g), salt of wormwood (0.19g) and potassiumiodide (0.05g), reflux 6 hours then.Filtering reacting liquid is behind the concentrated filtrate, with silica gel column chromatography (chloroform: methyl alcohol=10: 1) make with extra care, be carried out to reactant salt with 4N hydrochloric acid-salt acetoacetic ester solution then in ether, obtain the 0.061g title compound.
Fusing point: 214～216 ℃
MS(FAB,Pos,m/z)312(M ++1)
Embodiment 63
1) 2-[5-phthalimidomethyl-2-thienyl] imidazo [1,2-a] pyrimidine
Use the 2-aminopyrimidine, adopt and embodiment 62-1) same method, synthesising title compound.
1H-NMR(δppm,DMSO-d 6)
8.91(1H,dd),8.50(1H,dd),8.22(1H,s),7.90(4H,d),7.44(1H,d),7.00-7.13(2H,m),4.97(2H,s)
2) methyl 2-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl] imidazo [1,2-a] pyrimidine fumarate
With 2-[5-phthalimidomethyl-2-thienyl] imidazo [1,2-a] pyrimidine is starting raw material, uses fumaric acid to be carried out to reactant salt, adopt and embodiment 62-2) same method synthesising title compound.
Fusing point: 188～191 ℃
1H-NMR(δppm,DMSO-d 6)
8.92(1H,dd),8.51(1H,dd),8.21(1H,s),7.43(1H,d),7.05(1H,dd),6.99(1H,d),6.59(2H,s),3.88(2H,s),2.50(4H,brd),1.59-1.66(8H,br)
Embodiment 64
4-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl] ethyl benzoate
Under ice-cooled, in the anhydrous tetrahydro furan suspension 100ml of 2.5g chlorination two (triphenyl phosphine) nickel, add 3.8ml (1N) diisobutylaluminium hydride-toluene solution, stir after 10 minutes, add 4.3g 4-benzene iodide ethyl formate, under-78 ℃, utilize intubate and Ar Pressure to inject then by the formulated solution of 3.0g1-(2-thienyl) six hydrogen-1-azatropylidene, 60ml anhydrous tetrahydro furan, 9.6ml (1.6N) n-Butyl Lithium-hexane solution and 5.4ml (1N) dichloride ethereal solution (ジ シ Network ロ リ De ェ-テ Le), then, at room temperature stir an evening.The reaction solution diatomite filtration, after the concentrating under reduced pressure filtrate, in residue, add the 100ml saturated sodium bicarbonate, behind 100ml chloroform extraction 3 times, merge organic layer, after the saturated common salt water washing, concentrating under reduced pressure, recycle silicon glue column chromatography is refining, then, add 4N hydrochloric acid-ethyl acetate, filter the crystallization of separating out, obtain 290mg title compound (4%).
Fusing point: 194～197 ℃
1H-NMR(δppm,DMSO-d 6)
1.34(3H,t),1.55-1.90(8H,m),3.10-3.20(2H,m),3.30-3.50(2H,m),4.33(2H,q),4.62(2H,d),7.92(1H,d),7.70(1H,d),7.82(2H,d),8.01(2H,d),9.85(1H,br)
Embodiment 65
3-amino-5-[5-[(tetramethyleneimine-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
Operate equally with embodiment 38, obtain the 580mg title compound by 1.8g (7.99mmol) 2-(1-pyrrolidyl) thiotolene-5-carboxylic acid hydrazides.
Fusing point: 180～181 ℃
1H-NMR(δppm,DMSO-d 6)
11.96(1H,brs),7.21(1H,brs),6.87(1H,brs),6.05(2H,brs),3.70(2H,s),2.51-2.48(4H,m),1.73-1.66(4H,m)
Embodiment 66
1-[5-(5-amino-1H-1,2,4-triazole-3-yl)-3-thenyl] six hydrogen-1H-azatropylidene
Operate equally with embodiment 38, obtain the 2.03g title compound by 3.32g (13.1mmol) 4-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-2-carboxylic acid hydrazides.
Fusing point: 167～168 ℃
1H-NMR(δppm,DMSO-d 6)
12.02(1H,br),7.33(1H,s),7.18(1H,s),6.03(2H,br),3.56(2H,s),2.56-2.51(4H,m),1.55(8H,s)
Embodiment 67
1-[2-[5-(5-amino-1H-1,2,4-triazole-3-yl)-2-thienyl] ethyl] six hydrogen-1H-azatropylidene
Operate equally with embodiment 38, by 3.70g (13.84mmol) 5-[2-(six hydrogen-1H-azatropylidene-1-yl) ethyl] thiophene-2-carboxylic acid hydrazides acquisition 2.39g title compound.
Fusing point: 109～110 ℃
1H-NMR(δppm,DMSO-d 6)
11.94(1H,br),7.18(1H,s),6.79(1H,s),6.00(2H,br),2.90-2.86(2H,m),2.70-2.62(6H,m),1.59-1.56(8H,m)
Embodiment 68
3-amino-5-[5-(1H-imidazoles-1-ylmethyl)-2-thienyl]-1H-1,2, the 4-triazole
Operate equally with embodiment 38, obtain the 177mg title compound by 360mg (1.36mmol) 2-(1H-imidazoles-1-yl) thiotolene-5-carboxylic acid hydrazides.
Fusing point: 178～180 ℃
1H-NMR(δppm,DMSO-d 6)
12.03(1H,brs),7.75(1H,brs),7.24(1H,d),7.22(1H,brs),7.03(1H,d),6.91(1H,brs),6.09(2H,brs),5.38(2H,brs)
Embodiment 69
2-amino-5-[5-(1H-imidazoles-1-ylmethyl)-2-thienyl]-1H-1,3,4-oxadiazole hydrobromate
Operate equally with embodiment 43, obtain the 866mg title compound by 1.11g (5.0mmol) 2-(1H-imidazoles-1-yl) thiotolene-5-carboxylic acid hydrazides.
Fusing point: 261～262 ℃
1H-NMR(δppm,DMSO-d 6)
9.28(1H,s),7.86(1H,s),7.71(1H,s),7.43(1H,s),7.37-7.34(3H,m),5.77(2H,brs)
Embodiment 70
N-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1,3,4-oxadiazole-2-yl] benzamide hydrochloride salt
In the pyridine solution 15ml of 278mg (1.0mmol) embodiment 43 compounds, add 1.8ml (15.0mmol) Benzoyl chloride, stirred 10 days in 80 ℃.The concentrating under reduced pressure reaction solution adds chloroform in residue obtained then, and anhydrous magnesium sulfate drying is used in washing.Boil off solvent, residue obtained refining with silica gel column chromatography, with ethanol-diisopropyl ether the gained coarse crystallization is carried out recrystallization again, obtain the 241mg title compound.
Fusing point: 182～184 ℃
1H-NMR(δppm,DMSO-d 6)
12.23(1H,br),10.96(1H,br),8.04(2H,d),7.75(1H,d),7.68(1H,t),7.61-7.54(3H,m),4.65(2H,s),3.45-3.43(2H,br),3.10(2H,br),1.85(4H,brs),1.65(4H,br)
Embodiment 71
1-[5-(5-benzylamino-1,3,4-oxadiazole-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene
In the acetonitrile solution 25ml of 253mg (1.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, add 0.13ml (1.05mmol) benzyl mustard oil, after the stirring at room 40 hours, add 718mg (2.2mmol) 1,2-two bromo-1,1,2,2-tetrachloroethane, 1.22ml triethylamine and 1.16g triphenyl phosphine were in stirring at room 9 hours.Concentration of reaction solution adds chloroform in residue obtained, use anhydrous magnesium sulfate drying after the washing.Boil off solvent, residue obtained refining with silica gel column chromatography, obtain the free type title compound of 122mg.Make wherein 117mg salify with 27mg oxalic acid at last, obtain the 122mg title compound.
Fusing point: 104～105 ℃
1H-NMR(δppm,DMSO-d 6)
8.42(1H,t),7.45(1H,d),7.38?7.26(7H,m),4.43(2H,d),4.32(2H,br),3.00(4H,brs),1.72(4H,brs),1.59(4H,brs)
Embodiment 72
1-[5-(5-hydroxyl-1,3,4-oxadiazole-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene
760mg (3.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides is dissolved in 30ml tetrahydrofuran (THF) and 3ml N, in the dinethylformamide, add 583mg (3.6mmol) 1 then, 1 '-carbonyl dimidazoles and 0.84ml (6.0mmol) triethylamine, reflux 3 hours.Then, concentration of reaction solution adds chloroform in residue obtained, use anhydrous magnesium sulfate drying after the washing.Boil off solvent, residue obtained refining with silica gel column chromatography, obtain the 793mg title compound.
Fusing point: 117～119 ℃
1H-NMR(δppm,CDCl 3)
8.84(1H,br),7.44(1H,d),6.91(1H,d),3.89(2H,brs),2.74-2.71(4H,m),1.74-1.58(8H,m)
Embodiment 73
1-[5-[5-(2-pyridyl)-1,3,4-oxadiazole-2-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene oxalate
In the dichloromethane solution 50ml of 1010mg (4.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, add 8ml pyridine and 1.28g pyridine formyl chloride hydrochloride, one evening of stirring at room.Behind the washed reaction liquid, use anhydrous magnesium sulfate drying.After boiling off solvent,, obtain the 1.5g crystallization with 50ml methylbenzene azeotropic 4 times.Then, under ice-cooled, in the above-mentioned crystalline dichloromethane solution of 268mg (0.75mmol) 30ml, add 0.23ml triethylamine and 140mg (0.83mol) chlorination 1,2-chloro-1,3-methylimidazole, stirring at room 4 days.Behind the washed reaction liquid, use anhydrous magnesium sulfate drying.Boil off solvent, residue obtained refining with silica gel column chromatography, obtain the free type title compound of 87mg.Make wherein 75mg salify with 19mg oxalic acid at last, obtain the 76mg title compound.
Fusing point: 217～218 ℃
1H-NMR(δppm,DMSO-d 6)
8.80(1H,d),8.25(1H,d),8.08(1H,m),7.86(1H,d),7.66(1H,m),7.33(1H,brs),4.29(2H,brs),1.72(4H,brs),1.61(4H,brs)
Embodiment 74
1-[5-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene oxalate
Operate equally with embodiment 73, obtain the 81mg title compound with 507mg (2.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides and 0.23ml (2.4mmol) diacetyl oxide.
Fusing point: 91～92 ℃
1H-NMR(δppm,DMSO-d 6)
7.68(1H,d),7.28(1H,d),4.28(2H,s),2.56(3H,s),1.71(4H,brs),1.59(6Hbrs)
Embodiment 75
1-[5-(5-phenyl-1,3,4-oxadiazole-2-yl)-2-thenyl] six hydrogen-1H-azatropylidene
In the pyridine solution 7ml of 507mg (2.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, add 687mg (4.0mmol) benzo imido acid methyl ester hydrochloride, reflux 4 hours.Concentration of reaction solution adds chloroform in residue obtained, use anhydrous magnesium sulfate drying after the washing.Boil off solvent, residue obtained with silica gel column chromatography refining after.Obtain the 110mg title compound.
Fusing point: 95～97 ℃
1H-NMR(δppm,CDCl 3)
8.13-8.10(2H,m),7.68(1H,d),7.56-7.50(4H,m),3.89(2H,s),2.72-2.70(4H,m),1.73-1.60(8H,m)
Embodiment 76
N-benzyl-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2,4-triazole-3-carboxamide
The compound of 1.0g (3.0mmol) embodiment 40 is dissolved in 3.3ml (30.0mmol) benzylamine, stirred 4 hours in 80 ℃.In reaction solution, add chloroform, use anhydrous magnesium sulfate drying after the washing.Boil off solvent, residue obtained refining with silica gel column chromatography, the isopropyl ether washing gained crystallization of reusable heat is carried out recrystallization with ethyl acetate-normal hexane to it at last, obtains the 997mg title compound.
Fusing point: 137～139 ℃
1H-NMR(δppm,DMSO-d 6)
9.20(1H,br),7.53(1H,d),7.34(5H,br),7.25(1H,t),6.99(1H,d),4.48(2H,d),3.82(2H,s),2.61(4H,brs),1.54(8H,brs)
Embodiment 77
N-benzyl-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2,4-triazole-3-base methylamine 3/2 fumarate
The anhydrous tetrahydrofuran solution 10ml of Dropwise 5 94mg (1.5mmol) embodiment 76 compounds in the anhydrous tetrahydro furan suspension 5ml of 230mg (6.0mmol) lithium aluminium hydride, reflux 11 hours.Add 460mg (12.0mmol) lithium aluminium hydride again, reflux 3 days.In reaction mixture, add sodium sulfate 10 hydrates then, behind the elimination insolubles, boil off solvent, residue obtained refining with silica gel column chromatography, obtain the free type title compound of 104mg.Make wherein 74mg salify with the 33mg fumaric acid again, use recrystallizing methanol, obtain the 63mg title compound.
Fusing point: 155～157 ℃
1H-NMR(δppm,DMSO-d 6)
7.42-7.32(5H,m),7.26(1H,m),6.97(1H,brs),6.60(3H,s),3.86-3.84(4H,m),3.80(2H,brs),2.68-2.66(4H,m),1.58(8H,brs)
Embodiment 78
Phenylformic acid [5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2,4-triazole-3-yl] methyl esters
Operation similarly to Example 6 is by the compound acquisition 351mg title compound of 292mg (1.0mmol) embodiment 41.
FABMS(Pos,m/z)397(M ++1)
1H-NMR(δppm,CDCl 3)
8.04(2H,d),7.56(1H,t),7.50(1H,d),7.41(3H,t),6.87(1H,d),5.49(2H,s),3.87(2H,s),2.74-2.66(4H,m),1.70-1.54(8H,m)
Embodiment 79
1-[5-[5-(2-pyridyl)-1H-1,2,4-triazole-3-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene
In the methanol solution 13.5ml of 1.56g (15.0mmol) 2-cyanopyridine, add 81mg (1.5mmol) sodium methylate, in stirring at room after 3.5 hours, under ice-cooled, add 0.085ml (1.5mmol) acetate and 1.52g (6.0mmol) 2-(six hydrogen-1H-azatropylidene-1-yl) thiotolene-5-carboxylic acid hydrazides, stirring at room 24 hours.The crystallization that leaching is separated out obtains the 1.97g crystallization.Make 894mg (2.5mmol) wherein be dissolved in the 13ml acetate reflux 6.5 hours then.Boil off solvent, in residue obtained, add 28% ammoniacal liquor and chloroform, layering, organic layer anhydrous magnesium sulfate drying.Boil off solvent, residue obtained refining with silica gel column chromatography, obtain the 715mg title compound.
Fusing point: 160～162 ℃
1H-NMR(δppm,DMSO-d 6)
14.74(1H,br),8.72(1H,d),8.12(1H,d),8.01(1H,dt),7.54(1H,m),7.50(1H,d),6.98(1H,d),3.83(2H,s),2.68-2.60(4H,m),1.58(8H,brs)
Embodiment 80
1-[5-(2-methyl-2H-1,2,4-triazole-3-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene hydrochloride
At 820mg (2.8mmol) embodiment 53-1) drip 0.3ml (5.59mmol) methyl hydrazine among the acetic acid solution 5ml of gained compound, reflux is added 0.6ml (11.18mmol) methyl hydrazine after 5 days again, and reheat refluxed 2 days.Boil off solvent, in residue obtained, add 28% ammoniacal liquor and chloroform, layering, organic layer is cleaned with saturated aqueous common salt, uses anhydrous magnesium sulfate drying again.Boil off solvent, residue obtained with silica gel column chromatography refining after, with 4N HCl/ ethyl acetate 0.7ml salify, use the acetonitrile recrystallization again, obtain the 204mg title compound.
Fusing point: 232～233 ℃
1H-NMR(δppm,DMSO-d 6)
10.61(1H,br),8.00(1H,d),7.69(1H,d),7.54(1H,d),4.61(2H,brs),4.07(3H,s),3.40-3.34(2H,M),3.13-3.05(2H,m),1.83(4H,brs),1.66-1.58(4H,m)
Embodiment 81
1-[5-[3-(2-pyridyl)-1H-1,2,4-oxadiazole-5-yl]-the 2-thenyl] six hydrogen-1H-azatropylidene oxalate
Operation similarly to Example 1 is with 1.07g (4.0mmol) 5-[(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl] carboxylic acid, ethyl ester and 823mg (6.0mmol) 2-pyridyl amidoxime, obtain the free type title compound of 149mg.Make wherein 72mg salify with 18mg oxalic acid at last, obtain the 57mg title compound.
Fusing point: 164～166 ℃
1H-NMR(δppm,DMSO-d 6)
8.79(1H,d),8.14(1H,d),8.08-8.03(2H,m),7.64(1H,m),7.40(1H,d),4.34(2H,s),2.98(4H,br),1.73(4H,brs),1.61(4H,brs)
Embodiment 82
1) O-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl-2-Thenoyl]-3-phthaloyl imino propionyl amidoxime
The amino propionyl amidoxime of 9.59g (93.0mmol) 3-is dissolved in 288ml 1, and 3-dimethyl-2-imidazolone adds 14.46g (97.65mM) Tetra hydro Phthalic anhydride then, and after 1 hour, 140 ℃ were stirred 2 hours in stirring at room.Reaction solution is cooled to room temperature; add triethylamine 15.6ml (111.6mM), 5-(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thiophene phosphinylidyne ammonia hydrochloric acid salt 16.4g (55.8mmol); in stirring at room after one evening; add the 720ml saturated aqueous common salt; the crystallization that filtration is separated out; after cleaning with distilled water, obtain 19.96g O-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl-2-Thenoyl]-3-phthaloyl imino propionyl amidoxime (by (six hydrogen-1H-azatropylidene-1-yl) methyl-2 thiophen carbonyl chloride hydrochloride calculate yield be 79%).
1H-NMR(δppm,DMSO-d 6)
7.85(4H,s),7.00(1H,d),6.57(1H,d),3.82(2H,s),2.51(4H,br),1.56(8H,brs)
2) methyl N-[2-[5-[5-[(six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-1,2,4-oxadiazole-3-yl] ethyl] phthalimide hydrochloride
At 2.57g O-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl-2-Thenoyl]-add 100ml dimethylbenzene, reflux 8 hours in the 3-phthaloyl imino propionyl amidoxime.After making reaction solution be cooled to room temperature, filter, add 4N hydrochloric acid-ethyl acetate 2ml down ice-cooled, the crystallization that leaching is separated out obtains 2.2g title compound (yield 82%).
Embodiment 83
1-[5-(5-amino-1H-1,2,4-triazole-3-yl)-2-thenyl] six hydrogen-1H-azatropylidene
In 24.0g (81.6mmol) 5-(six hydrogen-1H-azatropylidene-1-yl) methyl-2 thiophen carbonyl chloride hydrochloride, add 500ml 1,3-dimethyl-2-imidazolone and 18.0g (163.2mM) GER-11, after the stirring at room 1 hour, add 16.3g (60% oiliness, 408mM) sodium hydride stirs an evening in 130 ℃.Reaction solution is cooled to room temperature, adds 50ml water and 500ml normal hexane, make its layering, after lower floor adds the 1000ml saturated aqueous common salt, use 500ml ethyl acetate extraction 7 times.Ethyl acetate layer with anhydrous sodium sulfate drying after, concentrating under reduced pressure adds the 1000ml acetonitrile then, ice-cooled down, add 4N hydrochloric acid/ethyl acetate 150ml again, the crystallization that leaching is separated out.Add 1N sodium hydroxide 200ml in the gained crystallization, use 200ml ethyl acetate extraction 3 times, again with behind the anhydrous sodium sulfate drying, be evaporated to 1/10 amount, the crystallization that leaching is separated out obtains 10.4g title compound (yield is 51%).
Enumerated the chemical structural formula of the compound of the foregoing description 1～83 gained in the following table.
Figure A9719596300561
Figure A9719596300571
Figure A9719596300581
Figure A9719596300591
Except above-named compound, method and amended slightly method or preparation method known to a person of ordinary skill in the art and amended slightly method thereof according to aforementioned preparation method, embodiment record do not need special experiment just can synthesize following compound.
5-benzylamino-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-amino-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-thiadiazoles
5-benzyl urea groups-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-thiadiazoles
5-benzamido-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-thiadiazoles
5-benzylamino-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-thiadiazoles
5-amino methyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-phthalimidomethyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
3-benzyl urea groups-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-oxadiazole
3-benzamido-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-oxadiazole
2-benzamido-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,3, the 4-oxadiazole
2-benzylamino-5-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,3, the 4-oxadiazole
4-benzyl urea groups-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
4-benzamido-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-benzyl urea groups-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-benzamido-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
1-benzyl-3-[[3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2,4-triazole-5-yl] methyl] urea
5-benzene carbon amide ylmethyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-benzyloxy methyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-benzyloxy methyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-benzoyloxy methyl-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
N-benzylamino formic acid [3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2,4-triazole-5-yl] methyl esters
5-amino-3-[5-[(tetramethyleneimine-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
5-amino-3-[4-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the 4-triazole
1-[5-(2-pyridyl)-2-thenyl] six hydrogen-1H-azatropylidene
1-[5-(2-furyl)-2-thenyl] six hydrogen-1H-azatropylidene
1-[5-(2-pyrimidyl)-2-thenyl] six hydrogen-1H-azatropylidene
1-[5-(4-amino-2-pyridyl)-2-thenyl] six hydrogen-1H-azatropylidene
1-[5-(4-aminophenyl)-2-thenyl] six hydrogen-1H-azatropylidene
5-amino-3-[5-(six hydrogen-1H-azatropylidene-1-yl) methyl-2-thienyl]-1,2, the 4-oxadiazole
2-amino-4-[5-(six hydrogen azatropylidene bases) methyl-2-thienyl] imidazoles

Claims (11)

1. the salt that allows on the thiophene derivant derivative that logical formula I is represented or its pharmacopedics,
Figure A9719596300021
(symbol has following implication in the formula:
R 1: formula-A 1-X 1-R 3,
R 2: formula-A 2-X 2-R 4Or do not exist,
B ring: 1) 4～10 yuan of nitrogenous cycloalkyl rings or
2) 5～6 yuan of nitrogenous unsaturated heterocycles,
The Ar ring: can have substituent aromatic ring or comprise 1～4 heteroatomic 5～6 yuan of hetero-aromatic ring or 8～10 yuan of dicyclo class hetero-aromatic rings that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom more than a kind or 2 kinds,
A 1, A 2And A 3: identical or different key or low-grade alkylidene,
X 1And X 2: identical or different key, formula-O-,-S-,-NR 5-,
Figure A9719596300023
Or-C ≡ C-,
R 5, R 6, R 7, R 8, R 9, R 10, R 11, R 12And R 13: be hydrogen atom or low alkyl group identical or differently,
R 3And R 4: identical or differently for hydrogen atom, can have substituently can maybe can have substituent low alkyl group, cycloalkyl, aryl or aralkyl respectively with the cyclic imide base of phenyl ring condensation),
But, when the Ar ring is thiazole ring, A 1And A 2In any be low-grade alkylidene, in addition, Ar ring is during for phenyl ring, R 1And R 2In any be methyl or halogen, another is for except the situation of hydrogen atom).
2. the salt that allows on thiophene derivant as claimed in claim 1 or its pharmacopedics, B ring wherein is 4～10 yuan of nitrogenous cycloalkyl rings.
3. the salt that allows on thiophene derivant as claimed in claim 1 or 2 or its pharmacopedics, B ring wherein is six hydrogen azatropylidene rings.
4. the salt as allowing on each described thiophene derivant of claim 1～3 or its pharmacopedics, A wherein 3Be methylene radical.
5. the salt as allowing on each described thiophene derivant of claim 1～4 or its pharmacopedics, Ar wherein encircles to comprise 2 or 3 heteroatomic 5 yuan of hetero-aromatic rings that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom more than a kind or 2 kinds, or comprises 2～4 heteroatomic 9 yuan of hetero-aromatic rings that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom more than a kind or 2 kinds.
6. the salt as allowing on each described thiophene derivant of claim 1～5 or its pharmacopedics, Ar ring wherein is triazole, oxadiazole, thiazole, thiadiazoles, imidazopyridine, imidazopyrimidine, Triazolopyridazines.
7.5-[5-[(methyl six hydrogen-1H-azatropylidene-1-yl)]-the 2-thienyl]-3-phthaloyl sub-aminoethyl-1,2,4-oxadiazole, 5-amino-3-[5-[(six hydrogen-1H-azatropylidene-1-yl) methyl]-the 2-thienyl]-1H-1,2, the salt that allows on 4-triazole or its pharmacopedics.
8. a medical composition is characterized in that, is made up of the carrier that allows on salt that allows on each described thiophene derivant of claim 1～7 or its pharmacopedics and the pharmacopedics.
9. medical composition as claimed in claim 8, its feature also are, are anti-PCR medicine.
10. medical composition as claimed in claim 9, its feature are that also anti-PCR medicine is psychotropic drug, antischizophrinic thing.
11. medical composition as claimed in claim 9, its feature are that also anti-PCR medicine is the dementia medicine, can improve dull-witted with medicine, the therapeutical agent of children's's hyponea and/or the therapeutical agent of autism of abnormal behaviour.
CN 97195963 1996-07-01 1997-06-30 Novel thiophene derivatives and drug compositions containing the same Pending CN1223648A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896482B (en) * 2007-12-10 2013-01-09 埃科特莱茵药品有限公司 Novel thiophene derivatives as S1P1/EDG1 agonist

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101896482B (en) * 2007-12-10 2013-01-09 埃科特莱茵药品有限公司 Novel thiophene derivatives as S1P1/EDG1 agonist

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