CN1033327C - Process for preparing tricyclotriazolo derivatives and their use - Google Patents

Process for preparing tricyclotriazolo derivatives and their use Download PDF

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CN1033327C
CN1033327C CN 92103991 CN92103991A CN1033327C CN 1033327 C CN1033327 C CN 1033327C CN 92103991 CN92103991 CN 92103991 CN 92103991 A CN92103991 A CN 92103991A CN 1033327 C CN1033327 C CN 1033327C
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methyl
piperidines
hnmr
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CN1066849A (en
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柴山胜弘
牧野哲也
今冈孝之
加藤彻哉
金子正之
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Toray Industries Inc
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Abstract

A novel tricyclic triazole derivative represented by general formula (I) and a pharmacologically acceptable salt thereof, useful as an antiinflammatory, antiallergic and anti-PAF drug, and a process for the production thereof.

Description

The manufacture method of three ring triazolo derivatives
The effect to platelet activity factor (PlateletActivating Factor-hereinafter to be referred as PAF) of the invention relates to have strong antagonism and have antihistamine effect, be applicable to useful new three ring triazolo derivatives, its Manufacturing approach and use as anti-inflammatory agent, anti-allergy agent.
In recent years, PAF has caused people's attention, and recently, it is more and more clearer that the cognation between PAF and various diseases is becoming.Promptly, verified, the rejection when PAF and inflammation, allergic disease, anaphylactic shock, lung mass formed by blood stasis shock, DIC, endotoxin shock, myocardium systemic disease, asthma, lung edema, digestive tract ulcer, ephritis, hepatitis and victory device are transplanted etc. has relation.(referring to modern chemistry supplementary issue 17, platelet activity factor-biochemical physiological and pathological-and respect Tibetan, aboveground Gui three volumes for a long time, the Tokyo chemistry is with people 1989).Therefore, people expectation has the compound of antagonism maybe can also have result of treatment to other disease of PAF antagonism to above-mentioned disease to the effect of PAF.
In fact, from the administration of PAF antagonist is suppressed typical inflammatory reaction, i.e. the local anaphylaxis of rat can be disclosed in the inflammatory reaction relation (Jpn.J.Pharmacol., 46,55P (1988)) with PAF.
On the other hand, with the PAF diseases associated in, know, in allergic disease except PAF because the result of antigen antibody reaction also discharges histamine, leukothrombin chemical transmitters such as (ロ イ コ ト リ エ Application) from each cell.Therefore, the compound that can expect to have simultaneously PAF antagonistic action and antihistamine effect has more effective resistance than independent PAF antagonist or independent antihistaminic agent and should act on.
At present, can enumerate thieno-triazolo-1,4-diaza based compound (spy open clear 61-176591, spy open flat 2-256681, the spy opens flat 2-256682) as known anti-PAF agent.In addition, as the compound that has antihistamine effect and PAF antagonistic action simultaneously, the present known benzocyclohepta pyridine based compound (No. 270818, EP) that has only.
In addition, as the existing known example of triazolo quinoxaline derivatives, but only report says to have anti-uneasy effect (J.Heterocyclic Chem., 27,691 (1990)).
On the other hand, report says that the triazolo benzimidazole compound has anti-microbial effect, and concrete have a following compound (Pestic.Sci., 29,143 (1990)).
Figure C9210399100091
What in addition, have a synthetic report has a following compound (J.Heterocycl.Chem., 15,1027 (1978)).
Figure C9210399100092
But, the report of anti-PAF effect, anti-allergy effect is not arranged as yet about above-claimed cpd.
Therefore, people's a kind of new, useful anti-PAF agent that waits in expectation, it has prevention and result of treatment for the very wide disease of scope.In addition, the antiallergic drugs that people also wait in expectation and not only have anti-PAF effect but also have antihistamine effect simultaneously is in order to prevent and to treat allergy, diseases associated with inflammation.
The objective of the invention is, a kind of salt of allowing on three new ring triazolo derivatives PAF antagonistic action and antihistamine effect, that can be used as antiphlogistic drug, antiallergic drugs, anti-PAF medicine and the pharmacology thereof that has simultaneously is provided.In addition, the present invention also aims to be provided for making the intermediate of above-claimed cpd.A further object of the invention provides the manufacture method of triazolo derivative of the present invention.
The invention provides the salt of allowing on the new three ring triazolo derivatives represented by (I) formula, its pharmacology and with its antiphlogistic, anti-allergy agent and anti-PAF agent as effective constituent.
Figure C9210399100101
(in the formula, R 1The cycloalkyl of expression hydrogen, low alkyl group or carbonatoms 3-5, R 2, R 3Represent hydrogen, low alkyl group, lower alkoxy or halogen respectively, W represents C=O, CR 4R 5(R 4, R 5Represent hydrogen, low alkyl group respectively), A represents straight or branched, the saturated or undersaturated alkylidene group of carbonatoms 1-5, also can contain heteroatoms, and l represents 0-2, and n represents 1-3, and  represents singly-bound or two key, and Y represents N or C, and Z represents C (B) Ar 1Ar 2(B represents hydrogen, hydroxyl or methoxyl group, Ar 1, Ar 2Represent the aryl of hydrogen, replacement or non-replacement respectively), CAr 1Ar 2(Ar 1, Ar 2The same), O-CHAr 1Ar 2(Ar 1, Ar 2The same) or condense aromatic nucleus.In addition, the present invention also provides as the dihydro triazolo quinoxaline derivatives intermediate of the triazolo derivative of the invention described above, that represented by (II) formula.
Figure C9210399100111
(in the formula, R 1, R 2, R 3, R 4And R 5Implication the same, J represent hydrogen or-A-B (implication of A is the same, B represent halogen ,-OR 10(R herein 10Represent pure protecting group) or-CO 2L (L herein represents hydrogen or low alkyl group)).
According to the present invention, provide to have new triazolo derivative antihistaminic effect and PAF antagonistic action, that can be used as anti-allergy agent, antiphlogistic or anti-PAF agent simultaneously.The salt of allowing on derivative of the present invention and the pharmacology thereof gives the phase except the above, all has for the various diseases relevant with histamine and PAF and gives anti-and result of treatment.Particularly can also be used to as anti-asthma agent, shock symptom negative catalyst, therapeutic agent for thrombosis etc.
In the definition of above-mentioned each symbol, halogen refers to fluorine, chlorine, bromine and iodine; Moieties in low alkyl group and the lower alkoxy refers to the alkyl of the straight or branched of carbonatoms 1-6, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl etc.Wherein, can enumerate methyl, ethyl as optimal group.In the definition of A, the straight or branched of so-called carbonatoms 1-5, saturated or undersaturated alkylidene group is represented be for example methylene radical, ethylidene, propylidene, tetramethylene, pentamethylene, methyl ethylidene, ethyl ethylidene, methyl propylidene, ethyl propylidene, methyl tetramethylene or following shown in structure.-CH 2-CH=CH--CH 2-CH=CH-CH 2--CH 2-C ≡ C--CH 2-C ≡ C-CH 2--CH 2OCH 2CH 2--CH 2CH 2OCH 2CH 2--CH 2CH (OH) CH 2Ar in the definition of-Z 1, Ar 2As aromatic hydrocarbons, the aryl of for example representing carbonatoms 6-10 such as phenyl, naphthyl also comprises annelated heterocycles such as furyl, thienyl, pyridine, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazoles, pyrazolyl or benzofuryl, benzothienyl, indyl, quinolyl, isoquinolyl as heterocycle.That substituting group in the above-mentioned definition in each group refers to is identical or different, replace number is the substituting group on aromatic ring of 1-3, alkyl, the alkoxyl group of carbonatoms 1-6, acyl group, alkylsulfonyl, halogen, haloalkyl, alkylamino, nitro, cyano group, hydroxyl, sulfydryl, the alkylthio that they are selected from carbonatoms 1-6.Therefore, so-called substituted aryl refers to the 4-chloro-phenyl-, the 4-bromophenyl, the 4-fluorophenyl, the 4-aminomethyl phenyl, the 4-p-methoxy-phenyl, the 4-trifluoromethyl, the 3-chloro-phenyl-, the 3-bromophenyl, the 3-fluorophenyl, the 3-aminomethyl phenyl, the 3-p-methoxy-phenyl, the 3-trifluoromethyl, the 2-chloro-phenyl-, the 2-bromophenyl, the 2-fluorophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 2-trifluoromethyl, 2, the 3-dichlorophenyl, 3, the 4-dichlorophenyl, 2, the 3-Dimethoxyphenyl, 3, the 4-Dimethoxyphenyl, 3,4, the 5-trimethoxyphenyl, 5-methyl-2-thienyl, 5-methyl-3-thienyl, 5-methyl-4-thienyl, 5-methyl-2-pyridyl, 5-methyl-3-pyridyl, 5-methyl-4-pyridyl etc.The aralkyl of described replacement or non-replacement refers to for example benzyl, 4-luorobenzyl, 4-benzyl chloride base, 2-thienyl methyl, 2-furyl methyl etc., preferably 4-luorobenzyl.Described fused aromatic rings refers to for example naphthalene, quinoline, benzoglyoxaline, cumarone, thionaphthene, benzoisoxazole, benzothiazole, imidazopyridine etc., preferably below shown in substituting group.
Figure C9210399100131
Described alkoxyalkyl for example refers to ethoxyethyl group, methoxy ethyl, methoxy-propyl etc., preferably ethoxyethyl group.Described by R 10The pure protecting group of expression for example can be enumerated the such low alkyl group of methyl, ethyl, sec.-propyl, benzyl, THP trtrahydropyranyl, methoxymethyl, methylthiomethyl etc.
As admissible salt on the pharmacology of (I) formula compound, can enumerate amino acid addition salts such as organic acid salts such as inorganic acid salts such as hydrochloride, hydrogen bromide salt, vitriol, borate, phosphoric acid salt, acetate, maleate, fumarate, tartrate, succinate, malate, lactic acid salt, Citrate trianion, malonate, benzoate, tosilate and Methionin, glycine, phenylalanine, L-glutamic acid.
The following describes the manufacture method of the compound of representing by (I) formula.But the manufacture method of each compound is not limited to these, in addition, suitably selects in the content that reaction conditions can be put down in writing from below in various manufacture method.
The compound that (I) of the present invention formula is represented can be made as described below:
Make hydrogen halide solution act on the represented compound of (III) formula
Figure C9210399100141
(in the formula, R 1, R 2, R 3, R 10, A, W, l implication the same), obtain the compound that (XVII) formula is represented
Figure C9210399100142
(X represents halogen atom in the formula, R 1, R 2, R 3, A, W, l implication the same), make compound of (IV) formula or compound or its acid salt that its acid salt (organic acid salts such as inorganic acid salts such as hydrochloride, vitriol, acetate) acts on (XVII) formula again. (Y, Z in the formula, n,  implication the same)
In the aforesaid method, can enumerate aqueous solution of hydrogen bromide, hydrogen bromide-acetic acid solution, concentrated hydrochloric acid etc. as hydrogen halide solution.When making hydrogen halide solution act on (III) formula compound, temperature of reaction is generally 30 ℃ to the solvent for use boiling point, the reaction times generally be 10 minutes to 1 week.The compound of representing by (XVII) formula that is generated, by adding the aqueous solution of sodium hydroxide, salt of wormwood, yellow soda ash, sodium bicarbonate etc., use organic solvent extraction, promptly can obtain, also can after reaction, heat up in a steamer dried solvent, the reaction below carrying out with the acid salt form.
(XVII) compound shown in the formula or its acid salt and (IV) reaction of the compound shown in the formula or its acid salt, usually in to the not active solvent of reaction (N, dinethylformamide, N,N-DIMETHYLACETAMIDE, 2-butanone, ethanol, propyl carbinol, tetrahydrofuran (THF), methylene dichloride etc. or their mixed solvent), carry out 10 minutes to a week.Temperature of reaction is preferably in 0 ℃-150 ℃, in order to improve speed of response, can react as catalyst with mineral alkalis such as organic basess such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, hydrolith, potassiumiodide, Potassium ethanoates.
In addition, (I) compound of formula can adopt the compound of (V) formula synthetic as follows as raw material.
That is, make compound of (V) formula and (VI) the compound reaction of formula, can obtain the compound of (I) formula.
Figure C9210399100151
(R in the formula 1, R 2, R 3, W, l implication same as above)
Figure C9210399100161
(X represents halogen atom in the formula, and A, Y, Z, n,  implication are same as above)
Be reflected in the reaction not active solvent (dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diox etc.) and have under the condition that mineral alkali (sodium hydride, potassium hydride KH, sodium amide, potassium hydroxide, tert.-butoxy potassium etc.) or organic bases (pyridine, triethylamine etc.) exist, to the reflux temperature of solvent for use, carried out 5 minutes to 5 hours at 0 ℃.
In addition, (I) compound of formula can also adopt the compound of (XVIII) formula to make as follows as raw material.
That is, make the compound of (XVIII) formula (R in the formula 2, R 3, A, W, Y, Z, l, n,  implication the same) wait with thiophosphoric anhydride, Lawesson reagent (registered trademark) and to vulcanize reagent reacts, obtain the compound of (XIXa) formula
Figure C9210399100171
(R in the formula 2, R 3, A, W, Y, Z, l, n,  implication with above) reaction carrying out under 30-100 ℃ 1 minute to 5 hours in to the not active solvent of reaction (pyridine, acetonitrile, toluene, dimethylbenzene, tetrahydrofuran (THF), chloroform, diox, diethyl ether, diglyme etc.) usually.
Perhaps, make the compound and the halogenating agent reaction of (XVIII) formula, obtain the compound of (XIXb) formula
Figure C9210399100172
(x represents halogen atom in the formula, R 2, R 3, A, W, Y, Z, l, n,  implication be with above) can enumerate phosphorus oxychloride, thionyl chloride, phosphorus trichloride etc. and thionyl chloride dimethyl formamide, phosphorus oxychloride-N-methyl formyl aniline etc. as halogenating agent.Be reflected in the not active solvent of reaction (benzene,toluene,xylene, chloroform etc.), to the solvent for use reflux temperature, carried out 5 minutes to 6 hours in 0 ℃.
Perhaps, make the compound and the alkylation reactions of (XVIII) formula, obtain the compound of (XIXc) formula
Figure C9210399100181
(R in the formula 11The expression low alkyl group, R 2, R 3, A, W, Y, Z, l, n,  implication be same as above.Can enumerate trialkyl oxygen a tetrafluoro borate, dialkyl group sulfuric acid etc. as alkylating agent.
Make represented compound of above operation resulting (XIXa), (XIXb), (XIXc) formula and (VIII) the represented compound of formula
R 1CONHNH 2(VIII) (R in the formula 1Implication is together above) in to the not active solvent of reaction (dimethylbenzene, propyl carbinol, n-hexyl alcohol, acetonitrile, hexalin etc.), to the solvent for use reflux temperature, reacted 30 minutes to 6 hours in 50 ℃, can obtain the compound of (I) formula.At this moment, for improving speed of response, can under the situation of organic acid (acetate, propionic acid etc.), mineral acid (hydrochloric acid, sulfuric acid etc.) or silica gel, react.
In addition, (I) compound of formula also can obtain as follows:
Make (XIXa), (XIXb) or (XIXc) the represented compound of formula and hydrazine reaction 5 minutes to 3 hours in to the not active solvent of reaction (methyl alcohol, ethanol, n-propyl alcohol, propyl carbinol) and under 0 ℃ of-50 ℃ of temperature, make the resulting compound of representing by (XX) formula
Figure C9210399100191
(R in the formula 2, R 3, A, W, Y, Z, l, n,  implication be the same) this compound again with the compound of representing by (X) formula
R 1C (OR 12) 3(X) (R in the formula 12Expression low alkyl group, R 1Implication is the same) or by (XI) expression compound
R 1CO 2H (XI) (R in the formula 1Implication is the same) or its reactive derivatives in to reaction not active solvent (toluene, dimethylbenzene, methyl alcohol, ethanol, propyl carbinol, acetonitrile, diox etc.) and 0 ℃ reacted 10 minutes to 8 hours down to the reflux temperature of solvent for use.At this moment, for improving speed of response, can under the condition that organic acid (acetate, propionic acid etc.), mineral acid (hydrochloric acid, sulfuric acid etc.) or silica gel exist, react.
In the compound of (I) formula representative, (Ib) formula (G represents CR in the formula 4R 5, q represents 0 or 1, R 1, R 2, R 3, R 4, R 5, A, Y, Z, n,  implication be the same) represented compound can be by making (XII) formula
Figure C9210399100201
(R in the formula 1, R 2, R 3, A, G, Y, Z, n, q,  implication be the same) represented compound and reductive agent reaction and creating.
As the reaction in employed reductive agent can list lithium aluminium hydride, aluminium alkane, borane, sodium borohydride, lithium borohydride etc., temperature of reaction be 0 ℃ to the solvent for use reflux temperature, the reaction times is 5 minutes to 6 hours.
In the compound of formula (I) representative, the compound of representing by (Ic) formula
Figure C9210399100202
(R in the formula 1, R 2, R 3, Ar 1, Ar 2, A, W, l, n implication be the same) can be by making the compound of (XIII) formula
Figure C9210399100203
(R in the formula 13The expression low alkyl group, R 1, R 2, R 3, A, W, l, n, implication be the same) or (XIV) compound of formula
Figure C9210399100211
(Ar in the formula 1, R 1, R 2, R 3, A, W, l, n, implication be the same) with (XV) compound of formula
(X represents that halogen atom, Ar represent Ar to ArMgX (XV) in the formula 1And/or Ar 2, Ar 1, Ar 2Implication is the same) or (XVI) compound of formula
(Ar represents Ar to ArLi (XVI) in the formula 1And/or Ar 2, Ar 1, Ar 2Implication is the same) reaction and create.
Reaction is to reach-78 ℃ to carry out 5 minutes to 10 hours to the solvent for use reflux temperature in to the not active solvent of reaction (diethyl ether, tetrahydrofuran (THF) etc.).
By the represented compound of (Id) formula
Figure C9210399100212
(R in the formula 1, R 2, R 3, Ar 1, Ar 2, A, W, l, n implication be the same) can prepare by the compound dehydration that makes (Ic) formula.
Dewatering agent can use strong acid such as concentrated hydrochloric acid, the vitriol oil or thionyl chloride etc., carries out 5 minutes to 5 hours under 0 ℃-100 ℃.
In above-mentioned reaction, the compound of formula can be by following reaction process preparation as (XIII) formula of raw material or (XIV).
Figure C9210399100221
Make the compound of (XIV) formula (R in the formula 13, the n implication is the same) with (XXII) compound of formula
X-A-X 1(XXII) (the A implication is the same in the formula, X, X 1Can be identical or different, the expression halogen) reaction, obtain the compound represented by (XXIII) formula, (A, X, R in the formula 13, the n implication is the same).Then, make compound of (XXIII) formula and (V) the compound reaction of formula, obtain the compound of (XIII) formula.
(XXI) compound of formula and (XXII) reaction of the compound of formula can carry out 10 fens to 1 week in to the not active solvent of reaction (dimethyl formamide, N,N-DIMETHYLACETAMIDE, 2-butanone, ethanol, propyl carbinol, tetrahydrofuran (THF), methylene dichloride etc. or their mixed solvent) and under 0 ℃-150 ℃.In addition, preferably add mineral alkalis such as organic basess such as triethylamine, pyridine, salt of wormwood, yellow soda ash, sodium bicarbonate, hydrolith, potassiumiodide, Potassium ethanoate as catalyzer.
(XXIII) compound of formula and (V) reaction of the compound of formula are in to the not active solvent of reaction (dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diox etc.) and under mineral alkali (sodium hydride, potassium hydride KH, sodium amide, potassium hydroxide, tert.-butoxy potassium etc.) or organic bases (pyridine, the triethylamine etc.) situation about existing, carried out 5 minutes to 5 hours to the solvent for use reflux temperature at 0 ℃.
(XXV) compound that the compound of formula can be by making (XXIV) formula reacts with (XXII) compound of formula and prepares.Reaction becomes (XXIII) formula compound identical operations according to the compound with (XXI) formula and carries out.(XIV) compound of formula can prepare by making (XXV) formula compound and the reaction of (V) formula compound.Reaction is carried out according to becoming the same operation of (XIII) formula compound with (XXIII) formula compound.
The following describes the manufacture method that in above-mentioned reaction, is used as the compound of raw material.
The manufacture method of the compound that (III) formula is represented at first is described.
(III) W is the synthetic of the compound (IIIa) that equaled 1 o'clock of C=0, l in the formula
Figure C9210399100241
(R in the formula 1, R 2, R 3, R 10, the A implication is the same)
(III) compound represented of (IIIa) formula in the compound of formula representative can adopt the compound of (XXVI) formula to make by following reaction process as initial substance.
Figure C9210399100242
Figure C9210399100251
That is, make the compound of (XXVI) formula and (XXVII) compound of formula
H 2N-A-OR 10(XXVII) (R in the formula 10, the A implication is the same) reaction, obtain the compound of (XXVIII) formula.Be reflected under the situation that does not have solvent, perhaps carrying out 1 hour to 1 month under in room temperature to the solvent for use reflux temperature in the presence of ortho-water or organic solvent (tetrahydrofuran (THF), ethanol, benzene, toluene, dimethyl formamide etc.) or their mixture.In order to promote reaction, also can in reactive system, there be reductor simultaneously.Can list mineral alkalis such as organic basess such as pyridine, triethylamine, salt of wormwood, yellow soda ash as reductor.
Make the compound reduction of (XXVIII) formula can obtain the compound of (XXIX) formula.Reaction for example can use platinum oxide, palladium, how to draw contact reduction such as nickel, carries out in water or organic solvent (methyl alcohol, ethanol, dimethyl formamide etc.) and under the 1-50 normal atmosphere.At this moment in reactive system also Ke Yi Tong Time have acetate, hydrochloric acid etc.Also can use metals such as iron, zinc, tin, under acidic conditionss such as hydrochloric acid, acetate, reduce.Under the situation of using zinc powder, can under neutrality or alkaline condition, carry out.In addition, also can utilize metal hydride (lithium aluminium hydride, sodium borohydride etc.) to reduce in inactive solvent (ether, tetrahydrofuran (THF), diox etc.), perhaps the sulphur based compound with sodium sulphite, sodium sulfhydrate, inferior two sulphur yellow soda ash etc. reduces in ethanol, toluene, water, ammoniacal liquor equal solvent.Reaction conditions is different according to the situation of method of reducing, generally is to carry out 30 minutes to a week under 0 ℃ of-100 ℃ of temperature.
Make compound of (XXIX) formula and (XXX) formula
Figure C9210399100261
(E represents OR in the formula 14, X, R 14Expression hydrogen or low alkyl group, X represents halogen atom) represented oxalic acid derivatives reaction, obtain the compound of (XXXI) formula.Be reflected in the non-active solvent (orthodichlorobenzene, toluene, dimethylbenzene etc.) and 0 ℃ to the solvent refluxing temperature, carried out 5 minutes to 6 hours.
For the compound of (XXXI) formula, according to become (XIXa-c) formula compound by (XVIII) formula compound and operate equally, can obtain the compound of (XXXII) formula, (in the formula Q represent halogen ,-SH or-OR 11(R 11Represent low alkyl group)).
For the compound of (XXXII) formula, similarly operate according to becoming (I) formula compound with compound by (XIXa-c) formula, can obtain the compound of (IIIa) formula.W is CR in the formula (III) 4R 5, l is 1 o'clock compound (IIIb) synthetic (R in the formula 1, R 2, R 3, R 4, R 5, R 10, the A implication is the same)
In the compound of (III) formula representative, (IIIb) compound of formula can be by obtaining by following reaction process as initial substance with (XXVI) formula compound.
Figure C9210399100272
Make the compound of (XXVI) formula and (XXXIII) compound of formula
Figure C9210399100281
(R in the formula 15The expression low alkyl group, R 4, R 5, R 10, the A implication is the same) reaction, obtain the compound of (XXXIV) formula.Reaction is according to similarly operating with becoming from (XXVI) formula compound to (XXVIII) formula compound.Make the compound reduction of (XXXIV) formula just obtain the compound of (XXXV) formula then.Reaction according to become (XXIX) formula compound from (XXVIII) formula compound and similarly operate.Then, according to similarly (XXXV) formula compound being operated with becoming from (XVIII) formula compound, obtain the compound of (XXXVI) formula to the compound of (XIXa-c) formula.To the compound of (XXXVI) formula, according to become (I) formula compound from (XIXa-c) formula compound and similarly operate, just obtained the compound of (IIIb) formula.
In above-mentioned reaction process, (XXXIII) compound of formula can be by following reaction manufacturing Make compound of (XXVII) formula and (XXXVII) formula (X represents halogen in the formula, R 4, R 5, R 15Implication is the same) reaction of represented compound, can make the compound of (XXXIII) formula.Be reflected in the non-active solvent (tetrahydrofuran (THF), ethanol, 2-butanone, benzene, toluene etc.) and 0 ℃ to the solvent for use reflux temperature, carried out 5 minutes to 24 hours.L is 0 o'clock compound (IIIc) synthetic in the formula (III)
Figure C9210399100292
(R in the formula 1, R 2, R 3, R 10, the A implication is the same)
In the compound of (III) formula representative, (IIIc) compound of formula can be that initial substance makes by following reaction process by the compound with (XXIX) formula.
Figure C9210399100293
Figure C9210399100301
Make the compound and the urea reaction of (XXIX) formula, obtain the compound of (XXXVIII) formula.Be reflected to reach under 80 ℃ of-200 ℃ of temperature under the condition that does not have solvent and carried out 20 hours.Then,, similarly operate, can obtain the compound of (XXXIX) formula according to becoming (XIXa-c) formula compound by (XVIII) formula compound to the compound of (XXXVIII) formula.At last, to the compound of (XXXIX) formula, according to become (I) formula compound by (XIXa-c) formula thing and similarly operate, can obtain the compound of (IIIc) formula.
(III) W is CR in the formula 4R 5, l is 2 o'clock compound (IIId) synthetic
Figure C9210399100302
(R in the formula 1, R 2, R 3, R 4, R 5, R 10, the A implication is the same)
In the compound of (III) formula representative, (IIId) compound of formula can be by being that initial substance makes according to following reaction process with (XXIX) formula compound.
Figure C9210399100311
Make compound of (XXIX) formula and (XL) formula
Figure C9210399100312
(E represents OR in the formula 14, X, R 14Expression hydrogen, low alkyl group, X represents halogen, R 4, R 5Implication is the same) compound reaction, obtain the compound of (XLI) formula.Reaction is similarly operated according to becoming (XXXI) formula compound with compound by (XXIX) formula.Then,, similarly operate, can obtain the compound of (XLII) formula according to the compound that is transformed into (XIXa-c) formula with compound by (XVIII) formula to the compound of (XLI) formula.Subsequently, to the compound of (XLII) formula, according to be transformed into (I) formula compound by (XIXa-c) formula compound and similarly operate, can obtain the compound of (XLIII) formula.At last, make the compound reduction of (XLIII) formula can obtain the compound of (IIId) formula.Can enumerate lithium aluminium hydride, aluminium alkane, borane, sodium borohydride, lithium borohydride etc. as the reductive agent that uses in the reaction, temperature of reaction be 0 ℃ to the solvent for use reflux temperature, 5 minutes to 6 hours reaction times.
In addition, (III) compound of formula can be made by the alkylation that makes (V) formula.That is compound that, can be by making (V) formula and (XLIV) formula
X-A-OR 10(XLIV) (X is a halogen in the formula, R 10, the A implication is the same) represented compound reacts and makes.Reaction is preferably having mineral alkalis such as yellow soda ash, potassium hydride KH, sodium hydride, sodium amide, hydrolith, tert.-butoxy potassium; Under the situation that organic bases such as triethylamine, pyridine or their mixture exist, in non-active solvent (ethanol, propyl carbinol, dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diox, 2-butanone etc.), reach 0 ℃ and to the solvent for use boiling temperature, carried out 1 minute to 24 hours.
The following describes the manufacture method of (V) formula compound.(Va) W is that C=0, l are 1 o'clock compound (Va) synthetic in the formula
Figure C9210399100331
(R in the formula 1, R 2, R 3Implication is the same)
In the compound of (V) formula representative, (Va) compound of formula can be that raw material is by following reaction process manufacturing by the compound with (XLV) formula.
Make compound of (XLV) formula and (XXX) the compound reaction of formula, can obtain the compound of (XLVI) formula.Reaction is similarly operated according to the compound that is transformed into (XXXI) formula with compound by (XXIX) formula.Then, to (XLVI) formula compound, according to be transformed into (XIXa-c) formula compound by (XVIII) formula compound and similarly operate, can obtain the compound of (XLVII) formula.At last,, similarly operate, can obtain the compound of (Va) formula according to the compound that is transformed into (I) formula with compound by (XIXa-c) formula to the compound of (XLVII) formula.
(V) W is CR in the formula 4R 5, l is 1 o'clock compound (Vb) synthetic (R in the formula 1, R 2, R 3, R 4, R 5Implication is the same)
In the compound of (V) formula representative, (Vb) compound of formula can be that raw material is by following reaction process manufacturing by the compound with (XLV) formula.
Figure C9210399100342
Make compound of (XLV) formula and (XLVIII) formula
X-CR 4R 5(E represents OR to-CO-E (XLVIII) in the formula 14, X, R 14Expression hydrogen, low alkyl group, X represents halogen, R 4, R 5Implication is the same) reaction of represented compound, can obtain the compound of (XLIX) formula.Be reflected in the inactive solvent (tetrahydrofuran (THF), ethanol, 2-butanone, benzene, toluene etc.) and 0 ℃ to the solvent for use reflux temperature, carried out 5 minutes to 24 hours.To the compound of (XLIX) formula,, can obtain the compound of (L) formula according to similarly operating with the compound that is transformed into (XIXa-c) formula by (XVIII) formula compound.To the compound of (L) formula, be transformed into (I) formula compound according to compound and similarly operate by (XIXa-c) formula, can obtain the compound of (Vb) formula.
(V) l is 0 o'clock compound (Vc) synthetic in the formula
Figure C9210399100351
(R in the formula 1, R 2, R 3Implication is the same)
In the compound of (V) formula representative, (Vc) compound of formula can be that raw material is by following reaction process manufacturing by the compound with (XLV) formula.
Figure C9210399100361
Make the compound and the urea reaction of (XLV) formula, can obtain the compound of (LI) formula.Reaction is similarly operated according to the compound that is transformed into (XXXVIII) formula with compound by (XXIX) formula.To the compound of (LI) formula, similarly operate according to the compound that is transformed into (XIXa-c) formula with compound by (XVIII) formula, can obtain the compound of (LII) formula.To the compound of (LI) formula, similarly operate according to the compound that is transformed into (I) formula with compound by (XIXa-c) formula, can obtain the compound of (Vc) formula.
(V) W is CR in the formula 4R 5, l is 2 o'clock compound (Vd) synthetic
Figure C9210399100362
(R in the formula 1, R 2, R 3, R 4, R 5Implication is the same)
In the compound of the representative of (V) formula, (Vd) compound of formula can be raw material by the compound with (XLV) formula, by following reaction process manufacturing.
Figure C9210399100371
Make compound of (XLV) formula and (XL) the compound reaction of formula, can obtain the compound of (LIII) formula.Reaction is similarly operated according to the compound that is transformed into (XLI) formula with compound by (XXIX) formula.To the compound of (LIII) formula, similarly operate according to the compound that is transformed into (XIXa-c) formula with compound by (XVIII) formula, can obtain the compound of (LIV) formula.To the compound of (LIV) formula, similarly operate according to being transformed into (I) formula compound with compound by (XIXa-c) formula, can obtain the compound of (LV) formula.To the compound of (LV) formula,, can obtain the compound of (Vd) formula according to similarly operating with the compound that is transformed into (Ib) formula by (XII) formula compound.
In addition, in the compound of (XVII) formula representative, W is CR 4R 5, l is 1 compound (XVIIb)
Figure C9210399100381
(X represents halogen in the formula, R 1, R 2, R 3, R 4, R 5, the A implication is the same) can be raw material by compound with (Vb) formula, make as follows. That is, make (Vb) formula
Figure C9210399100391
(R in the formula 1, R 2, R 3, R 4, R 5Implication is the same) compound and (LVI) formula
LO 2The compound reaction of C-A '-X (LVI) (X represents halogen in the formula, the alkylidene group (also can contain heteroatoms) of the saturated or undersaturated straight or branched of A ' expression carbonatoms 1-4, the L implication is the same) obtains (LVII) formula
Figure C9210399100392
(R in the formula 1, R 2, R 3, R 4, R 5, A ', L implication be the same) represented compound.Be reflected in the reaction not active solvent (dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diox etc.) and have under the existence of mineral alkali (sodium hydride, potassium hydride KH, sodium amide, potassium hydroxide, tert.-butoxy potassium etc.) or organic bases (pyridine, triethylamine etc.) and to the solvent for use reflux temperature, carried out 5 minutes to 5 hours in 0 ℃.
Then, reductive agent is acted on the compound of (LVII) formula, can obtain the compound of (LVIII) formula (R in the formula 1, R 2, R 3, R 4, R 5, A ' implication is the same).The reductive agent that uses in the reaction can be enumerated lithium aluminium hydride, aluminium alkane, borane, sodium borohydride, lithium borohydride etc., and temperature of reaction is 0 ℃ of reflux temperature to solvent for use, 5 minutes to 6 hours reaction times.
At last, halogenating agent is acted on the compound of (LVIII) formula, can make the compound of (XVIIb) formula.As halogenating agent, can enumerate phosphorus oxychloride, thionyl chloride, phosphorus trichloride etc. and thionyl chloride-dimethyl formamide, phosphorus oxychloride-N-methyl formyl aniline etc.Be reflected in the non-active solvent (benzene,toluene,xylene, chloroform etc.) and 0 ℃ to the reflux temperature of solvent for use, carried out 5 minutes to 6 hours.
Adopt known methods such as recrystallization, chromatography, the compound of resulting (I) formula can be isolated from reaction mixture not and be made with extra care.(I) compound of formula adopts ordinary method to handle with mineral acid, organic acid or amino acid, can make it to be transformed into the salt of allowing on the pharmacology mentioned above.
In the compound of the present invention, have under the situation of unsymmetrical carbon, what obtain usually is racemic modification.This racemic modification can adopt ordinary method to be divided into optically active isomer.Such optically active isomer also can create as initial substance by the compound that use has an opticity.Exist under the situation of diastereoisomer, each diastereomer can be by recrystallize or chromatography are made with extra care respectively.
In the manufacture method of the compound of (I) formula and intermediate thereof, employed compound in the reaction is not as long as hinder reaction to adopt the form of various salt all to be fine, for example inorganic salt such as hydrochloride, vitriol; Organic acid salt such as tartrate, fumarate etc.
Compound and the salt of being represented by (I) formula thereof of the present invention has shown anti-PAF effect, antihistamine effect can be used for anti-and the healing potion of giving as following disease: inflammatory disease, the allergy illness (pant by segmental bronchus, chronic eczema etc.), the disease that causes by PAF (thrombus for example, cerebral apoplexy, myocardial infarction, angina pectoris, thrombophlebitis, ephritis, diabetic ephritis, endotoxin shock, the vessel inner blood that is caused by intracellular toxin solidifies syndrome, anaphylactoid is poisoned and is suffered a shock, circulation disorders such as hemorrhagic shock, digestive system such as stomach ulcer, pneumonia, the rejection of following the PAF generation to increase during organ transplantation and producing, internal organs when winning the device operation are unsound), and to the effective disease of PAF antagonist (high endothelium disease).
(I) compound of formula representative and acid salt thereof, powder form that can be original or with the form oral administration of the pharmaceutical composition of suitable agent shape or non-oral administration to the Mammals administration.
As what the agent shape of oral administration can specifically be enumerated tablet, pill, powder, capsule, granule, syrup, emulsion, clouding agent etc. are arranged.Various doses of shapes can be contained normally used carrier or vehicle in the field of pharmaceutical preparations by the known method manufacturing, for example, as the vehicle excipients of tablet, can enumerate lactose, starch, sucrose, Magnesium Stearate etc.
As not peroral administration dose shape, for example can enumerate ointment, injection, compress agent, Liniment, seat agent, transdermic absorbent etc.Injection can be by known method modulation, and for example the compound or its salt with the representative of (I) formula dissolves in aseptic water-based liquid that is generally used for injection or oiliness liquid, outstanding turbid or emulsification modulation.The aqueous solution as injection can be enumerated physiological saline, glucose solution, can enumerate sesame oil, soybean wet goods as oiliness liquid, also can use various solubility promoters simultaneously.The seat agent that is used for administration in the intestines can be adopted known method, for example compound or its salt shown in (I) formula is mixed, prepares by moulding with base with suppository commonly used.
(I) effective dosage of the salt of allowing on the compound of formula and the pharmacology thereof and administration number of times are according to the character of administering mode, patient age, body weight, the disease that will treat or severity extent and different, per day for adults 0.1-1000mg usually, preferably 1-200mg can once or divide administration several times.
In addition, above-mentioned various doses of shapes, so long as not can owing to the cooperating of compound or its salt of (I) formula produce poor interaction, also can contain other for the treatment effective composition.The for example free inhibitor of steroid dose, on-steroidal anti-inflammatory agent, lipoxygenase inhibitor, leukothrombin antagonist, bronchodilator, thromboxane synthetic inhibitor, thromboxane antagonist, histamine, serotonin antagonist, adenosine receptor antagonist, adrenergic, immunosuppressor, immunomodulator etc.
Provide the composition example of the tablet that uses The compounds of this invention below.
The formulation example tablet
Modulate the tablet that constitutes by following ingredients with ordinary method
The compound 20mg of embodiment 6
Lactose 80mg
W-Gum 30mg
Polyvinyl alcohol 2mg
Magnesium Stearate 1mg
The tar colorant trace
Enumerate embodiment below the present invention is described in further detail.But the present invention is not limited to these embodiment.
Embodiment 1
4-(3-ethoxycarbonyl propyl)-2-hydroxyl-quinoxaline-3 (4H)-ketone
(1)
Figure C9210399100431
26.9g oxalyl chloride and 200ml o-dichlorobenzene solution are stirred down at 60 ℃, in whipping process, in 42 minutes, divide to add 35.5g N-(3-ethoxycarbonyl propyl)-O-Phenylene Diamine and 220ml o-dichlorobenzene solution several times.Heat up, stirred 1 hour, filter down hot then, make the filtrate cooling, add ether, leach xln at 130 ℃, washing, clean after, merge with secondary crystal and to obtain 25.2g (1) formula compound.IR(KBr)cm -1：2868，1690，1665，1311，1122，756 1HNMR(DMSO-d6)δ：7.35(1H，m)，7.20-7.17(3H，m)，4.17(2H，t，J＝7.1)，3.52-3.29(4H，m)，1.86(2H，quint，J＝6.9)，1.11(3H，t，J＝6.9)MS：248(M+)
Embodiment 2
4-(3-ethoxycarbonyl propyl)-2-chloro-quinoxaline-3 (4H)-ketone
(2)
Figure C9210399100441
In 22.5g (1), add 330ml toluene, 10ml dimethyl formamide, 10ml thionyl chloride, reflux 2 hours.Filter down hot, concentrated filtrate is with silica gel column chromatography (ethyl acetate: hexane=1: 3-1: 2) purify, obtain (2) that 23.5g is yellow oily.IR(Neat)cm -1：2976，2870，1669，1605，1468，1114，1083，756，629 1HNMR(CDCl3)δ：7.83(1H，m)，7.55(2H，m)，7.36(1H，m)，4.43(2H，t，J＝7.0)，3.52(2H，t，J＝5.8)，3.49(2H，q，J＝7.0)，2.07(2H，m)，1.23(3H，t，J＝7.0)MS：266(M+)
Embodiment 3
5-(3-ethoxycarbonyl propyl)-4,5-dihydro-1-methyl-(1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-ketone (3)
Figure C9210399100442
In 23.3g (2) and 7.79g acethydrazide, add 180ml propyl carbinol, reflux 0.9 hour.Add the 60ml propyl carbinol, reflux 1.5 hours.Heat up in a steamer and desolvate, add methylene dichloride, water, extraction, washing, drying.Heat up in a steamer and desolvate, clean, dry by recrystallize in the Virahol with ethyl acetate, obtain (3) that 18.9g is yellow crystals.mp：120.5～123℃IR(KBr)cm -1：2966，1678，1429，775，768 1HNMR(CDCl3)δ：8.02(1H，dd，J＝7.9，1.5)，7.65-7.21(3H，m)，4.46(2H，t，J＝7.4)，3.62-3.39(4H，m)，3.09(3H，s)，2.05(2H，m)，1.22(3H，t，J＝7.0)MS：286(M+)
Embodiment 4
4,5-dihydro-1-methyl-5-(3-(4-diphenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-ketone (4)
The aqueous solution of hydrogen bromide of 18ml 48% is added among the 2.51g (3) reflux 2.7 hours.Under reduced pressure heat up in a steamer and desolvate, add 1.96g 4-(diphenylmethylene) piperidines, 2.33g yellow soda ash, 18ml dimethyl formamide then, stirred 4.9 hours down at 60-70 ℃.Heat up in a steamer and desolvate, add entry and methylene dichloride, elimination diatomite, extraction filtrate, washing, drying.Heat up in a steamer and desolvate, with silica gel column chromatography (ethyl acetate: methyl alcohol=6: 1) purify after, by recrystallize in ethanol and a small amount of propyl carbinol, obtain the 2.50g crystalline (4) that is white in color.Mp:188.5～189.5 ℃ ultimate analysis: in C31H31N5O1/4H2O
Calculated value: C, 75.35; H, 6.43; N, 14.17
Measured value: C, 75.21; H, 6.36; N, 14.27IR (KBr) cm -1: 1673,1427,760,702 1HNMR (CDCl3) δ: 8.01 (1H, dd, J=8.3,1.5), 7.69 (1H, d, J=7.3), (7.51 1H, td, J=8.1,1.5), 7.36 (1H, td, J=7.8,1.0), 7.28 (4H, t-like, J=5.9), 7.20 (2H, t-like, J=7.3), 7.12 (4H, m), 4.44 (2H, t, J=7.3), 3.09 (3H, s), 2.51 (6H, t-like), 2.39 (4H, t-like, J=5.6), 1.98 (2H, quint, J=7.3) MS:489 (M+)
Embodiment 5
4,5-dihydro-1-methyl-5-(3-4-(diphenyl-methyl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-ketone (5)
Figure C9210399100471
4-(diphenylmethylene) piperidines in using 1-(diphenyl-methyl) piperazine replacement embodiment 4, identical with embodiment 4, obtain colourless amorphous (5).Ultimate analysis: in C30H32N6O
Calculated value: C, 73.14; H, 6.55; N, 17.06
Measured value: C, 73.27; H, 6.38; N, 17.27IR (KBr) cm -1: 2814,1686,1427,750,708 1HNMR (CDCl3) δ: 7.99 (1H, dd, J=8.3,1.0), 7.64 (1H, d, J=7.8), (7.47 1H, td, J=7.8,1.5), 7.41 (4H, AB, J=7.3), (7.34 1H, td, J=7.8,1.0), 7.27 (4H, t, J=7.3), 7.17 (2H, t, J=7.3), 4.40 (2H, t, J=6.8), 4.20 (1H, s), 3.08 (3H, s), 2.49 (2H, t, J=6.8), 2.47 (8H, brs), 1.94 (2H, quint, J=6.8) MS:492 (M)+
Embodiment 6
4,5-dihydro-1-methyl-5-(3-(4-((4-chloro-phenyl-)-phenyl methyl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-ketone (6)
Figure C9210399100481
Identical with embodiment 4 except replace 4-(diphenylmethylene) piperidines among the embodiment 4 with 1-((4-chloro-phenyl-) phenyl methyl) piperazine, obtain colourless amorphous (6).IR(KBr)cm -1：2810，1675，1425，1240，755 1HNMR(CDCl3)δ：7.99(1H，dd，J＝8.6，1.2)，7.62(1H，d，J＝8.6)，7.47(1H，td，J＝7.9，1.2)，7.37-7.33(3H，m)，7.35(2H，AB，J＝8.5)，7.28(2H，t，J＝7.9)，7.24(2H，AB，J＝7.9)，7.19(1H，tt，J＝7.3，1.2)，4.40(2H，t，J＝7.3)，4.19(1H，s)，3.09(3H，s)，2.50(2H，t，J＝6.7)，2.42(8H，brs)，1.95(2H，quint，J＝6.7)MS：5.27(M+H).+
Embodiment 7
4,5-dihydro-1-methyl-5-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-keto hydrochloride (7)
The compound dissolution of 0.69g embodiment 6 in ethyl acetate, is blown into hydrogen chloride gas, after concentrating, filters out xln, obtain (7) of 0.54g after the drying.mp：158～161℃IR(KBr)cm -1：3400，2940，2800，1675，1420，755
Embodiment 8
4,5-dihydro-1-methyl-5-(3-((4-benzyl chloride base) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-ketone (8)
Except replace 4-(diphenylmethylene) piperidines among the embodiment 4 with 1-(4-benzyl chloride base) piperazine, identical with embodiment 4, obtain colourless amorphous (8).Ultimate analysis: in C24H27N6OCl calculated value: C, 63.92; H, 6.03; N, 18.63;
Cl, 7.86 measured values: C, 64.18; H, 6.26; N, 18.27;
Cl，8.02IR(KBr)cm -1：2814，1682，1427，754. 1HNMR(CDCl3)δ：8.01(1H，dd，J＝8.4，1.1)，7.64(1H，AB，J＝8.4)，7.51(1H，td，J＝8.4，1.1)，7.37(1H，td，J＝7.9，1.1)，7.28(2H，AB，J＝8.4)，7.25(2H，AB，J＝8.4)，4.24(2H，t，J＝7.3)，3.46(2H，s)，3.10(3H，s)，2.49(2H，t，J＝7.0)，2.47(8H，brs)，1.95(2H，quint，J＝7.0)MS：450(M+)
Embodiment 9
4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines-4 (5H)-ketone (9)
Figure C9210399100501
Identical with embodiment 4 except replace 4-(phenylbenzene methylene radical) piperidines among the embodiment 4 with 4-(3-indyl) piperidines, obtain colourless amorphous (9).Mp:198～215 ℃ ultimate analysis: in C26H28N6O calculated value: C, 70.89; H, 6.41; N, 19.08 measured values: C, 70.68; H, 6.63; N, 18.84IR (KBr) cm -1: 3346,1671,1460,1433,743 1HNMR (CDCl3) δ: 10.76 (1H, s), 8.14 (1H, dd, J=7.3,1.2), 7.81 (1H, d, J=7.3), 7.58 (1H, td, J=7.3,1.2), 4.49 (1H, d, J=7.9), 7.40 (1H, t, J=7.3), 7.32 (1H, d, J=7.9), 7.04 (1H, t, J=7.3), 7.01 (1H, d, J=2.4), 6.94 (1H, t, J=7.3), 4.37 (2H, t, J=7.3), 2.98 (3H, s), 2.88 (2H, d, J=11.6), 2.69 (1H, t, J=11.6), 2.46 (2H, t, J=6.7), 2.00 (2H, t, J=11.9), 1.88-1.86 (4H, m), 1.47 (2H, qd, J=11.9,3.1) MS:440 (M+)
Embodiment 10
1,2-dihydro-quinoxaline-3 (4H)-thioketones (10)
Figure C9210399100511
The 280ml diglyme is added to 52g 1, in 2-dihydro-3-hydroxy quinoxaline, 47g thiophosphoric anhydride and the 59g sodium bicarbonate, stirred 1 hour down at 60 ℃.Decompression is heated up in a steamer and is desolventized, and adds 500ml water, filters out crystallization, obtains 47g after cleaning and is yellow-green colour crystalline title compound.By recrystallize in the benzene, obtain clean product.mp：120～123℃IR(KBr)cm -1：3250，3180，3100，2970，1562，1510，1307 1HNMR(CDCl3)δ：9.75(1H，brs)，7.12-6.64(4H，m)，4.33(2H，s)
Embodiment 11
1,2-dihydro-2-methyl-quinoxaline-3 (4H)-thioketones (11)
Figure C9210399100521
Except with 1,2-dihydro-2-methyl-3-hydroxy quinoxaline replaces 1, and 2-dihydro-3-hydroxy quinoxaline is operation similarly to Example 10 outward, obtains being (11) of yellow-green colour xln.mp：92～94℃IR(KBr)cm -1：2978，1551，1502，1383，1075，748 1HNMR(CDCl3)δ：10.08(1H，brs)，7.06-6.66(4H，m)，4.38(1H，q，J＝6.6)，1.54(3H，d，J＝6.6)MS：178(M+)
Embodiment 12
1,2-dihydro-2,2-dimethyl quinoxaline-3 (4H)-thioketones (12)
Figure C9210399100522
Except with 1,2-dihydro-2,2-dimethyl-3-hydroxy quinoxaline replaces 1, beyond 2-dihydro-3-hydroxy quinoxaline, carries out same operation with embodiment 10, obtains being (12) of yellow-green colour xln.mp：140～142℃IR(KBr)cm -1：2978，1535，1502，1359，1319，1062，745，621 1HNMR(CDCl3)δ：9.74(1H，brs)，7.0-6.6(4H，m)，1.53(6H，s)MS：192(M+)
Embodiment 13
4,5-dihydro-1-methyl (1,2,4) triazolo (4,3-a) quinoxalines (13)
Figure C9210399100531
The 750ml propyl carbinol is added in the compound and 56g acethydrazide of 62g embodiment 10, reflux 4 hours, decompression is heated up in a steamer and is desolvated, and adds entry, uses dichloromethane extraction.After washing, drying, decompression is heated up in a steamer and is desolvated, and by recrystallize in the Virahol, obtains the title compound that 49g is filbert acicular crystals.Mp:173～174 ℃ ultimate analysis value: in C10H10N4 calculated value: C, 64.50; H, 5.41; N, 30.09 measured values: C, 64.34; H, 5.51; N, 29.73IR (KBr) cm -1: 3230,1562,1510,1499,1431 1HNMR (CDCl3) δ: 7.50-6.82 (4H, m), 4.58 (2H, d, J=1.8), 4.18 (1H, brs), 2.78 (3H, s) MS:186 (M+)
Embodiment 14
4,5-dihydro-1,4-dimethyl (1,2,4) triazolo (4,3-a) quinoxalines (14)
Except using (11) replacements (10),, obtain being (14) of filbert acicular crystals according to operation similarly to Example 13.Mp:172～173 ℃ ultimate analysis value: in C11H12N4
Calculated value: C, 65.98; H, 6.04; N, 27.98
Measured value: C, 65.84; H, 6.07; N, 27.91IR (KBr) cm -1: 3242,1615,1533,1499,1431,1307,1135,745 1HNMR (CDCl3) δ: 7.45 (1H, d, J=7.9), 7.21-6.83 (3H, m), 4.70 (1H, q, J=6.3), 2.78 (3H, s), 1.70 (3H, d, J=6.3) MS:200 (M+)
Embodiment 15
4,5-dihydro-1,4,4-trimethylammonium (1,2,4) triazolo (4,3-a) quinoxalines (15)
Figure C9210399100551
Except replace operation similarly to Example 13 (10) with (12), obtain being (15) of filbert acicular crystals.Mp:177～178 ℃ ultimate analysis value: in C12H14N4
Calculated value: C, 67.26; H, 6.59; N, 26.15
Measured value: C, 66.99; H, 6.59; N, 26.00IR (KBr) cm -1: 2986,1615,1531,1495,1307,737 1HNMR (CDCl3) δ: 7.52 (1H, d, J=8.2), 7.47-6.87 (3H, m), 2.84 (3H, s), 1.69 (6H, s) MS:214 (M+)
Embodiment 16
1-ethyl-4,5-dihydro-(1,2,4) triazolo (4,3-a) quinoxalines (16)
Figure C9210399100561
The compound dissolution of 25g embodiment 10 in 360ml ethanol, is at room temperature added the hydrazine hydrate of 180ml 80%, stirred 30 minutes.Heat up in a steamer desolvate, drying, add 350ml ethanol, 92ml triethyl orthopropionate, 23ml sulfuric acid, at room temperature stirred 1.3 hours.Add the sodium bicarbonate aqueous solution neutralization, use dichloromethane extraction.Merge organic layer, washing is under reduced pressure heated up in a steamer after the drying and is desolvated.By recrystallize in the Virahol, obtain 14g and be flaxen title compound.Mp:157～159 ℃ ultimate analysis value: in C11H12N4
Calculated value: C, 65.90; H, 6.10; N, 28.10
Measured value: C, 65.84; H, 6.07; N, 27.91IR (KBr) cm -1: 3256,1562,1499,1437,1315,745 1HNMR (CDCl3) δ: 7.49-6.84 (4H, m), 4.58 (2H, d, J=1.8), 4.18 (1H, brs), 3.13 (2H, q, J=7.5), 1.51 (3H, t, J=7.3) MS:200 (M+)
Embodiment 17
4,5-dihydro-1-propyl group (1,2,4) triazolo (4,3-a) quinoxalines (17)
Figure C9210399100571
Identical except replacing the triethyl orthopropionate with the operation of embodiment 16 with of the original acid triethyl, obtain flaxen (17).Mp:130～132.5 ℃ ultimate analysis value: in C12H14N4
Calculated value: C, 67.26; H, 6.59; N, 26.15
Measured value: C, 66.80; H, 6.55; N, 25.92IR (KBr) cm -1: 3244,1499,1431,1320,1299,1270,750 1HNMR (CDCl3) δ: 7.46-6.85 (4H, m), 4.56 (2H, d, J=1.2), 4.25 (1H, brs), 3.07 (2H, t, J=7.0), 1.91 (2H, quint, J=7.7), 1.10 (3H, t, J=7.0) MS:214 (M+)
Embodiment 18
5-(3-ethoxycarbonyl propyl)-4,5-dihydro-1-methyl (1,2,4) triazolo (4,3-a) quinoxalines (18)
The 200ml dimethyl formamide is added in the sodium hydride of 10g 60%, at 0 ℃ of compound that adds 32g embodiment 13 down.Stirred 30 minutes down at 0 ℃, splash into 35g 1-bromo-3-ethyl propyl ether, at room temperature stirred 1 hour, add water, use dichloromethane extraction.After washing, the drying, decompression is heated up in a steamer and is desolvated, and by recrystallize in the Virahol, obtains the title compound of the faint yellow acicular crystals of 36g.Mp:118～119 ℃ ultimate analysis value: in C15H20N4O
Calculated value: C, 66.15; H, 7.40; N, 20.57
Measured value: C, 66.23; H, 7.44; N, 20.65IR (KBr) cm -1: 1555,1504,1477,1427,1108,752 1HNMR (CDCl3) δ: 7.50-6.91 (4H, m), 4.44 (2H, s), 3.48 (6H, m), 2.78 (3H, s), 1.95 (2H, m), 1.26 (3H, t, J=3.7) MS:272 (M+)
Embodiment 19
5-(3-bromopropyl)-4,5-dihydro-1-methyl (1,2,4) triazolo (4,3-a) quinoxalines (19)
Figure C9210399100591
Hydrogen bromide-the acetic acid solution that in the compound of 2.5g embodiment 18, adds 15ml 30%, stirred 4.1 hours down at 100 ℃, add aqueous sodium hydroxide solution, use dichloromethane extraction, after washing, the drying, with silica gel column chromatography (ethyl acetate: methyl alcohol=7: 1) purify, obtain 1.3g title compound crystal.IR(KBr)cm -1：1502，1431，750 1HNMR(CDCl3)δ：7.47(1H，m)，7.18(1H， m)，7.02-6.85(2H，m)，4.44(2H，s)，3.53(2H，t，J＝7.0)，3.49(2H，t，J＝6.1)，2.78(3H，s)，2.23(2H，m)MS：306(M+)
Embodiment 20
N-(3-methoxy-propyl) glycine ethyl ester (20)
Me-O(CH 2) 3NHCH 2CO 2Et (20)
Solution 100ml in tetrahydrofuran (THF) immerses in the ice-water bath with the 52g 3 methoxypropyl amine, splashes into the solution of 27g bromoethyl acetate in tetrahydrofuran (THF) of 30ml in 1 hour time.At room temperature stirred 2 hours, decompression is heated up in a steamer and is desolvated and superfluous 3 methoxypropyl amine, with silica gel column chromatography (ethanol: methylene dichloride=1: 20) purify, obtain 19g colorless oil title compound.IR(Neat)cm -1：2982，2938，1736，1452，1185，1122 1HNMR(CDCl3)δ：4.20(2H，q，J＝7.2)，3.48(2H，t，J＝6.2)，3.44(2H，s)，3.34(3H，s)2.76(2H，t，J＝6.8)，1.81(2H，quint，J＝6.6)，1.28(3H，t，J＝7.2)
Embodiment 21
N-(3-methoxy-propyl) alanine ethyl ester (21)
MeO(CH 2) 3NHCHMeCO 2Et (21)
Except with identical the 2-chloropropionate replacement bromoethyl acetate, obtain (21) of colorless oil with embodiment 20 operations.IR(Neat)cm -1：2934，2876，1742，1464，1373，1195，1120 1HNMR(CDCl3)δ：4.18(2H，q，J＝7.2)，3.44(2H，t，J＝6.4)，3.32(3H，s)，3.32(1H，q，J＝7.1)，2.64(2H，td，J＝6.8，2.2)，1.74(2H，quint，J＝6.6)，1.29(3H，d，J＝7.1)，1.28(3H，t，J＝7.2)
Embodiment 22
N-(5-chloro-2-nitrophenyl)-N-(3-methoxy-propyl) glycine methyl ester (22)
With compound, the 3.9g 2 of 3.3g embodiment 20,4-dichloronitrobenzene, 3.0g sodium bicarbonate are added in 35ml ethanol, the 4.5ml water, and reflux added 2N hydrochloric acid and makes it to become acidity after 1 week, used dichloromethane extraction then.After washing, the drying, heat up in a steamer and desolvate, be dissolved in the 40ml methyl alcohol, immerse in the ice-water bath, in 5 minutes, splash into the 4.0g thionyl chloride, stir and at room temperature stir a night after 30 minutes.Decompression is heated up in a steamer and is desolvated, with silica gel column chromatography (ethyl acetate: methylene dichloride=20: 1) purify, obtain the orange buttery title compound of 4.7g.IR(Neat)cm -1：2984，1744，1522，1197，1118，1031 1HNMR(CDCl3)δ：7.71(1H，d，J＝8.8)，7.33(1H，d，J＝2.2)，6.87(1H，dd，J＝8.8，2.2)3.88(2H，s)，3.71(3H，s)，3.41(4H，t，J＝6.2)，3.31(3H，s)，1.78(2H，quint，J＝6.2)
Embodiment 23
N-(5-fluoro-2-nitrophenyl)-N-(3-methoxy-propyl) glycine methyl ester (23)
Figure C9210399100621
Except with 2, the 4-difluoro nitrobenzene replaces 2, and outside the 4-dichloronitrobenzene, operation obtains orange buttery (23) similarly to Example 22.IR(Neat)cm -1：2934，1748，1622，1520，1205，969，837 1HNMR(CDCl3)δ：7.84(1H，m)，7.00(1H，dd，J＝11.0，2.4)，6.68(1H，m)，3.89(2H，s)3.71(3H，s)，3.42(4H，t，J＝6.0)，3.31(3H，s)，1.80(2H，quint，J＝6.0)
Embodiment 24
N-(4-fluoro-2-nitrophenyl)-N～(3-methoxy-propyl) glycine methyl ester (24)
Except with 2, the 5-difluoro nitrobenzene replaces 2, and operation similarly to Example 22 obtains orange buttery (24) outside the 4-dichloronitrobenzene.IR(Neat)cm -1：2934，1742，1535，1499，1193，1120 1HNMR(CDCl3)δ：7.46(3H，m)，3.88(2H，s)，3.68(3H，s)，3.36(4H，t，J＝6.2)，3.28(3H，s)，1.68(2H，quint，J＝6.2)
Embodiment 25
N-(3-methoxy-propyl)-N-(2-nitrophenyl) alanine methyl ester (25)
Figure C9210399100631
Except replacing 2 with the 2-chloronitrobenzene, 4-dichloronitrobenzene, usefulness (21) replace operation similarly to Example 22 outside (20), obtain orange buttery (25).IR(Neat)cm -1：2954，1730，1522，1357，1120，777 1HNMR(CDCl3)δ：7.49(2H，m)，7.18(2H，m)，3.87(1H，m)，3.66(3H，s)，3.37(4H，m)，3.27(3H，s)，1.65(2H，quint，J＝6.8)，1.45(3H，d，J＝7.2)
Embodiment 26
7-chloro-1,2-dihydro-1-(3-methoxy-propyl) quinoxaline-3 (4H) ketone (26)
Figure C9210399100641
5.6g reduced iron, 5ml acetate are added in the 50ml water, are heated to 80 ℃.Add the ethanolic soln 50ml of the compound of embodiment 22, stirred 1 hour, leach throw out, use dichloromethane extraction.Heat up in a steamer after washing, the drying and desolvate,, obtain the title compound of 2.7 gram white crystals bodies by recrystallize in the ethyl acetate.mp：190～200℃IR(KBr)cm -1：2930，1684，1518，1108，835 1HNMR(CDCl3)δ：8.72(1H，brs)，6.65(3H，m)，3.88(2H，s)，3.44(2H，t，J＝5.7)，3.36(3H，s)，3.33(2H，t，J＝7.2)，1.86(2H，quint，J＝6.6)MS：254(M+)
Embodiment 27
7-chloro-1,2-dihydro-1-(3-methoxy-propyl) quinoxaline-3 (4H) thioketones (27)
Figure C9210399100651
In the compound of 2.3g embodiment 26,2.3g thiophosphoric anhydride, 1.2g sodium bicarbonate, add the 15ml diglyme, stirred 4 hours, heat up in a steamer and desolvate, add water, leach the throw out of separating out, obtain 2.4 gram yellow crystal body title compounds after the washing at 80 ℃.mp：140～142℃IR(KBr)cm -1：3174，2894，1584，1547，1400，1106，1009，806 1HNMR(CDCl3)δ：9.89(1H，brs)，6.68(3H，m)，4.23(2H，s)，3.47(2H，t，J＝5.9)，3.36(3H，s)，3.33(2H，t，J＝7.2)，1.85(2H，quint，J＝6.6)MS：270(M+)
Embodiment 28-33
Resemble and similarly operate the compound that obtains embodiment 26, replace 22 to obtain 28 with 23, replace 22 to obtain 29 with 24, obtain 30 with 25 replacements 22.Like that similarly operate according to the compound that obtains embodiment 27, obtain 31, obtain 32, replace 26 to obtain 33 each compound with 30 with 29 replacements 26 with 28 replacements 26.
Figure C9210399100661
Compound Y R 2R 3R 4R 528 O 7-F H H29 O 6-F H H30 O H Me H31 S 7-F H H32 S 6-F H H33 S H Me H28:7-fluoro-1,2-dihydro-1-(3-methoxy-propyl) quinoxaline-3
(4H) ketone 29:6-fluoro-1,2-dihydro-1-(3-methoxy-propyl) quinoxaline-3
(4H) ketone 30:1,2-dihydro-1-(3-methoxy-propyl)-2-methyl-quinoxaline-
3 (4H) ketone 31:7-fluoro-1,2-dihydro-1-(3-methoxy-propyl) quinoxaline-3
(4H) thioketones 32:6-fluoro-1,2-dihydro-1-(3-methoxy-propyl) quinoxaline-3
(4H) thioketones 33:1,2-dihydro-1-(3-methoxy-propyl)-2-methyl-quinoxaline-
3 (4H) thioketones
Above-claimed cpd has following physics value compound spectroscopic data 28: white crystals
mp ：174～177℃
IR(KBr)cm -1?：2882，1680，1522，
1417，1309，1114，826
1HNMR(CDCl3)δ：9.78(1H，brs)，6.73
(1H，m)，6.42(2H，m)，
4.24(2H，s)，3.43
(2H，t，J＝5.7)，3.35
(3H，s)，3.32(2H，t，
J＝6.6)，1.84(2H，
Quint, J=5.7) 29: white crystals
mp： 131～133℃
IR(KBr)cm -1：?2884，1690，1531，
1406，1270，859，793
1HNMR(CDCl3)δ：8.68(1H，brs)，6.69
(1H，s)，6.62(2H，m)，
3.80(2H，s)，3.46
(2H，t，J＝5.7)，3.35
(3H，s)，3.32(2H，t，
J＝6.0)，1.78(2H，
Quint, J=5.9) 30: colorless oil
IR(Neat)cm -1：2930，1684，1510，
1388，1243，1118，745
1HNMR(CDCl3)δ：8.74(1H，brs)，6.98
(1H，m)，6.77(3H，m)，3.99(1H，q，
J＝6.8，3.44(4H，t，J＝5.9)，3.34
(3H，s)，1.87(2H，quint，J＝5.9)
1.19(3H，d，J＝6.8)
MS:234 (M+) 31: yellow crystal
IR(KBr)cm -1：2898，1560，1512，
1406，1203，1102，808
1HNMR(CDCl3)δ：9.78(1H，brs)，6.81
-6.36(3H，m)，4.24(2H，s)，3.43
(2H，t，J＝5.7)，3.35(3H，s)，
3.32(2H，t，J＝7.6)，1.84(2H，
quint，J＝6.8)
MS:254 (M+) 32: yellow crystal
IR(KBr)cm -1：2932，1557，1510，
1270，1139，1106，845
1HNMR(CDCl3)δ：9.76(1H，brs)，6.68
(3H，m)，4.16(2H，s)，3.43(2H，t，
J＝5.7)3.35(3H，s)，3.31(2H，t，
J=7.9), 1.83 (2H, quint, J=6.4) 33: yellow crystal
IR(KBr)cm -1：3108，2988，1547，
1512，1392，1303，1104，893
1HNMR(CDCl3)δ：9.77(1H，brs)，7.09
(1H，m)，6.80(2H，s)，4.45(1H，q，
J＝6.8)，3.43(2H，m)，3.35(3H，
s)，3.14(2H，m)，1.86(2H，quint，
J＝6.6)，1.25(3H，d，J＝6.8)
MS：250(M+)
Embodiment 34
7-chloro-4,5-dihydro-1-methyl-5-(3-methoxy-propyl) (1,2,4) triazolo (4,3-a) quinoxalines (34)
The 24ml propyl carbinol is added in the compound, 1.8g acethydrazide of 2.3g embodiment 27, reflux 8 hours adds water, uses dichloromethane extraction.Heat up in a steamer after washing, the drying and desolvate, with silica gel column chromatography (ethanol: methylene dichloride=1: 10) purify, obtain the filbert crystalline title compound of 1.8 grams.Mp:101-104 ℃ of ultimate analysis value: in C14H17N4OCl calculated value: C, 57.44; H, 5.85; N, 19.14;
Cl, 12.11 measured values: C, 57.68; H, 5.97; N, 19.33;
Cl，12.35IR(KBr)cm -1：2878，1549，1512，1441，1199，1114，1004， 1HNMR(CDCl3)δ：7.37(1H，d，J＝8.3)，6.95(1H，d，J＝2.8)，6.86(1H，dd，J＝8.3，2.8)4.46(2H，s)，3.44(4H，t，J＝5.7)，3.36(3H，s)，2.76(3H，s)，1.91(2H，quint，J＝6.0)MS：292(M+)
Embodiment 35-41
Operate similarly to Example 18, obtain compound 35, obtain compound 36, obtain compound 37, replace the bromo ethoxycarbonyl propyl to obtain compound 38 with bromo oxyethyl group butyl with 15 replacements 13 with 17 replacements 13 with 16 replacements 13.Similarly operate with embodiment 34, obtain compound 39, obtain compound 40, replace 27 to obtain compound 41 with 33 with 32 replacements 27 with 31 replacements 27.
Figure C9210399100701
Compound R 1R 2R 3R 4R 5M R 1035 Et H H H, 3 Et36 Pr H H H, 3 Et37 Me H Me Me, 3 Et38 Me H H H, 4 Et39 Me 7-F H H, 3 Me40 Me 8-F H H, 3 Me41 Me H Me H, 3 Me35:1-ethyls-4; 5-dihydro-5-(3-ethoxycarbonyl propyl) (1; 2
4) triazolo (4,3-a) quinoxaline 36:4,5-dihydro-1-propyl group-5-(3-ethoxycarbonyl propyl) (1,2,
4) triazolo (4,3-a) quinoxaline 37:4,5-dihydro-1,4,4-trimethylammonium-5-(3-ethoxycarbonyl propyl)
(1,2,4) triazolo (4,3-a) quinoxaline 38:4,5-dihydro-1-methyl-5-(4-oxyethyl group butyl) (1,2,
4) triazolo (4,3-a) quinoxaline 39:7-fluoro-4,5-dihydro-1-methyl-5-(3-methoxy-propyl)
(1,2,4) triazolo (4,3-a) quinoxaline 40:8-fluoro-4,5-dihydro-1-methyl-5-(3-methoxy-propyl)
(1,2,4) triazole (4,3-a) quinoxaline 41:4,5-dihydro-1,4-dimethyl-5-(3-methoxy-propyl)
(1,2,4) triazole (4,3-a) quinoxaline
Above-claimed cpd has following physics value.Compound spectroscopic data 35: yellow oil
IR(Neat)cm -1：3414，2978，2872，
1611，1557，1502，1473，1437，
1112，748，427
1HNMR(CDCl3)δ：7.49-6.91(4H，m)，
4.43(2H，s)，3.61-3.37(6H，m)，
3.12(2H，q，J＝7.3)，2.04-1.75
(2H，m)，1.50(3H，t，J＝7.5)，
1.22(3H，t，J＝6.8)
MS:286 (M+) 36: yellow oil
IR(Neat)cm -1：3500，2972，2874，
1502，1435，748，480
1HNMR(CDCl3)δ：7.49-6.92(4H，m)，
4.42(2H，s)，3.60-3.15(6H，m)，
3.02(2H，q，J＝8.1)，2.17-1.75
(4H，m)，1.31-1.01(6H，m)
MS:300 (M+) 37: colorless oil
IR(Neat)cm -1：2976，1680，1539，
1504，1187，750
1HNMR(CDCl3)δ：750-7.15(2H，m)，
6.95(2H，d，J＝7.7)，3.48(2H，q，
J＝7.0)3.44(4H，t，J＝6.6)，2.78
(3H，s)，1.82(2H，quint，J＝6.6)，
1.62(6H，s)，1.22(3H，t，J＝7.0)
MS:300 (M+) 38: colorless oil
IR(Neat)cm -1：3414，2976，2938，
2868，1611，1557，1504，1433，
1112，750
1HNMR(CDCl3)δ：7.6-6.8(4H，m)，
4.42(2H，s)，3.65-3.2(6H，m)，
2.77(3H，s)1.9-1.5(4H，m)，
1.20(2H，t，J＝6.9)
MS:286 (M+) 39: white crystals
mp：112～115℃
IR(KBr)cm -1：2930，1555，1512，
1429，1313，1116，855
1HNMR(CDCl3)δ：7.40(1H，dd，J＝8.8，
5.5)，6.70(2H，m)，4.46(2H，s)，
3.44(4H，t，J＝6.2)，3.36(3H，s)，
2.76(3H，s)，1.84(2H，quint，J＝
6.0)
MS:276 (M+) 40: white crystals
mp：140～142℃
IR(KBr)cm -1：2928，1557，1506，
1193，1116，849
1HNMR(CDCl3)δ：7.21(1H，d，J＝9.0)，
6.89(2H，m)，4.38(2H，s)，3.44
(4H，m)，3.35(3H，s)，2.77(3H，
s)，1.89(2H，quint，J＝6.4)
MS:276 (M+) 41: colorless oil
IR(Neat)cm -1：2930，1553，1504，
1429，1118，750
1HNMR(CDCl3)δ：7.46(1H，d，J＝7.6)，
7.22(1H，d，J＝8.2)，6.90(2H，m)，
4.85(1H，q，J＝6.8)，3.40(4H，m)，
3.33(3H，s)，2.78(3H，s)，1.88
(2H，quint，J＝6.2)，1.27(3H，d，
J＝6.8)
MS：272(M+)
Embodiment 42
4,5-dihydro-1-methyl-5-(3-(4-(diphenyl methyl) piperazine-1-yl) ethyl) (1,2,4) triazolo (4,3-a) quinoxalines (42)
The 4ml dimethyl formamide is added in the compound, 0.40g (4-(diphenyl methyl) piperazine-1-yl) diethylaluminum monochloride hydrochloride of 0.13g embodiment 13, at room temperature add 60% sodium hydride, 35% potassium hydride KH, stirred 3 hours down at 60 ℃ then, confirm that the compound of embodiment 13 disappears.Add entry, use ethyl acetate extraction.Under reduced pressure heat up in a steamer organic layer after washing, the drying.With silica gel column chromatography (ethyl acetate: methyl alcohol=6: 1) purify, obtain 0.19g oily matter.IR(KBr)cm -1：2814，1504，1009，748，708 1HNMR(CDCl 3)δ：7.45(1H，dd，J＝8.3，1.5)，7.41(4H，AB，J＝7.3)，7.27(4H，t，J＝7.3)，7.21(1H，m)，7.17(2H，t，J＝7.3)，6.92-6.88(2H，m)，4.51(2H，s)，4.22(1H，s)，3.47(2H，t，J＝6.8)，2.76(3H，s)，2.66(2H，t，J＝6.8)，2.55(4H，brs)，2.42(4H，brs)MS：464(M+)
Embodiment 43
4,5-dihydro-1-methyl-5-(3-(4-(diphenyl methyl) piperazine-1-yl) ethyl) (1,2,4) triazolo (4,3-a) quinoxaline fumarates (43)
The compound dissolution of 0.18g embodiment 42 in ethanol, is added the ethanolic soln of 0.093g fumaric acid, concentrate back crystallization from Virahol, obtain 0.25g as light yellowish pink crystalline title compound.
Fusing point: 171-172 ℃
Ultimate analysis: in C29H32N61.25C4H404
Calculated value: C; 66.98, H; 6.12, N; 13.78
Measured value: C; 66.88, H; 6.17, N; 13.51
IR(KBr)cm -1：1702，1502，1276，984，
752，648
Embodiment 44
4,5-dihydro-1-methyl-5-(3-(4-(diphenyl methyl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (44)
Figure C9210399100762
The compound dissolution of 1.12g embodiment 5 in the 20ml dry tetrahydrofuran, was stirred 3 hours after adding the tetrahydrofuran solution of 10ml (0.5M) aluminum hydride.After adding water and ethyl acetate, carry out diatomite filtration, separate organic layer.Carry out column chromatography after concentrating and purify, obtain the 0.21g title compound.
Fusing point: 175-185
Ultimate analysis: in C30H34N6
Calculated value: C, 75.28; H, 7.16; N, 17.56
Measured value: C, 75.01; H, 7.14; N, 17.36
IR(KBr)cm -1：2808，1508，1011，746，
704
1HNMR(CDCl3)δ：7.46-7.41(5H，m)，
7.27(4H，t，J＝7.3)，7.17(3H，td，
J＝7.6，1.4)，6.94(1H，d，J＝8.3)，
6.89(1H，t，J＝7.8)，4.42(2H，s)，
4.22(1H，s)，3.37(2H，t，J＝7.3)，
2.77(3H，s)，2.47(8H，brs)，2.41
(2H，t，J＝7.3)，1.82(2H，quint，J＝
7.3)
MS：478(M+)
Embodiment 45
4,5-dihydro-1-methyl-5-(3-(4-(two (4-fluorophenyl) methyl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (45)
Figure C9210399100781
In the compound of 0.50g embodiment 19 and 0.52g 1-(two (4-fluorophenyl) methyl) piperazine and 0.27g yellow soda ash, add 5ml 2-butanone, reflux 5.5 hours.Heat up in a steamer and desolvate, use dichloromethane extraction after adding water.In washing, after the drying, (ethyl acetate: methyl alcohol=6: 1) purify, recrystallize from ethyl acetate then must be as the 0.49g title compound of light yellowish pink with silica gel column chromatography.
Fusing point: 144-146 ℃
Ultimate analysis: in C30H32N6F2
Calculated value: C, 70.02; H, 6.27; N, 16.33
Measured value: C, 69.63; H, 6.31; N, 16.36
IR(KBr)cm -1：1506，1202，826，746
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.9，
1.2)，7.34(4H，m)，7.19(1H，td，
J＝7.9，1.2)，6.96(4H，t，J＝8.9)，
6.94(1H，m)，6.89(1H，t，J＝7.9)，
4.42(2H，s)，4.22(1H，s)，3.37
(2H，t，J＝7.0)，2.77(3H，s)，2.46
(8H，brs)，2.40(2H，t，J＝7.0)，
1.82(2H，quint，J＝7.0)
MS：514(M+)
Embodiment 46
4,5-dihydro-1-methyl-5-(3-(4-(phenylbenzene methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (46)
Figure C9210399100791
In the compound of 1.0g embodiment 18, add 15ml 47% hydrogen bromide water, stirred 1.5 hours at 110 ℃.Under reduced pressure heat up in a steamer and desolvate, carry out drying, add 15ml dimethyl formamide, 0.78g yellow soda ash and 0.92g 4-(phenylbenzene methylene radical) piperidines then, stirred 1.5 hours at 90 ℃.Under reduced pressure heat up in a steamer and desolvate, adding methylene dichloride, water extract, and behind the washing and drying, steam solvent, with silica gel column chromatography (ethyl acetate: methyl alcohol=3: 2) purify, behind the recrystallize, obtain the 14g title compound of colourless crystallization from propyl carbinol.
Fusing point: 204-205 ℃
Ultimate analysis: as C31H33N5
Calculated value: C, 78.28; H, 6.99; N, 14.73
Measured value: C, 78.14; H, 7.10; N, 14.65
IR(KBr)cm -1：2892，1508，1429，1348，
745，704
1HNMR(CDCl3)δ：7.45(1H，dd，J＝8.1，
1.1)，7.28(4H，t，J＝7.0)，7.21
(3H，q，J＝7.3)，7.12(4H，d，J＝
7.0)，6.98(1H，d，J＝8.4)，6.90
(1H，t，J＝7.9)，4.44(2H，s)，3.41
(2H，t，J＝7.3)，2.77(3H，s)，2.53
(4H，brs)，2.44(6H，m)，1.90(2H，
quint，J＝7.0)
MS：475(M+)
Embodiment 47
4,5-dihydro-1-methyl-5-(3-4-(phenylbenzene methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline tartrates (47)
The compound of dissolving 4.78g embodiment 46 adds the tartaric ethanolic soln of 2.26g L-then in the 150ml hot ethanol.The crystallization that cooled and filtered is separated out obtains the 5.93g title compound of colourless crystallization.
Fusing point: 135-139 ℃
Ultimate analysis: in C31H33N51.5C4H6O61H2O
Calculated value: C, 61.83; H, 6.17; N, 9.74
Measured value: C, 61.92; H, 6.20; N, 9.68
IR(KBr)cm -1：3322，1738，1562，1504，
1309，1267，1216，1137，681
Embodiment 48
4,5-dihydro-1-methyl-5-(3-(4-(phenylbenzene methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline malates (48)
Figure C9210399100811
In the 50ml hot ethanol, dissolve the compound of 4.45g embodiment 46, add the ethanolic soln of 1.90g L MALIC ACID then.After the cooling, filter the crystallization of separating out, obtain the 3.88g title compound of colourless crystallization.
Fusing point: 130-133 ℃
Ultimate analysis: in C31H33N51.5C4H6O50.5H2O
Calculated value: C, 64.80; H, 6.32; N, 10.21
Measured value: C, 64.51; H, 6.50; N, 10.38
IR(KBr)cm -1：3420，1719，1562，1504，
1433，1284，706
Embodiment 49
4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (49)
Figure C9210399100821
Except that replace 4-(phenylbenzene methylene radical) piperidines with 4-(3-indyl) piperidines, carry out 46 identical operations with embodiment, obtain the title compound of white crystals.
Fusing point: 193-196 ℃
Ultimate analysis: in C26H30N6
Calculated value: C, 73.21; H, 7.09; N, 19.70
Measured value: C, 72.83; H, 7.05; N, 19.50
IR(KBr)cm -1：3400，3178，2924，1562，
1504，1425，1352，745
1HNMR(CDCl3)δ：8.09(1H，s)，7.65(1
H，AB，J＝8.3)，7.46(1H，d，J＝6.8)，
7.36(1H，AB，J＝8.3)，7.25-7.16
(2H，m)，7.10(1H，t，J＝7.8)，7.00
-6.99(2H，m)，6.90(1H，t，J＝8.3)，
4.46(2H，s)，3.43(2H，t，J＝7.3)，
3.04(2H，d，J＝11.7)，2.85(1H，tt，
J＝11.7，3.7)，2.78(3H，s)，2.46
(2H，t，J＝7.3)，2.18-2.07(4H，m)，
1.94-1.77(4H，m)
MS：426(M+)
Embodiment 50
4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumarates (50)
Figure C9210399100831
The compound of dissolving 3.50g embodiment 49 in 20ml ethanol chloroform (1: 1), the ethanolic soln with 5ml 0.96g fumaric acid adds wherein then.Heat up in a steamer and desolvate and make its crystallization, obtain the 4.45g title compound of white crystals.
Fusing point: 145-147 ℃
Ultimate analysis: in C26H30N6C4H4O4
Calculated value: C, 66.40; H, 6.32; N, 15.49
Measured value: C, 66.38; H, 6.21; N, 15.46
IR(KBr)cm -1：3410，1678，1562，1433，
1342，1228，982，748，648
Embodiment 51-68
Below carry out 49 identical operations with embodiment, replace 18 to obtain 51 compound with 38, replace 18 to obtain 52 compound with 35, replace 18 to obtain 53 compound with 36, replace 4-(3-indyl) piperidines to obtain 54 compound with 4-(5-methoxyl group-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 55 compound with 4-(5-chloro-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 56 compound with 4-(5-bromo-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 57 compound with 4-(5-fluoro-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 58 compound with 4-(5-methyl-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 59 compound with 4-(6-methoxyl group-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 60 compound with 4-(6-methyl-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 61 compound with 4-(6-fluoro-3-indyl) piperidines, replace 4-(3-indyl) piperidines to obtain 62 compound with 4-(2-methyl-3-indyl) piperidines, with 4-(1,2,3,6-tetrahydrochysene-4-(3-indyl) piperidines replaces 4-(3-indyl) piperidines to obtain 63 compound, replace 4-(3-indyl) piperidines to obtain 64 compound with 4-(1-ethyl-3-indyl) piperidines, replace 18 to obtain 65 compound with 34, replace 18 to obtain 66 compound with 39, obtain 67 compound with 40 replacements 18, replace 18 to obtain 68 compound with 41.
Figure C9210399100841
Compound R 1R 2R 3R 4R 5M  R 7R 8R 951 Me H H H 4- H H H52 Et H H H 3- H H H53 Pr H H H 3- H H H54 Me H H H 3- H H 5-MeO55 Me H H H 3- H H 5-Cl56 Me H H H 3- H H 5-Br57 Me H H H 3- H H 5-F58 Me H H H 3- H H 5-Me59 Me H H H 3- H H 6-MeO60 Me H H H 3- H H 6-Me61 Me H H H 3- H H 6-F62 Me H H H 3- Me H H63 Me H H H 3 ＝ H H H64 Me H H H 3- H Et H65 Me 7-Cl H H 3- H H H66 Me 7-F H H 3- H H H67 Me 8-F H H 3- H H H68 Me H Me H 3- H H H
51:4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) butyl) (1,2,4) triazolo (4,3-a) quinoxaline
52:1-ethyl-4,5-dihydro-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
53:4,5-dihydro-1-propyl group-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
54:4,5-dihydro-1-methyl-5-(3-(4-(5-methoxyl group-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
55:4,5-dihydro-1-methyl-5-(3-(4-(5-chloro-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
56:4,5-dihydro-1-methyl-5-(3-(4-(5-bromo-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
57:4,5-dihydro-1-methyl-5-(3-(4-(5-fluoro-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
58:4,5-dihydro-1-methyl-5-(3-(4-(5-methyl--3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
59:4,5-dihydro-1-methyl-5-(3-(4-(6-methoxyl group-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
60:4,5-dihydro-1-methyl-5-(3-(4-(6-methyl-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
61:4,5-dihydro-1-methyl-5-(3-(4-(6-fluoro-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
62:4,5-dihydro-1-methyl-5-(3-(4-(2-methyl-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
63:4,5-dihydro-1-methyl-5-(3-(1,2,3,6-tetrahydrochysene-4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
64:4,5-dihydro-1-methyl-5-(3-(4-(1-ethyl-3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumarate
65:7-chloro-4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
66:7-fluoro-4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
67:8-fluoro-4,5-dihydro-1-methyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumarate
68:4,5-dihydro-1,4-dimethyl-5-(3-(4-(3-indyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
The physical parameter compound spectroscopic data 51 of above-mentioned each compound is shown below: white crystals
Fusing point: 228-237 ℃
Ultimate analysis: in C27H32N6
Calculated value: C, 73.60; H, 7.32; N, 19.70
Measured value: C, 73.38; H, 7.57; N, 20.03
IR(KBr)cm -1：3430，2934，1502，
1460，1431，1383，746
1HNMR(CD3OD)δ：10.8(1H，brs)，8.21
(1H，dd，J＝7.0，1.1)，7.78(1H，
d，J＝7.7)，7.63(1H，m)，7.48(1H，
d，J＝7.1)，7.46(1H，m)，7.31(1H，
dd，J＝6.2，1.1)，7.12-6.93(3H，
m)，4.82(2H，s)，4.43(2H，t，J＝
7.7)，3.09(2H，m)，3.08(3H，s)，
2.85(1H，m)，2.51(2H，m)，2.21
(2H，m)，2.05(2H，m)，1.9-1.8
(4H，m)，1.75(2H，m)
MS:440 (M+) 52: faint yellow crystallization
Fusing point: 202～205 ℃
Ultimate analysis: in C27H32N61/4H2O
Calculated value: C, 72.95; H, 7.37; N, 18.90
Measured value: C, 72.87; H, 7.27; N, 18.67
IR(KBr)cm -1：3420，3168，2930，
1562，1502，1460，1437，741
1HNMR(CDCl3)δ：8.03(1H，brs)，7.65
(1H，d，J＝8.3)，7.45(1H，dd，J＝
6.8，1.2)，7.37(1H，d，J＝7.8)，
7.25-7.16(2H，m)，7.10(1H，t，
J＝6.8)，7.00-6.99(2H，m)，6.90
(1H，t，J＝7.3)，4.46(2H，s)，
3.42，(2H，t，J＝7.3)，3.12(2H，q，
J＝7.3)，3.05(2H，d，J＝11.7)，
2.86(1H，tt，J＝11.7，3.4)，2.47
(2H，t，J＝7.3)，2.18-2.06(4H，
m)，1.94-1.74(4H，m)，1.51(3H，
t，J＝7.3)
MS:440 (M+) 53: faint yellow crystallization
Fusing point: 186～188 ℃
Ultimate analysis: in C28H34N6
Calculated value: C, 73.98; H, 7.54; N, 18.49
Measured value: C, 74.12; H, 7.68; N, 18.36
IR(KBr)cm -1：3420，3182，2934，
1562，1502，1460，1433，1342，
739
1HNMR(CDCl3)δ：8.22(1H，s)，7.65(1
H，d，J＝7.8)，7.44(1H，dd，J＝6.8，
1.0)，7.36(1H，d，J＝7.8)，7.26-
7.16(2H，m)，7.10(1H，t，J＝6.8)，
7.00-6.99(2H，m)，6.91(1H，td，
J＝7.3，1.0)，4.44(2H，s)，3.41
(2H，t，J＝7.3)，3.08-3.03(4H，
m)，2.85(1H，tt，J＝11.7，3.4)，
2.47(2H，t，J＝6.8)，2.18-2.03
(4H，m)，2.00-1.78(6H，m)，1.09
(3H，t，J＝7.3)
MS:454 (M+) 54: faint yellow crystallization
Fusing point: 147～151 ℃
Ultimate analysis: in C27H32N6O
Calculated value: C, 71.30; H, 7.06; N, 18.40
Measured value: C, 71.53; H, 7.17; N, 18.63
IR(KBr)cm -1：3238，2938，1671，
1502，1475，1431，1212，1174，
750
1HNMR(CDCl3)δ：7.93(1H，brs)，7.46
(1H，dd，J＝8.1，1.5)，7.27-7.21
(2H，m)，7.06(1H，d，J＝2.2)，
6.98(2H，m)，6.91(1H，t，J＝7.7)，
6.85(1H，dd，J＝8.8，2.2)，4.46
(2H，s)，3.87(3H，s)，3.43(2H，t，
J＝7.3)，3.06(2H，d，J＝11.3)，
2.81(1H，m)，2.78(3H，s)，2.49
(2H，t，J＝7.1)，2.18(2H，t-like)，
2.08(2H，d-like)，2.0-1.7(4H，m)
MS:457 (M+H)+55: yellow crystal
Fusing point: 176～180 ℃
Ultimate analysis: in C26H29N6Cl
Calculated value: C, 67.74; H, 6.34; N, 18.23;
Cl，7.69
Measured value: C, 67.93; H, 6.27; N, 18.41;
Cl，7.49
IR(KBr)cm -1：2926，1560，1506，
1460，1435，1352，1288，895，791，
748
1HNMR(CDCl3)δ：8.33(1H，brs)，7.57
(1H，d，J＝2.1)，7.47(1H，dd，J＝
7.9，1.2)，7.29(1H，J＝8.6)，
7.25(1H，m)，7.12(1H，dd，J＝8.7，
2.0)，7.03(1H，d，J＝2.1)，6.99
(1H，d，J＝8.2)，6.93(1H，t，J＝
7.0)，4.45(2H，s)，3.44(2H，t，
J＝7.0)，3.16(2H，d，J＝10.7)，
2.83(1H，m)，2.79(3H，s)，2.60
(2H，t-like)，2.30(2H，m)，2.10-
1.86(6H，m)
MS:460 (M+) 56: faint yellow crystallization
Fusing point: 152～154 ℃
Ultimate analysis: in C26H29N6Br
Calculated value: C, 61.78; H, 5.78; N, 16.63;
Br，15.81
Measured value: C, 61.97; H, 5.89; N, 16.74;
Br，15.57
IR(KBr)cm -1：3218，2938，1562，
1504，1454，1433，750
1HNMR(CDCl3)δ：8.38(1H，brs)，7.72
(1H，s)，7.47(1H，dd，J＝8.1，
1.4)，7.28-7.24(3H，m)，7.01-
6.99(2H，m)，6.94(1H，t，J＝7.8)，
4.44(2H，s)，3.45(2H，t，J＝7.0)，
3.21(2H，d-like)，2.85(1H，m)，
2.79(3H，s)，2.65(2H，t-like)，
2.37(2H，m)，2.1-1.9(6H，m)
MS:504 (M+) 57. faint yellow crystallizations
Fusing point: 158～164 ℃
Ultimate analysis: in C26H29N6F
Calculated value: C, 70.25; H, 6.58; N, 18.90;
F，4.27
Measured value: C, 70.37; H, 6.39; N, 18.64;
F，4.11
IR(KBr)cm -1：3176，2926，1562，
1504，1475，1429，1352，1168，
936，743
1HNMR(CDCl3)δ：8.29(1H，brs)，7.47
(1H，dd，J＝8.1，1.4)，7.29(1H，
dd，J＝8.8，4.4)，7.25-7.21(2H，
m)，7.06(1H，d，J＝2.1)，7.00(1H，
d，J＝8.6)，6.96(1H，d，J＝9.2)，
6.93(1H，m)，4.43(2H，s)，3.46
(2H，t，J＝6.9)，3.28(2H，m)，
2.87(1H，m)，2.79(3H，s)，2.72
(2H，m)，2.45(2H，m)，2.2-2.0(6
H，m)
MS:444 (M+) 58: faint yellow crystallization
Fusing point: 207～212 ℃
Ultimate analysis: in C27H32N6
Calculated value: C, 73.60; H, 7.32; N, 19.07
Measured value: C, 73.89; H, 7.56; N, 19.32
IR(KBr)cm -1：3232，1562，1502，
1468，1454，1433，750
1HNMR(CDCl3)δ：7.85(1H，s)，7.64(1
H，d，J＝7.9)，7.36(1H，s)，7.31
(1H，t，J＝7.2)，7.20(1H，d，J＝
8.2)，7.11(1H，d，J＝8.2)，6.96
(1H，s)6.98(1H，t-like)，6.90(1
H，t，J＝8.2)，4.45(2H，s)，3.47
(2H，t，J＝7.2)，3.09(2H，d，J＝
11.9)，2.83(1H，m)，2.77(3H，s)，
2.54(2H，t，J＝7.6)，2.40(3H，s)，
2.25(2H，t-like)，2.04(2H，m)，
1.96(2H，m)，1.86(2H，m)
MS:440 (M+) 59: faint yellow crystallization
Fusing point: 184-187 ℃
Ultimate analysis: in C27H32N6O
Calculated value: C, 71.03; H, 7.06; N, 18.41
Measured value: C, 70.86; H, 6.93; N, 18.56
IR(KBr)cm -1：1562，1504，1460，
1425，1162，745
1HNMR(CDCl3)δ：7.88(1H，brs)，7.51
(1H，d，J＝8.8)，7.46(1H，dd，J＝
7.8，1.2)，7.23(1H，td，J＝7.8，
1.2)，7.00(1H，d，J＝7.8)，6.91
(1H，td，J＝7.3，1.0)，6.88(1H，d，
J＝1.0)，6.86(1H，d，J＝1.4)，
6.78(1H，dd，J＝8.3，2.2)，4.46
(2H，s)，3.84(3H，s)，3.43(2H，d，
J＝7.1)，3.05(2H，d-like)，2.81
(1H，m)，2.78(3H，s)，2.48(2H，t，
J＝7.1)，2.16(2H，t，J＝11.5)，
2.06(2H，d-like)，1.76-1.95
(4H，m)，
MS:456 (M+) 60: white crystals
Fusing point: 203-208 ℃
Ultimate analysis: in C27H32N6
Calculated value: C, 73.60; H, 7.32; N, 19.07
Measured value: C, 73.77; H, 7.14; N, 19.31
IR(KBr)cm -1：3224，2926，1560，
1504，1473，1460，1423，1350，
799，745
1HNMR(CDCl3)δ：7.86(1H，brs)，7.46
(1H，dd，J＝8.3，1.2)，7.46(1H，
dd，J＝8.0，1.2)，7.23(1H，td，J＝
8.1，1.2)，7.16(1H，s)，7.00(1H，
d，J＝7.3)，6.88-6.95(3H，m)，
4.46(2H，s)，3.43(2H，t，J＝7.3)，
3.04(2H，d，J＝11.2)，2.82(1H，
m)，2.78(3H，s)，2.44-2.48(5H，
m)，2.14(2H，t-like)，2.07(2H，
d-like)，1.76-1.94(4H，m)
MS:440 (M+) 61: greenish orange look crystallization
Fusing point: 194-198 ℃
Ultimate analysis: in C26H29N6F
Calculated value: C, 70.25; H, 6.58; N, 18.90;
F，4.27
Measured value: C, 70.03; H, 6.39; N, 18.69;
F，4.19
IR(KBr)cm -1：3204，2938，1560，
1502，1460，1435，1350，1145，
797，752
1HNMR(CDCl3)δ：7.99(1H，brs)，7.54
(1H，dd，J＝8.8，5.4)，7.47(1H，
dd，J＝8.3，1.5)，7.23(1H，td，J＝
7.8，1.2)，7.04(1H，dd，J＝9.8，
2.4)，6.99(1H，d，J＝8.3)，6.97
(1H，d，J＝1.5)，6.84-6.93(2H，
m)，4.47(2H，s)，3.43(2H，t，J＝
7.1)，3.05(2H，d，J＝11.2)，2.81
(1H，m)，2.79(3H，s)，2.47(2H，
t，J＝7.1)，2.15(2H，t，J＝11.7)，
2.06(2H，d-like)，1.75-1.93(4
H，m)
MS:444 (M+) 62: yellow crystal
Fusing point: 176～182 ℃
Ultimate analysis: in C27H32N6
Calculated value: C, 73.60; H, 7.32; N, 19.07
Measured value: C, 73.47; H, 7.12; N, 19.24
IR(KBr)cm -1：1560，1502，1460，
1433，745
1HNMR(CD3OD)δ：7.76(1H，dd，J＝8.0，
1.2)，7.60(1H，d，J＝7.8)，7.34
(1H，d，J＝7.3)，7.21(1H，d，J＝
7.8)，7.14(1H，d，J-7.3)，7.02
(1H，d，J＝7.3)，6.97(1H，d，J＝
7.1)，6.90(1H，t，J＝7.1)，4.46
(2H，s)，3.51(2H，t，J＝7.0)，
3.33(2H，m)，2.93(1H，m)，2.83
(2H，m)，2.77(3H，s)，2.57(2H，
m)，2.37(3H，s)，2.35(2H，m)，
2.07(2H，m)，1.82(2H，m)
MS:440 (M+) 63: faint yellow crystallization
Fusing point: 161～168 ℃
Ultimate analysis: in C26H28N6
Calculated value: C, 73.56; H, 6.65; N, 19.80
Measured value: C, 73.44; H, 6.73; N, 19.93
IR(KBr)cm -1：1504，1431，741
1HNMR(CDCl3)δ：8.16(1H，brs)，7.91
(1H，d，J＝7.8)，7.47(1H，dd，J＝
7.8，1.5)，7.38(1H，d，J＝8.3)，
7.3-7.1(4H，m)，7.01(1H，d，J＝
7.3)，6.91(1H，td，J＝7.8，1.0)，
6.22(1H，brs)，4.47(2H，s)，
3.46(2H，t，J＝7.3)，3.24(2H，d，
J＝2.9)，2.79(3H，s)，2.76(2H，
t，J＝5.6)，2.65(2H，brs)，2.57
(2H，t，J＝6.8)，1.96(2H，m)
MS:424 (M+) 64: white crystals
Fusing point: 142～152 ℃
Ultimate analysis: in C28H34N6C4H4O4
Calculated value: C, 67.35; H, 6.71; N, 14.73
Measured value: C, 67.57; H, 6.58; N, 14.89
IR(KBr)cm -1：1678，1611，1560，
1504，1473，1433，1352，984
746，646cm
1HNMR(CDCl3)δ：7.57(1H，d，J＝7.8)，
7.43(1H，d，J＝7.8)，7.30(1H，d，
J＝8.3)，7.25(1H，m)，7.19(1H，
t，J＝7.1)，7.08(1H，t，J＝7.8)，
7.0-6.9(2H，m)，6.87(1H，s)，
4.41(2H，s)，4.11(2H，q，J＝7.3)，
3.54(2H，d-like)，3.44(2H，t，J＝
7.0)，3.0-2.9(3H，m)，2.77(3H，
s)，2.62(2H，m)，2.4-2.0(6H，m)，
1.42(3H，t，J＝7.3)
MS:454 (M-C4H4O4)+65: light yellowish pink crystallization
Fusing point: 203～209 ℃ (decomposition)
Ultimate analysis: in C26H29N6Cl0.9H2O
Calculated value: C, 65.44; H, 6.50; N, 17.61
Measured value: C, 65.75; H, 6.30; N, 17.35
IR(KBr)cm -1：2926，1555，1508，
1441，1166，733
1HNMR(CDCl3)δ：8.07(1H，brs)，7.64
(1H，d，J＝8.0)，7.36(2H，d，J＝
8.5)，7.18(1H，t，J＝7.0)，7.10
(1H，t，J＝7.0)，7.00(2H，s)，
6.86(1H，dd，J＝8.5，2.4)，4.49
(2H，s)，3.43(2H，t，J＝7.0)，
3.08(2H，d，J＝11.6)，2.87(1H，
m)，2.76(3H，s)，2.49(2H，t，J＝
6.7)，2.21(2H，t，J＝11.3)，2.09
(2H，d，J＝12.8)，1.92(4H，quint，
J＝7.0)
MS:460 (M+) 66: white crystals
Fusing point: 181～184 ℃
Ultimate analysis: in C26H29N6F0.8H20
Calculated value: C, 68.04; H, 6.72; N, 18.31;
F，4.14
Measured value: C, 68.32; H, 6.54; N, 17.95;
F，4.17
IR(KBr)cm -1：2928，1560，1512，
1352，1311，1011，745
1HNMR(CDCl3)δ：8.08(1H，s)，7.64
(1H，d，J＝7.3)，7.40(1H，dd，J＝
9.2，5.5)，7.36(1H，d，J＝7.5)，
7.18(1H，td，J＝7.3，1.2)，7.10
(1H，t，J＝7.9)，7.01(1H，d，J＝
2.4)，6.79(1H，dd，J＝11.0，
2.4)，6.59(1H，td，J＝8.5，2.4)，
4.49(2H，s)，3.43(2H，t，J＝6.7)，
3.19(2H，d，J＝11.6)，2.88(1H，
m)，2.76(3H，s)，2.51(2H，t，J＝
6.7)，2.24(2H，d，J＝11.6)，2.10
(2H，d，J＝12.9)，1.94(4H，m)
MS:444 (M+) 67: filbert non-crystalline state
Ultimate analysis: in C26H29N6FC4H4O4
Calculated value: C, 64.27; H, 5.93; N, 14.99;
F，3.39
Measured value: C, 64.15; H, 6.08; N, 14.85;
F，3.57
IR(KBr)cm -1：2928，1562，1419，
1193，743
1HNMR(CDCl3)δ：8.10(1H，s)，7.74
(1H，m)，7.62(1H，dd，J＝7.9，
3.7)，7.37(1H，d，J＝9.2)，7.23
(1H，dd，J＝7.6，2.4)，7.18(1H，
t，J＝7.9)，7.10(1H，t，J＝7.6)，
7.00(1H，dd，J＝11.0，3.7)，6.98
(1H，dd，J＝7.3，2.4)，4.40(2H，
s)，3.41(2H，t，J＝7.3)，3.21(2H，
brs)，2.78(3H，s)，2.39(2H，brs)，
2.13(2H，d，J＝13.5)，1.71(6H，
m)
MS:444 (M+) 68: filbert non-crystalline state
Ultimate analysis: in C27H32N6
Calculated value: C, 73.60; H, 7.32; N, 19.07
Measured value: C, 73.38; H, 7.56; N, 18.86
IR(KBr)cm -1：2930，1555，1502，
1431，1350，1247，745
1HNMR(CDCl3)δ：8.14(1H，s)，7.63
(1H，d，J＝8.1)，7.47(1H，dd，J＝
8.1，1.5)，7.36(1H，d，J＝8.1)，
7.24(1H，td，J＝8.1，1.5)，7.17
(1H，td，J＝8.1，1.1)，7.09(1H，
td，J＝7.4，1.1)，6.99(1H，m)，
6.96(1H，d，J＝8.0)，6.91(1H，td，
J＝7.4，1.1)，4.89(1H，q，J＝6.6)，
3.59(1H，quint，J＝6.6)，3.23(1H，
quint，J＝7.0)，3.05(2H，t，J＝9.8)，
2.88(1H，m)，2.78(3H，s)，2.47
(2H，m)，2.17(2H，m)，2.07(2H，
d，J＝13.1)，1.89(4H，m)，1.28
(3H，d，J＝6.6)
MS：440(M+)
Embodiment 69-94
Except that replacing 4-(3-indyl) piperidines, according to obtaining each compound with the same operation of embodiment 49 with following compound.Obtain 69 with 1-((4-chloro-phenyl-) phenyl methyl) piperazine, obtain 70 with 1-(4-benzyl chloride base) piperazine, obtain 71 with 1-(1-(1-ethoxyethyl group) benzimidazolyl-2 radicals-yl) piperazine, obtain 72 with the high piperazine of 1-(1-(1-ethoxyethyl group) benzimidazolyl-2 radicals-yl), obtain 73 with 4-(1-(4-luorobenzyl) benzimidazolyl-2 radicals-amino) piperidines, get 74 with 4-(hydroxy benzophenone base) piperidines, obtain 75 with 4-(hydroxyl two (4-fluorophenyl) methyl) piperidines, obtain 76 with 4-(phenylbenzene methoxy base) piperidines, obtain 77 with 4-(two (4-fluorophenyl) methylene radical) piperidines, with 4-(5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 78, obtain 79 with 4-(diphenyl methyl) piperidines, with 4-(1,2-benzoisoxazole-3-yl) piperidines obtains 80, obtain 81 with 4-(2-ketone group-1-benzimidazoline base) piperidines, with 4-(1H-pyrrolo-(2,3-b) pyridin-3-yl) piperidines obtains 82, with 4-(1H-pyrrolo-(3,2-c) pyridin-3-yl) piperidines obtains 83, with 4-(1H-pyrrolo-(3,2-b) pyridin-3-yl) piperidines obtains 84, obtain 85 with 3-(phenylbenzene methylene radical) tetramethyleneimine, obtain 86 with 4-(2-p-methoxy-phenyl) piperazine, with 4-(10,11-dihydro-5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 87, with 4-(6,11-dihydro-dibenzo (b, e) oxa-seven ring-11-subunits) piperidines obtains 88, obtains 89 with 4-(2-chloro-Thiaxanthene-9-subunit) piperidines.
With 41 replacing 18, obtaining 90 with 4-(hydroxyl two (4-fluorophenyl) methyl) piperidines replacement 4-(3-indyl) piperidines, with 41 replacing 18, obtaining 91 with 4-(two (4-fluorophenyl) methylene radical) piperidines replacement 4-(3-indyl) piperidines, with 35 replacing 18, obtaining 92 with 4-(phenylbenzene methylene radical) piperidines replacement 4-(3-indyl) piperidines, with 41 replacing 18, replace 4-(3-indyl) piperidines to obtain 93, with 37 replacements 18, obtain 94 with 4-(phenylbenzene methylene radical) piperidines replacement 4-(3-indyl) piperidines with 4-(phenylbenzene methylene radical) piperidines.Structural formula of compound 69 70
Figure C9210399101042
71
Figure C9210399101051
72
Figure C9210399101052
73
Figure C9210399101061
74
Figure C9210399101062
75
Figure C9210399101071
76
Figure C9210399101072
77 78
Figure C9210399101082
79
Figure C9210399101083
80
Figure C9210399101084
81
Figure C9210399101091
82
Figure C9210399101092
83
Figure C9210399101093
84 85
Figure C9210399101102
86
Figure C9210399101103
87 88 89 90
Figure C9210399101113
91
Figure C9210399101121
92
Figure C9210399101122
93
Figure C9210399101123
94
69:4,5-dihydro-1-methyl-5-(3-(4-(4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
70:4,5-dihydro-1-methyl-5-(3-(4-(4-benzyl chloride base) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumarate
71:4,5-dihydro-1-methyl-5-(3-(4-(1-(1-ethoxyethyl group) benzimidazolyl-2 radicals-yl) piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumarate
72:4,5-dihydro-1-methyl-5-(3-(4-(1-(1-ethoxyethyl group) benzimidazolyl-2 radicals-yl) high piperazine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline tartrate
73:4,5-dihydro-1-methyl-5-(3-(4-(1-(4-luorobenzyl) benzoglyoxaline-2-amino)-piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
74:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl diphenyl methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline tartrate
75:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (4-fluorophenyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline tartrate
76:4,5-dihydro-1-methyl-5-(3-(4-(phenylbenzene methoxy base) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline tartrate
77:4,5-dihydro-1-methyl-5-(3-(4-(two (4-fluorophenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
78:4,5-dihydro-1-methyl-5-(3-(4-(5H-dibenzo (a, d) suberene-5-subunit) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
79:4,5-dihydro-1-methyl-5-(3-(4-(diphenyl methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
80:4,5-dihydro-1-methyl-5-(3-(4-(1,2-benzoisoxazole-3-yl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
81:4,5-dihydro-1-methyl-5-(3-(4-(2-ketone group-1-benzimidazoline base) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
82:4,5-dihydro-1-methyl-5-(3-(4-(1H-pyrrolo-(2,3-b) pyridin-3-yl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumarate
83:4,5-dihydro-1-methyl-5-(3-(4-(1H-pyrrolo-(3,2-c) pyridin-3-yl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
84:4,5-dihydro-1-methyl-5-(3-(4-(1H-pyrrolo-(3,2-b) pyridin-3-yl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
85:4,5-dihydro-1-methyl-5-(3-(3-(phenylbenzene methylene radical) tetramethyleneimine-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
86:4,5-dihydro-1-methyl-5-(3-(4-(2-p-methoxy-phenyl) piperazine-1-yl) propyl group) (1,24) triazolo (4,3-a) quinoxaline
87:4,5-dihydro-1-methyl-5-(3-(4-(10,11-dihydro-5H-dibenzo (a, d) suberene-5-subunit) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
88:4,5-dihydro-1-methyl-5-(3-(4-(6,11-dihydro-dibenzo (b.e) oxa-seven ring-11-subunits) piperidines-1-yl) propyl group (1,2,4) triazolo (4,3-a) quinoxaline
89:4,5-dihydro-1-methyl-5-(3-(4-(2-chlorine Thiaxanthene-9-subunit) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
90:4,5-dihydro-1,4-dimethyl-5-(3-(4-(hydroxyl two (4-fluorophenyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
91:4,5-dihydro-1,4-dimethyl-5-(3-(4 (two (4-fluorophenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline fumaric acid
92:1-ethyl-4,5-dihydro-5-(3-(4-(phenylbenzene methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
93:4,5-dihydro-1,4-dimethyl-5-(3-(4-(phenylbenzene methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
94:4,5-dihydro-1,4,4-trimethylammonium-5-(3-(4-phenylbenzene methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
Above-claimed cpd has following physical parameter compound spectroscopic data 69: white crystals
Fusing point: 176～178 ℃ (decomposition)
Ultimate analysis: in C30H33N6Cl
Calculated value: C, 70.23; H, 6.48; N, 16.38;
Cl，6.91
Measured value: C, 70.37; H, 6.43; N, 16.39;
Cl，6.93
IR(KBr)cm -1：2814，1504，1143，
1089，1011，756
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.8，
1.5)，7.38-7.35(3H，m)，7.37(2H，
AB，J＝8.3)，7.34-7.27(1H，m)，
7.24(2H，AB，J＝8.3)，7.19(2H，m)，
6.93(1H，dd，J＝7.8，1.0)，6.89(1
H，td，J＝7.8，1.0)，4.42(2H，s)，
4.21(1H，s)，3.37(2H，t，J＝7.3)，
2.77(3H，s)，2.47(8H，brs)，2.41
(2H，t，J＝6.8)，1.82(2H，quint，J＝
7.1)
MS:512 (M+) 70: filbert crystallization
Fusing point: 140～142 ℃
Ultimate analysis: in C24H29N6Cl2C4H4O4
Calculated value: C, 57.44; H, 5.57; N, 12.56;
Cl，5.30
Measured value: C, 57.69, H, 5.83; N, 12.77;
Cl，5.58
IR(KBr)cm -1：2942，2814，1504，
1431，1350，1156，1013，748
1HNMR(CDCl3)δ：7.46(1H，AB，J＝7.8)，
7.29-7.20(5H，m)，6.95(1H，AB，
J＝8.3)，6.90(1H，t，J＝7.8)，4.44
(2H，s)，3.47(2H，s)，3.39(2H，t，
J＝7.3)，2.78(3H，s)，2.47(8H，
brs)，2.40(2H，t，J＝7.3)，1.83(2
H，m)
MS:436 (M+) 71: colourless non-crystalline state
Ultimate analysis: in C28H36N8O2C4H4O4
Calculated value: C, 59.01; H, 6.05; N, 15.29
Measured value: C, 58.78; H, 6.26; N, 15.53
IR(KBr)cm -1：2934，2854，1522，
1504，1466，1122，7，48
1HNMR(CDCl3)δ：7.62(1H，m)，7.47(1H，
dd，J＝8.3，1.5)，7.31(1H，m)，
7.25(1H，m)，7.18(2H，m)，7.01(1
H，d，J＝7.8)，6.92(1H，t，J＝7.3)，
4.46(2H，s)，4.20(2H，t，J＝5.9)，
3.83(2H，t，J＝5.9)，3.48(2H，t，
J＝6.8)，3.46(2H，q，J＝6.8)，3.41
(4H，t，J＝4.6)，2.79，(3H，s)，
28.5(4H，brs)，2.50(2H，t，J＝6.8)，
1.89(2H，quint，J＝6.8)，1.15(3H，
t，J＝6.8)
MS:501 (M+H)+72: white crystals
Fusing point: 92～95 ℃
Ultimate analysis: in C29H38N8O2 (C4H606)
Calculated value: C, 54.54; H, 6.19; N, 13.75
Measured value: C, 54.90; H, 6.20; N, 13.48
IR(KBr)cm -1：3406，2974，2880，
1729,1611,1504,1125,75273: white crystals
Fusing point: 139～146 ℃ (decomposition)
Ultimate analysis: in C32H35N8F1.5 (C4H6O6H2O)
Calculated value: C, 58.08, H, 5.90; N, 14.26
Measured value: C, 58.47; H, 6.20; N, 13.98
IR(KBr)cm -1：3320，1562，1504，
1309,1267,748,681,48774: faint yellow crystallization
Fusing point: 139～142 ℃
Ultimate analysis: in C31H35N5OC4H6O6H2O
Calculated value: C, 63.53; H, 6.55; N, 10.58
Measured value: C, 63.82; H, 6.54; N, 10.16
IR(KBr)cm -1，3324，1562，1502，
1433，1307，1265，1069，752，704，
68175: white crystals
Fusing point: 141～144 ℃ (decomposition)
Ultimate analysis: in C31H33N5OF2C4H6O6H2O
Calculated value: C, 60.25; H, 5.92; N, 10.04
Measured value: C, 60.49; H, 5.86; N, 9.91
IR(KBr)cm -1：3322，1603，1506，
1307，1265，1220，837，752，681，
57176: white crystals
Fusing point: 191～192 ℃
Ultimate analysis: in C31H35N5OC4H6O6H2O
Calculated value: C, 63.53; H, 6.55; N, 10.58
Measured value: C, 63.76; H, 6.17; N, 10.48
IR(KBr)cm -1：3322，1678，1427，
1307,1265,1067,681,48577: white crystals
Fusing point: 130～132 ℃
Ultimate analysis: in C31H31N5F2
Calculated value: C, 72.78; H, 6.11; N, 13.69
Measured value: C, 72.50; H, 6.19; N, 13.65
IR(KBr)cm -1：1508，1224，835，745，
559
1HNMR(CDCl3)δ：7.46(1H，dd，J＝7.8，
1.5)，7.22(1H，td，J＝7.3，1.5)，
7.07-7.04(4H，m)，7.00-6.95(5H，
m)，6.91(1H，td，J＝7.3，1.5)，
4.44(2H，s)，3.41(2H，t，J＝7.1)，
2.78(3H，s)，2.50(4H，t，J＝5.4)，
2.44(2H，t，J＝7.1)，2.39(4H，t，
J＝5.4)，1.87(2H，quint，J＝7.1)
MS:511 (M+) 78: faint yellow crystallization
Fusing point: 168～174.5 ℃
Ultimate analysis: in C33H33N5
Calculated value: C, 79.32; H, 6.66; N, 14.02
Measured value: C, 78.92; H, 6.74; N, 13.86
IR(KBr)cm -1：1504，1433，803，756
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.8，
1.5)，7.34-7.30(4H，m)，7.25-
7.18(5H，m)，6.94(1H，dd，J＝7.3，
1.0)，6.91(2H，s)，6.88(1H，dd，
J＝7.3，1.0)，4.42(2H，s)，3.37
(2H，t，J＝7.1)，2.77(3H，s)，2.57
(2H，m)，2.36(4H，m)，2.16(4H，m)，
1.81(2H，quint，J＝7.1)
MS:500 (M+H)+79: white crystals
Fusing point: 182～184 ℃
Ultimate analysis: in C31H35N5
Calculated value: C, 77.95; H, 7.39; N, 14.66
Measured value: C, 78.16; H, 7.54; N, 14.38
IR(KBr)cm -1：3446，1657，1562
1510，1460，582
1HNMR(CDCl3)δ、7.44(1H，dd，J＝7.8，
1.5)，7.29-7.13(11H，m)，6.95-
6.88(2H，m)，4.41(2H，s)，3.51(1
H，d，J＝11.2)，3.37(2H，t，J＝6.8)，
2.90(2H，d，J＝10.7)，2.77(3H，s)，
2.41(2H，t，J＝6.8)，2.16-1.85(5
H，m)，1.58(2H，d，J＝13.2)，1.30-
1.24(2H，m)
MS:478 (M+H)+80: faint yellow crystallization
Fusing point: 138～141 ℃
Ultimate analysis: in C25H28N6O
Calculated value: C, 70.07; H, 6.59; N, 19.61
Measured value: C, 69.86; H, 6.72; N, 19.53
IR(KBr)cm -1：2948，1611，1555，
1508，1.433，1352，1236，743
1HNMR(CDCl3)δ7.76(1H，d，J＝7.8)，
7.59-7.52(2H，m)，7.47(1H，dd，
J＝7.8，1.2)，7.30(1H，td，J＝7.1，
1.5)，7.24(1H，m)，7.01(1H，dd，
J＝8.3，1.0)，6.92(1H，td，J＝7.8，
1.2)，4.46(2H，s)，3.44(2H，t，
J＝7.1)，3.17-3.06(3H，m)，2.79
(3H，s)，2.48(2H，t，J＝6.8)，2.25
-2.10(6H，m)，1.90(2H，m)
MS:428 (M+) 81: white crystals
Fusing point: 190～195 ℃
Ultimate analysis: in C25H29N7O
Calculated value: C, 67.70; H, 6.59:N, 22.11
Measured value: C, 67.44; H, 6.48; N, 21.89
IR(KBr)cm -1：1694，1506，1487，
1429，1379，1350，1282，752
1HNMR(CDCl3)δ：7.65(1H，dd，J＝8.1，
1.2)，7.36-7.30(2H，m)，7.13(1H，
d，J＝8.3)，7.08-7.03(3H，m)，
6.99(1H，td，J＝7.8，1.0)，4.46(2
H，s)，4.31(1H，m)，3.48(2H，t，J＝
7.1)，3.14(2H，d，J＝11.7)，2.77
(3H，s)，2.59-2.48(4H，m)，2.21
(2H，t-like)，1.94(2H，m)，1.80-
1.76(2H，m)
MS:443 (M+) 82: white crystals
Fusing point: 103-108 ℃
Ultimate analysis: in C25H29N7C4H4O4
Calculated value: C, 64.07; H, 6.12; N, 18.04
Measured value: C, 64.28; H, 6.37; N, 18.38
IR(KBr)cm -1：1560，1504，1475，
1429，754，741
1HNMR(CDCl3)δ：8.99(1H，brs)，8.29
(1H，dd，J＝4.9，1.5)，7.97(1H，dd，
J＝7.8，1.5)，7.47(1H，dd，J＝7.8，
1.2)，7.23(1H，td，J＝7.6，1.5)，
7.10(1H，brs)，7.06(1H，dd，J＝8.3，
8.3，4.4)，6.99(1H，d，J＝8.3)，
6.91(1H，td，J＝7.3，1.2)，4.47
(2H，s)，3.43(2H，t，J＝6.8)，3.04
(2H，d-like)，2.81(1H，m)，2.79
(3H，s)，2.46(2H，t，J＝6.7)，2.14
(2H，t-like)，2.10-2.00(2H，m)，
1.95-1.70(4H，m)
MS:427 (M+) 3: white non-crystalline state
Ultimate analysis: in C25H29N7
Calculated value: C, 70.23; H, 6.84; N, 22.93
Measured value: C, 70.11; H, 6.98; N, 23.16
IR(KBr)cm -1：
1HNMR(CDCl3)δ：7.76(1H，d，J＝7.8)，
7.59-7.52(2H，m)，7.47(1H，dd，
J＝7.8，1.2)，7.30(1H，td，J＝7.1，
15)，7.24(1H，m)，7.01(1H，dd，
J＝8.3，1.0)，6.92(1H，td，J＝7.8，
1.2)，4.46(2H，s)，3.44(2H，t，J＝
7.1Hz)，3.17-3.06(3H，m)，2.79
(3H，s)，2.48(2H，t，J＝6.8)，2.25
-2.10(6H，m)，1.90(2H，m)
MS:427 (M+) 84: white non-crystalline state
Ultimate analysis: C25H29N7 meter
Calculated value: C, 70.23; H, 6.84, N, 22.93
Measured value: C, 70.45; H, 7.04; N, 22.79
IR(KBr)cm -1：2938，1673，1504，
1433，781，750
1HNMR(CDCl3)δ：8.38(1H，dd，J＝4.7，
1.7)，7.67(1H，dd，J＝8.1，1.3)，
7.47(1H，dd，J＝8.1，1.7)，7.27-
7.23(2H，m)，7.10(1H，m)，6.98(1
H，d，J＝8.1)，6.93(1H，t，J＝8.1)，
4.46(2H，s)，3.41(2H，t，J＝7.3)，
3.12(1H，m)，3.1-3.0(2H，d＝like)，
2.78(3H，s)，2.48(2H，t，J＝6.8)，
2.25-2.10(6H，m)，1.92(1H，m)，
1.8-1.7(1H，m)
MS:427 (M+) 85: faint yellow non-crystalline state
Ultimate analysis: in C30H31N5C4H4O4
Calculated value: C, 70.69; H, 6.11; N, 12.12
Measured value: C, 70.52; H, 6.23; N, 12.01
IR(KBr)cm -1：2942，2802，1611，
1557，1504，1475，1431，1350，754
1HNMR(CDCl3)δ：7.58-7.03(12H，m)，
6.98-6.75(2H，m)，4.42(2H，s)，
3.57-3.20(4H，m)，2.77(3H，s)，
2.75-2.40(6H，m)，2.02-1.80(2
H，m)
MS:462 (M+H)+86: filbert crystallization
Fusing point: 111～112 ℃
Ultimate analysis: in C24H30N6O
Calculated value: C, 68.87; H, 7.23; N, 20.08
Measured value: C, 68.72; H, 7.20; N, 19.84
IR(KBr)cm -1：2946，2818，1504，
1243，746
1HNMR(CDCl3)δ：7.46(1H，d，J＝7.8)，
7.23(1H，t，J＝7.8)，7.03-6.86
(6H，m)，4.46(2H，s)，3.86(3H，s)，
3.43(2H，t，J＝7.3)，3.12(4H，m)，
2.78(3H，s)，2.67(4H，s)，2.49
(2H，t，J＝7.3)，1.89(2H，quint，J＝
7.3)
MS:418 (M+) 87: yellow crystal
Fusing point: 160～161.5 ℃
Ultimate analysis: in C33H35N5
Calculated value: C, 79.01; H, 7.03; N, 13.96
Measured value: C, 78.93; H, 7.15; N, 13.80
IR(KBr)cm -1：2900，1504，1431，
1350，745
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.2)，7.21(1H，t，J＝7.3)，7.12-
7.06(8H，m)，6.97(1H，d，J＝8.3)，
6.90(1H，t，J＝7.3)，4.44(2H，s)，
3.45-3.36(2H，m)，3.40(2H，t，J
＝7.3)，2.82(2H，m)，2.77(3H，s)，
2.67(2H，m)，2.41(6H，m)；2.19(2
H，m)，1.85(2H，quint，J＝7.3)
MS:501 (M+) 88: white crystals
Fusing point: 148～150 ℃
Ultimate analysis: in C32H33N5O1/2H2O
Calculated value: C, 74.97; H, 6.69; N, 13.66
Measured value: C, 74.84; H, 6.68; N, 13.31
IR(KBr)cm -1：2952，1504，1481，752
1HNMR(CDCl3)δ：7.46(1H，dd，J＝7.8，
1.5)，7.36(1H，ABd，J＝6.8，1.5)，
7.31(1H，td，J＝7.3，1.5)，7.28-
7.20(2H，m)，7.15(1H，ABd，J＝7.3，
1.5)，7.09(1H，td-like，J＝7.8，
1.5)，7.01(1H，dd，J＝7.3，1.5)，
6.97(1H，d，J＝7.3)，6.90(1H，td，
J＝7.3，1.5)，6.81(1H，td，J＝7.3，
1.0)，6.76(1H，dd，J＝8.3，1.0)，
5.72(1H，AB，J＝12.2)，4.78(1H，
AB，J＝12.2)，4.45(2H，s)，3.41(2
H，t，J＝6.8)，2.77(3H，s)，2.75-
2.57(4H，m)，2.40(4H，m)，2.26(1
H，m)，2.10(1H，m)，1.85(2H，quint，
J＝6.8)
MS:503 (M+) 89: yellow non-crystalline state
Ultimate analysis: in C31H30N5SCl
Calculated value: C, 68.94; H, 5.60; N, 12.97;
S，5.94；Cl，6.56
Measured value: C, 69.13; H, 5.77; N, 13.11;
S，6.25；Cl，6.83
IR(KBr)cm -1：2932，1560，1504，1433，
1096，754
1HNMR(CDCl3)δ：7.48-7.45(2H，m)，
7.40(1H，AB，J＝8.3)，7.31＝7.19
(5H，m)，7.16(1H，dd，J＝8.3，2.0)，
6.97(1H，d，J＝8.3)，6.91(1H，t，
J＝7.3)，4.44(2H，s)，3.41(2H，t，
J＝7.3)，2.78(3H+2H，s+m)，2.71
(4H，m)，2.41(2H，t，J＝6.8)，2.13
(2H，m)，1.87(2H，quint，J＝6.8)
MS:539 (M+) 90: colourless non-crystalline state
Ultimate analysis: in C32H35N5OF2
Calculated value: C, 70.70; H, 6.49; N, 12.88;
F，6.99
Measured value: C, 70.93; H, 6.28; N, 13.03;
F，7.18
IR(KBr)cm -1：3328，1504，1224，
1160，833，748，571
1HNMR(CDCl3)δ：7.42(5H，m)，7.21(1
H，td，J＝7.3，1.9)，6.97(4H，m)，
6.90(2H，m)，4.90(1H，q，J＝6.6)，
3.56(1H，quint，J＝6.2)，3.15(1H，
quint，J＝7.3)，2.92(2H，t，J＝12.8)，
2.75(3H，s)，2.42(1H，m)，2.34
(4H，m)，1.96(4H，m)，1.82(2H，m)，
1.24(3H，d，J＝6.6)
MS:544 (M+H)+91: colourless non-crystalline state
Ultimate analysis: in C32H33N5F2C4H4O4
Calculated value: C, 67.88; H, 5.81; N, 10.91;
F，5.92
Measured value: C, 67.56; H, 5.68; N, 11.14;
F，5.84
IR(KBr)cm -1：2958，1506，1222，835，
748，559
1HNMR(CDCl3)δ：7.47(1H，dd，J＝7.8，
1.5)，7.23(1H，td，J＝7.5，1.5)，
7.07-7.02(4H，m)，6.99-6.89(6H，
m)，4.89(1H，q，J＝6.8)，3.57(1H，
quint，J＝6.8)，3.21(1H，quint，J＝
6.8)，2.78(3H，s)，2.38(10H，s)，
1.83(2H，quint，J＝6.8)，1.27(3H，
d，J＝6.8)
MS:526 (M+H)+92: colourless non-crystalline state
Ultimate analysis: in C32H35N5
Calculated value: C, 78.49; H, 7.20; N, 14.30
Measured value: C, 78.19; H, 7.03; N, 14.58
IR(Neat)cm -1：2946，2810，1557，
1502，1473，1009，702
1HNMR(CDCl3)δ：7.43(1H，d，J＝7.8)，
7.29-7.12(11H，m)，6.97(1H，d，
J＝7.8)，6.89(1H，t，J＝7.8)，4.43
(2H，s)，3.40(2H，t，J＝7.8)，3.10
(2H，q，J＝6.8)，2.50-2.17(10H，
m)，1.86(2H，quint，J＝6.8)，1.49
(3H，t，J＝6.8)
MS:490 (M+H)+93: colourless non-crystalline state
Ultimate analysis: in C32H35N5
Calculated value: C, 78.49; H, 7.20; N, 14.30
Measured value: C, 78.69; H, 7.37; N, 14.01
IR(KBr)cm -1：29.30，1553，1502，
1468，1429，1350，750，704
1HNMR(CDCl3)δ：7.46(1H，d，J＝7.8)，
7.29-7.25(4H，m)，7.22-7.16(4
H，m)，7.12-7.10(3H，m)，6.93(1
H，d，J＝7.8)，6.90(1H，t，J＝7.3)，
4.88(1H，q，J＝6.9)，3.57(1H，
quint，J＝6.8)，3.21(1H，quint，J＝
6.8)，2.78(3H，s)，2.47-2.40(10
H，m)，1.84(2H，quint，J＝6.8)，1.27
(3H，d，J＝6.9)
MS:490 (M+H)+94: colourless non-crystalline state
Ultimate analysis: in C33H37N5
Calculated value: C, 78.49; H, 7.40; N, 13.90
Measured value: C, 78.58; H, 7.13; N, 14.27
IR(KBr)cm -1：2934，1537，1502，
1466，1427，748，702
1HNMR(CDCl3)δ：7.45(1H，d，J＝8.3)，
7.30-7.24(4H，m)，7.24-7.14(4H，
m)，7.14-7.11(3H，m)，6.97(1H，d，
J＝8.3)，6.90(1H，t，J＝7.8)，3.41
(2H，t，J＝7.3)，2.77(3H，s)，2.54
-2.37(10H，m)，1.77(2H，quint，J＝
7.8)；1.62(6H，s.)
MS：504(M+H)+
Embodiment 95
1-(3-chloropropyl)-4-benzoyl piperidines (95)
In the mixed solvent of forming by 200ml toluene, 64ml 25% aqueous sodium hydroxide solution, add 50.0g 4-benzoyl group piperidine hydrochlorate, 69.5g 1-bromo-3-chloropropane and 1.36g hydrogen sulfate tetrabutylammonium, stirring at room 30 hours.After in reaction solution, adding 200ml water, use ethyl acetate extraction.After concentrating organic layer, purify, obtain the 39.6g title compound of colourless crystallization with column chromatography.
Fusing point: 72-73 ℃ (decomposition)
IR(KBr)cm -1：2942，2816，1649，
1562，1456，1292，984，700
1HNMR(CDCl3)δ：8.00-7.82(2H，m)，
7.65-7.22(3H，m)，3.61(2H，t，J＝
6.4)，3.42-2.81(3H，m)，2.58(2H，
t，J＝7.0)，2.32-1.61(8H，m)
MS：265(M+)
Embodiment 96
1-(3-chloropropyl)-4-(hydroxyl (4-dimethylamino phenyl) phenyl methyl) piperidines (96)
Figure C9210399101332
The compound of dissolving 5.0g embodiment 95 in the 30ml dry tetrahydrofuran.After being cooled to 0 ℃, splash into the tetrahydrofuran solution (1M solution) of 30ml to dimethylamino phenyl magnesium bromide.After 1 hour, add saturated aqueous ammonium chloride in stirring at room, use the ethyl acetate extracting then.After concentrating organic layer, purify, obtain as faint yellow amorphous 5.5g title compound with column chromatography.
IR(neat)cm -1：3302，2940，1611，
1524，1439，948，818，727，700
1HNMR(CDCl3)δ：7.51-7.12(7H，m)，
6.78-6.57(2H，m)，3.56(2H，t，J＝
6.7)，3.08-2.81(8H，m)，2.57-
2.32(2H，m)，2.16-1.31(9H，m)
MS：386(M+)
Embodiment 97
1-(3-chloropropyl)-4-oxyethyl group carboxyl piperidines (97)
In the 250ml 2-butanone, add 26.1g isonipecotic acid ethyl ester, 52.5g 1-bromo-3-chloropropane and 34.4g salt of wormwood, refluxed 5 hours.After leaching inorganics, concentrated filtrate, (120 ℃/0.2mmHg) obtain 18.0g title compound of underpressure distillation as colorless oil.
IR(neat)cm -1：2954，2812，1734，
1450，1379，1296，1261，1181，
1050
1HNMR(CDCl3)δ：4.13(2H，q，J＝7.3)，
3.58(2H，t，J＝6.6)，3.00-2.72
(2H，m)，258-1.61(1.1H，m)，
1.25(3H，t，J＝7.0)
Embodiment 98
1-(3-chloropropyl)-4-(hydroxyl two (4-dimethylamino phenyl) methyl) piperidines (98)
Figure C9210399101351
The compound of dissolving 2.5g embodiment 97 in the 20ml dry tetrahydrofuran.After being cooled to 0 ℃, splash into the tetrahydrofuran solution (1M solution) of 30ml to dimethylamino phenyl magnesium bromine.After 1 hour, add saturated aqueous ammonium chloride in stirring at room, use the ethyl acetate extracting then.After concentrating organic layer, purify, obtain colourless amorphous 3.5g title compound with column chromatography.
IR(KBr)cm -1：3336，2794，1611，
1516，1444，1325，1131，1064，944，
814
1HNMR(CDCl3)δ：7.38-7.16(4H，m)，
6.78-6.56(4H，m)，3.57(2H，t，
J＝6.7)，3.05-2.80(14H，m)，2.52
-2.28(2H，m)，2.16-1.31(9H，m)
MS：429(M+)
Embodiment 99-105
Below carry out the operation same with embodiment 96, with a toluene magnesium bromo for dimethylamino phenyl magnesium bromine is obtained 99 compounds, with m-methoxyphenyl magnesium bromo for dimethylamino phenyl magnesium bromine is obtained 100 compounds, with 3,4-Dimethoxyphenyl magnesium bromo is for dimethylamino phenyl magnesium bromine is obtained 101 compounds.
Moreover, carry out same operation with embodiment 98, with o-tolyl magnesium bromo for dimethylamino phenyl magnesium bromine is obtained 102 compounds, with o-methoxyphenyl magnesium bromo for dimethylamino phenyl magnesium bromine is obtained 103 compounds, with 3,4-Dimethoxyphenyl magnesium bromo replaces dimethylamino phenyl magnesium bromine is obtained 105 compounds with 2-furyl lithium for dimethylamino phenyl magnesium bromine is obtained 104 compounds.
Figure C9210399101361
Compd A r1 Ar2 99 3-tolyl Ph100 3-MeO-Ph Ph101 3,4-(MeO) 2Ph Ph102 2-Tolyl 2-tolyl 103 2-MeO-Ph 2-MeO-Ph104 3,4-(MeO) 2Ph 3,4-(MeO) 2Ph105 2-furyl 2-furyl
99:1-(3-chloropropyl)-4-(hydroxy phenyl (3-tolyl) methyl) piperidines
100:1-(3-chloropropyl)-4-(hydroxyl (3-p-methoxy-phenyl) phenmethyl) piperidines
101:1-(3-chloropropyl)-4-(hydroxyl (3, the 4-Dimethoxyphenyl) phenmethyl) piperidines
102:1-(3-chloropropyl)-4-(hydroxyl two (2-tolyl) methyl) piperidines
103:1-(3-chloropropyl)-4-(hydroxyl two (2-p-methoxy-phenyl) methyl) piperidines
104:1-(3-chloropropyl)-4-(hydroxyl two (3, the 4-Dimethoxyphenyl) methyl) piperidines
105:1-(3-chloropropyl)-4-(hydroxyl two (2-furyl) methyl) piperidines
Above compound has following physical parameter compound spectroscopic data 99: colourless non-crystalline state
IR(KBr)cm -1：3400，2950，2812，
1738，1603，1491，1448，1257，
1143，739，708
1HNMR(CDCl3)δ：7.56-6.90(9H，m)，
3.57(2H，t，J＝6.8)，3.07-2.81(2
H，m)，2.56-2.32(5H，m)，2.13-
1.38(9H，m)
MS:357 (M+) 100: colorless oil
IR(Neat)cm -1：3500，2950，2814，
1736，1601，1489，1448，1251，
1050，739，706
1HNMR(CDCl3)δ：7.56-6.92(8H，m)，
6.76-6.67(1H，m)，3.77(3H，s)，
3.57(2H，t，J＝6.7)，3.06-2.83
(2H，m)，2.59-2.31(2H，m)，2.18
-1.42(9H，m)
MS:373 (M+) 101: light green non-crystalline state
IR(KBr)cm -1：3370，2950，1516，
1448，1259，1137，1027，737，700
1HNMR(CDCl3)δ：7.58-6.72(8H，m)，
3.83(6H，s)，3.56(2H，t，J＝6.8)，
3.05-2.80(2H，m)，2.58-2.30(2
H，m)，2.21-1.41(9H，m)
MS:403 (M+) 102: white non-crystalline state
IR(KBr)cm -1：3380，2952，2774，
1487，1460，1379，745，656，634
1HNMR(CDCl3)δ：8.30-7.52(2H，br.)，
7.15-7.11(4H，m)，7.04-6.95
(2H，m)，3.59(2H，t，J＝6.35)，
3.10(2H，d，J＝7.32)，2.04(6H，
s)，2.70-2.40(3H，br.)，2.30-
1.40(9H，m)
MS:371 (M+) 103: white crystals
Fusing point: 141.5-142.5 ℃
IR(KBr)cm -1：3492，2936，2810，1487，
1468，1437，1381，1286，1243，
1058，1023，750
1HNMR(CDCl3)δ：7.61(2H，d，J＝7.6)，
7.16(2H，dt，J＝7.6，0.9)，6.97(2
H，dt，J＝7.6，1.2)，6.75(2H，dd，
J＝7.6，0.9)，5.22(1H，br.)，3.58
(2H，t，J＝6.6)，3.49(6H，s)，2.97
(2H，d，J＝11.0)，2.82(1H，m)，
2.51(2H，t，J＝7.0)，2.20-2.02(2
H，m)，1.99(2H，quint.，J＝6.7)，
1.75(2H，q，J＝11.3)，1.60-1.30
(2H，br.)
MS:403 (M+) 104: colourless non-crystalline state
IR(KBr)cm -1：3410，2942，1512，1462，
1412，1259，1139，1025，762
1HNMR(CDCl3)δ：7.20-6.72(6H，m)，
3.84(12H，s)，3.58(2H，t，J＝6.8)，
3.14-2.88(2H，m)，2.62-2.31(2H，
m)，2.16-1.41(9H，m)
MS:463 (M+) 105: faint yellow crystallization
Fusing point: 74-74.5 ℃
IR(KBr)cm -1：3076，2952，2786，1154，
1042，1013，1002，984，959，806，
735，600
1HNMR(CDCl3)δ：7.40(2H，s)，6.35-
6.30(4H，m)，3.57(2H，m)，3.02
(2H，br.)，2.82(1H，br.)，2.53(2
H，br.)，2.31(1H，br.)，2.04(4H，
br.)，1.55(4H，br.)
MS：323(M+)
Embodiment 106
1-(3-chloropropyl)-4-(phenyl (4-tolyl) methylene radical) piperidines (106)
In 5.3g 4-(phenyl (4-tolyl) methylene radical) piperidines and 3ml1-bromo-3-chloropropane and 5.3g salt of wormwood, add the 60ml 2-butanone, reflux 5 hours, carry out the aftertreatment same with embodiment 32, with silica gel column chromatography (hexane: ethyl acetate=1: 3) purify, obtain the 5.3g title compound of colorless oil.
IR(Neat)cm -1：2924，2808，1512，1441，
1375，1299，1129，816，758，700
1HNMR(CDCl3)δ：7.19-6.85(9H，m)，
3.61(2H，t，J＝6.4)，2.60-2.31
(13H，m)，1.98(2H，quint，J＝6.8)
MS：339(M+)
Embodiment 107
1-(3-chloropropyl)-4-(two (4-tolyl) methylene radical) piperidines (107)
Figure C9210399101411
At 6.37g 4-(two (4-tolyl) methylene radical) piperidines, add 20ml toluene, 10ml 25% sodium hydroxide and 0.27g hydrogen sulfate tetrabutylammonium in the 1-bromo-3-chloropropane, after 10 hours, add ethyl acetate extraction in stirring at room, wash and drying.Heat up in a steamer desolvate after, with silica gel column chromatography (methylene dichloride～methylene dichloride: ethyl acetate=1: 1) purify, obtain the 3.53g title compound of colorless oil.
IR(KBr)cm -1：2940，2906，1602，1511，
1440，1002，818，774
1HNMR(CDCl3)δ：7.21-7.02(4H，m)，
7.00-6.83(4H，m)，3.60(2H，t，J＝
6.8)，2.61-2.29(10H，m)，2.30(6
H，s)，1.98(2H，quint，J＝6.8)
MS：353(M+)
Embodiment 108
1-(3-chloropropyl)-4-(phenyl (3-tolyl) methylene radical) piperidines (108)
Figure C9210399101421
In 10ml ethanol, the compound of dissolving 2.35g embodiment 99 adds the 10ml concentrated hydrochloric acid then, stirs 1 hour in 100 ℃.After the cooling, add in water, the sodium hydroxide and after, use ethyl acetate extraction.After concentrating organic layer, purify, obtain the 1.89g title compound of colorless oil with column chromatography.
IR(KBr)cm -1：2931，2802，1501，1438，
1371，1301，1127，756，704
1HNMR(CDCl3)δ：7.56-6.90(9H，m)，
3.58(2H，t，J＝6.4)，2.61-2.22
(13H，m)，1.96(2H，quint，J＝6.8)
MS：339(M+)
Embodiment 109-125
Below, carry out the operation same with embodiment 106, replace 4-(phenyl (4-tolyl) methylene radical) piperidines to obtain 114 compounds with 4-((4-p-methoxy-phenyl) phenylmethylene) piperidines, replace 4-(phenyl (4-tolyl) methylene radical) piperidines to obtain 115 compounds with 4-((4-chloro-phenyl-) phenylmethylene) piperidines, replace 4-(phenyl (4-tolyl) methylene radical) piperidines to obtain 116 compounds with 4-(phenyl (4-trifluoromethyl) phenylmethylene) piperidines, replace 4-(phenyl (4-tolyl) methylene radical) piperidines to obtain 117 compounds with 4-(two ((4-trifluoromethyl) phenyl) methylene radical) piperidines, replace 4-(phenyl (4-tolyl) methylene radical) piperidines to obtain 118 compounds with 4-((4-fluorophenyl) phenylmethylene) piperidines.
Also have, carry out the operation same with embodiment 107, replace 4-(two (4-tolyl) methylene radical) piperidines to obtain 119 compounds with 4-((3-chloro-phenyl-) phenylmethylene) piperidines, replacing 4-two (4-tolyl) methylene radical with 4-(two (3-chloro-phenyl-) methylene radical) piperidines) piperidines obtains 120 compounds, replace 4-(two (4-tolyl) methylene radical) piperidines to obtain 124 compounds with 4-(phenyl (2-pyridyl) methylene radical) piperidines, replace 4-(two (4-tolyl) methylene radical) piperidines to obtain 125 compounds with 4-(naphthyl phenylmethylene) piperidines.
In addition, carry out the operation same with embodiment 108, replace 99 compounds to obtain 109 compounds with 100 compounds, replace 99 compounds to obtain 110 compounds with 101 compounds, replace 99 compounds to obtain 111 compounds with 102 compounds, replace 99 compounds to obtain 112 compounds with 103 compounds, replace 99 compounds to obtain 113 compounds with 104 compounds, replace 99 compounds to obtain 121 compounds with 96 compounds, replace 99 compounds to obtain 122 compounds with 98 compounds, replace 99 compounds to obtain 123 compounds with 105 compounds. Compd A r1 Ar2109 3-MeO-Ph Ph110 3; 4-(MeO) 2-Ph Ph111 2-tolyl 2-tolyl 112 2-MeO-Ph 2-MeO-Ph113 3; 4-(MeO) 2-Ph 3,4-(MeO) 2-Ph114 4-MeO-Ph Ph115 4-Cl-Ph Ph116 4-CF3-Ph Ph117 4-CF3-Ph 4-CF3-Ph118 4-F-Ph Ph119 3-Cl-Ph Ph120 3-Cl-Ph 3-Cl-Ph121 4-NMe2-Ph Ph122 4-NMe2-Ph 4-NMe2-Ph123 2-furyl 2-furyl 124 2-pyridine radicals Ph125 2-naphthyl Ph
109:1-(3-chloropropyl)-4-((3-p-methoxy-phenyl) phenylmethylene) piperidines
110:1-(3-chloropropyl)-4-((3, the 4-Dimethoxyphenyl) phenylmethylene) piperidines
111:1-(3-chloropropyl)-4-(two (2-tolyl) methylene radical) piperidines
112:1-(3-chloropropyl)-4-(two (2-p-methoxy-phenyl) methylene radical) piperidines
113:1-(3-chloropropyl)-4-(two (3, the 4-Dimethoxyphenyl) methylene radical) piperidines
114:1-(3-chloropropyl)-4-((4-p-methoxy-phenyl) phenylmethylene) piperidines
115:1-(3-chloropropyl)-4-((4-chloro-phenyl-) phenylmethylene) piperidines
116:1-(3-chloropropyl)-4-((4-(trifluoromethyl) phenyl) phenylmethylene) piperidines
117:1-(3-chloropropyl)-4-(two ((4-(trifluoromethyl) phenyl) methylene radical) piperidines
118:1-(3-chloropropyl)-4-((4-fluorophenyl) phenylmethylene) piperidines
119:1-(3-chloropropyl)-4-((3-chloro-phenyl-) phenylmethylene) piperidines
120:1-(3-chloropropyl)-4-(two (3-chloro-phenyl-) methylene radical) piperidines
121:1-(3-chloropropyl)-4-((4-dimethylamino phenyl) phenylmethylene) piperidines
122:1-(3-chloropropyl)-4-(two (4-dimethylamino phenyl) methylene radical) piperidines
123:1-(3-chloropropyl)-4-(two (2-furyl) methylene radical) piperidines
124:1-(3-chloropropyl)-4-(phenyl (2-pyridyl) methylene radical) piperidines
125:1-(3-chloropropyl)-4-((2-naphthyl) phenylmethylene) piperidines
Above compound has following physical parameter compound spectroscopic data 109: colorless oil
IR(Neat)cm -1：2958，2808，1597，
1576，1431，1299，1251，1145，
1051，756，704
1HNMR(CDCl3)δ：7.38-7.06(6H，m)，
6.83-6.62(3H，m)，3.76(3H，s)，
3.60(2H，t，J＝6.4)，2.60-2.25
(10H，m)，1.94(2H，quint，J＝6.8)
MS:355 (M+) 110: faint yellow oily thing
IR(Neat)cm -1：2962，2812，1591，
1565，1433，1275，1127，762，700
1HNMR(CDCl3)δ：7.58-6.72(8H，m)，
3.80(6H，s)，3.59(2H，t，J＝6.3)，
2.62-2.28(10H，m)，1.93(2H
quint，J＝6.7)
MS:385 (M+) 111: faint yellow oily thing
IR(neat)cm -1：2956，2808，1458，
1377，1299，1243，1131，754，729
HNMR(CDCl3)δ：7.17-6.94(8H，m)，
3.60(2H，t，J＝6.4)，2.76-2.10
(10H，m)，2.34(3H，s)，2.19(3H，
s)，1.97(2H，t，J＝6.4)
MS:353 (M+) 112: white crystals
Fusing point: 47-48 ℃
IR(KBr)cm -1：2940，2834，1491，1462，
1435，1294，1267，1245，1116，
1054，1029，754，418
1HNMR(CDCl3)δ：7.23-6.98(4H，m)，
6.88-6.69(4H，m)，3.88-3.63
(6H，br.)，3.60(2H，t，J＝6.7)，
2.75-2.05(10H，m)，1.97(2H，t，
J＝6.7)
MS:385 (M+) 113: faint yellow oily thing
IR(Neat)em -1：2954，2825，1597，
1572，1421，1263，1132，752，700
1HNMR(CDCl3)δ：7.21-6.70(6H，m)，
3.84(12H，s)，3.60(2H，t，J＝6.4)，
2.61-2.27(10H，m)，1.95(2H，
quint，J＝6.7)
MS:445 (M+) 114: faint yellow non-crystalline state
IR(KBr)cm -1：2956，2808，1607，1510，
1301，1245，1176，1038，830，756，
700
1HNMR(CDCl3)δ：7.18-6.72(9H，m)，
3.78(3H，s)，3.60(2H，t，J＝6.4)，
2.62-2.26(10H，m)，1.95(2H，
quint，J＝6.8)
MS:355 (M+) 115: colourless non-crystalline state
IR(KBr)cm -1：2926，2774，1510，1444，
1375，1299，1131，787，760，700
1HNMR(CDCl3)δ：7.41-6.95(9H，m)，
3.60(2H，t，J＝6.4)，2.62-2.30
(10H，m)，1.98(2H，quint，J＝6.8)
MS:359 (M+) 116: yellow oil
IR(Neat)cm -1：2960，2810，1615，
1326，1166，1125，1067，835，758
1HNMR(CDCl3)δ：7.62-7.50(2H，m)，
7.38-7.02(7H，m)，3.60(2H，t，J＝
6.4)，2.62-2.31(10H，m)，1.97
(2H，quint，J＝6.8)
MS:393 (M+) 117: colourless non-crystalline state
IR(KBr)cm -1：2962，2810，1615，1325，
1166，1127，1067，1019，835，760
1HNMR(CDCl3)δ：7.63-7.49(4H，m)，
7.41-7.02(4H，m)，3.60(2H，t，
J＝6.4)，2.63-2.30(10H，m)，1.94
(2H，quint，J＝6.8)
MS:461 (M+) 118: colorless oil
IR(Neat)cm -1：2960，2808，1603，
1508，1224，832，758，700
1HNMR(CDCl3)δ：7.31-6.76(9H，m)，
3.50(2H，t，J＝6.4)，2.58-2.17
(10H，m)，1.96(2H，quint，J＝6.8)
MS:343 (M+) 119: faint yellow oily thing
IR(Neat)cm -1：2960，2808，1593，
1564，1444，1299，1131，1079，785，
739，702
1HNMR(CDCl3)δ：7.45-6.92(9H，m)，
3.61(2H，t，J＝6.4)，2.63-2.25
(10H，m)，2.00(2H，quint，J＝6.8)
MS:359 (M+) 120: faint yellow oily thing
IR(Neat)cm -1：2960，2810，1593，
1564，1470，1299，1079，789，758，
714
1HNMR(CDCl3)δ：7.52-6.92(8H，m)，
3.60(2H，t，J＝6.4)，2.61-2.18
(10H，m)，1.98(2H，quint，J＝6.8)
MS:393 (M+) 121: faint yellow oily thing
IR(Neat)cm -1：2950，2894，2804，
1609，1520，1444，1352，1195，
1021，818，768，702
1HNMR(CDCl3)δ：7.36-6.92(7H，m)，
6.72-6.57(2H，m)，3.61(2H，t，J＝
6.4)，3.13(6H，s)，2.62-2.31(10
H，m)，193(2H，quint，J＝6.8)
MS:368 (M+) 122: white crystals
IR(KBr)cm -1：2890，2770，1611，1522，
1350，1220，1191，1131，948，816，
754
1HNMR(CDCl3)δ：7.00-6.96(4H，m)，
6.64-6.60(4H，m)，3.60(2H，t，J＝
6.7)，2.92(12H，s)，2.60-2.35
(10H，m)，1.96(2H，quint，J＝6.8)
MS:411 (M+) 123: faint yellow oily thing
IR(neat)cm -1：2954，2810，1375，
1154，1015，808，737
1HNMR(CDCl3)δ：7.40(2H，dd，J＝2.0，
1.0)，6.40(2H，dd，J＝3.4，2.0)，
6.15(2H，dd，J＝3.4，1.0)，3.63
(2H，t，J＝6.4)，2.71-2.67(10H，
m)，2.07(2H，br)
MS:305 (M+) 124: faint yellow oily thing
IR(Neat)cm -1：2954，2808，1584，
1468，1429，1301，1129，994，748，
702
HNMR(CDCl3)δ：8.65-8.56(1H，m)，
7.72-7.49(1H，m)，7.21-7.00(7H，
m)，3.60(2H，t，J＝6.4)，2.61-
2.30(10H，m)，1.91(2H，quint，J＝
6.8)
MS:326 (M+) 125: yellow oil
IR(Neat)cm -1：3056，2960，2808，
1599，1504，1468，1441，1375，
1125，820，752，702
1HNMR(CDCl3)δ：7.88-7.12(12H，m)，
3.60(2H，t，J＝6.6)，2.62-2.14
(10H，m)，1.99(2H，quint，J＝6.8)
MS：375(M+)
Embodiment 126
4,5-dihydro-1-methyl-5-(3-(4-ethoxy carbonyl piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (126)
Figure C9210399101531
At the dry N of 18ml, the compound of dissolving 1.36g embodiment 13 and the compound of 1.86g embodiment 97 are cooled to-10 ℃ in the dinethylformamide.After splashing into the tetrahydrofuran solution (1M solution) of 10ml tBuOK, in stirring at room 3 hours.After the cooling, add saturated aqueous ammonium chloride again, use chloroform extraction then.After concentrating organic layer, purify and obtain faint yellow crystalline 2.01g title compound with column chromatography.
Fusing point: 60.5-61.5 ℃
IR(KBr)cm -1：2950，1727，1555，1510，
1427，1282，1261，1238，1048，746
1HNMR(CDCl3)δ：7.62-6.85(4H，m)，
4.52(2H，s)，4.23(2H，q，J＝7.3)，
3.49(2H，t，J＝7.5)，3.00(2H，d，
J＝6.6)，2.86(3H，s)，2.43(2H，d，
＝6.6)2.30-1.70(9H，m)，1.35
(3H，t，J＝7.3)
MS：383(M+)
Embodiment 127
4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (2-thienyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (127)
The compound of dissolving 1.89g embodiment 126 in the 20ml dry tetrahydrofuran, be cooled to 0 ℃ after, splash into the tetrahydrofuran solution (1M) of 11ml 2-thienyl lithium.After at room temperature stirring 2 hours, add saturated aqueous ammonium chloride, use chloroform extraction.After concentrating organic layer, purify, obtain yellow amorphous 1.74g title compound with column chromatography.
Ultimate analysis: C27H31N5OS2
Calculated value: C, 64.13; H, 6.18, N, 13.85;
S，12.68
Measured value: C, 63.96; H, 6.36; N, 13.98;
S，12.83
IR(KBr)cm -1：3354，2948，1502，1433，
753，700
HNMR(CDCl3)δ：7.44(1H，dd，J＝7.8，
1.2)，7.21(2H，dd，J＝3.7，1.2)，
7.18(1H，t，J＝7.3)，7.03(2H，dd，
J＝3.7，1.2)，6.96-6.93(3H，m)，
6.88(1H，t，J＝7.3)，4.41(2H，s)，
3.35(2H，t，J＝7.3)，2.93(2H，d，
J＝11.0)，2.75(3H，s)，2.45-2.34
(3H，m)，2.08-1.92(2H，m)，1.79
(2H，quint，J＝6.8)，1.54-1.46(4H，
m)
MS：505(M+)
Embodiment 128
4,5-dihydro-1-methyl-5-(3-(4-benzoyl piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (128)
At the dry N of 15ml, the compound of dissolving 1.05g embodiment 13 and the compound of 1.50g embodiment 95 are cooled to 0 ℃ then in the dinethylformamide.After splashing into the tetrahydrofuran solution (1M solution) of 6.8ml tBuOK, in stirring at room 1 hour.Be cooled to 0 ℃ again, behind the adding saturated aqueous ammonium chloride, use ethyl acetate extraction.After concentrating organic layer, purify, obtain colourless amorphous 1.71g title compound with column chromatography.
Fusing point: 72-73 ℃
Ultimate analysis: C25H29N5O
Calculated value: C, 72.26; H, 7.03; N, 16.85
Measured value: C, 72.41; H, 7.17; N, 17.04
IR(KBr)cm -1：3451(br.)，2928，1710，
1686，1560，1504，1433，1267，984，
748，700
1HNMR(CDCl3)δ：7.95-7.92(2H，m)，
7.58-7.54(1H，m)，7.47(3H，t，J＝
7.8)，7.35-7.22(1H，m)，6.99(1H，
d，J＝8.3)，6.90(1H，t，J＝7.3)，
4.44(2H，s)，3.41(2H，t，J＝7.3)，
3.30-3.29(1H，m)，2.99(2H，d，J＝
11.7)，2.77(3H，s)，2.43(2H，t，
J＝6.8)，2.13(2H，dt，J＝10.7，
3.4)，1.90-1.82(6H，m)
MS：415(M+)
Embodiment 129
4,5-dihydro-1-methyl-5-(3-(4-(hydroxy phenyl (2-thienyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (129)
The compound of dissolving 2.00g embodiment 128 in the 20ml dry tetrahydrofuran, be cooled to 0 ℃ after, splash into the tetrahydrofuran solution (1M) of 5.5ml 2-thienyl lithium.After 2 hours, add saturated ammonium chloride solution in stirring at room, use the chloroform extracting then.After concentrating organic layer, purify, obtain yellow amorphous 1.44g title compound with column chromatography.
Ultimate analysis: C29H33N5OS
Calculated value: C, 69.71; H, 6.65; N, 14.02;
S，6.42
Measured value: C, 69.45; H, 6.84; N, 14.13;
S，6.65
IR(KBr)cm -1：3390，2948，1502，1433，
748，700
1HNMR(CDCl3)δ：7.53(2H，d，J＝7.3)，
7.44(1H，dd，J＝7.8，1.5)，7.32
(2H，t，J＝7.8)，7.22-7.18(3H，m)，
7.00-6.90(3H，m)，6.89(1H，t，J＝
7.8)，4.41(2H，s)，3.36(2H，t，J＝
7.3)，3.02(1H，d，J＝11.2)，2.93
(2H，d，J＝11.7)，2.75(3H，s)，
2.45-2.34(3H，m)，2.08-1.92(2H，
m)，1.79(2H，quint，J＝6.8)，1.54-
1.46(4H，m)
MS：499(M)+
Embodiment 130
4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl (3, the 4-Dimethoxyphenyl) phenyl methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (130)
At 15ml N, the compound of dissolving 0.92g embodiment 13 and the compound of 2.00g embodiment 101 are cooled to 0 ℃ then in the dinethylformamide.After splashing into the tetrahydrofuran solution (1M solution) of 9ml tBuOK, stirring at room 1 hour.After being cooled to 0 ℃ again, add saturated aqueous ammonium chloride, use ethyl acetate extraction.After concentrating organic layer, purify, obtain colourless amorphous 1.08g title compound with column chromatography.
Ultimate analysis: C33H39N5O3
Calculated value: C, 71.58; H, 7.10; N, 12.65
Measured value: C, 71.86; H, 7.25; N, 12.73
IR(KBr)cm -1：3370，2946，1504，1433，
1259，1141，1027，745
1HNMR(CDCl3)δ：7.49-7.42(3H，m)，
7.31-7.27(2H，m)，7.21-7.16(2H，
m)，7.07(1H，d，J＝4.4)，6.99-
6.86(3H，m)，6.79(1H，d，J＝8.8)，
4.42(2H，s)，3.83(6H，d，J＝2.9)，
3.36(2H，t，J＝7.3)，2.93(2H，m)，
2.75(3H，s)，2.45-2.30(3H，m)，
2.08-1.92(2H，m)，1.85-1.80(2H，
m)，1.54-1.46(4H，m)
MS：553(M+)
Embodiment 131-139
Below, carry out the operation same with embodiment 127, obtain 134 compound with 3-toluyl magnesium bromo for 2-thienyl lithium, replace 2-thienyl lithium to obtain 135 compound with 3-p-methoxy-phenyl magnesium bromo.
In addition, carry out the operation same with embodiment 130, the compound of the compound replacement 101 with 96 obtains 131 compound, the compound of the compound replacement 101 with 99 obtains 132 compound, the compound of the compound replacement 101 with 100 obtains 133 compound, the compound of the compound replacement 101 with 102 obtains 136 compound, the compound of the compound replacement 101 with 103 obtains 137 compound, the compound of the compound replacement 101 with 104 obtains 138 compound, and the compound with 105 replaces 101 compounds to obtain 139 compound. Compd A r1 Ar2131 4-NMe2-Ph Ph132 3-tolyl Ph133 3-MeO-Ph Ph134 3-tolyl 3-tolyl 135 3-MeO-Ph 3-MeO-Ph136 2-tolyl 2-tolyls 137 2-MeO-Ph 2-MeO-Ph138 3; 4-(MeO) 2-Ph 3,4-(MeO) 2-Ph139 2-furyl 2-furyl
131:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl (4-dimethylamino phenyl) phenyl methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
132:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyphenyl (3-tolyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolos (4:3-a) quinoxaline
133:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl (3-p-methoxy-phenyl) phenmethyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
134:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (3-tolyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
135:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (3-p-methoxy-phenyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
136:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (2-tolyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
137:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (2-p-methoxy-phenyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
138:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (3, the 4-Dimethoxyphenyl) methyl) piperidines-1-yl) propyl group (1,2,4) triazolo (4,3-a) quinoxaline
139:4,5-dihydro-1-methyl-5-(3-(4-(hydroxyl two (2-furyl) methyl) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxaline
Above-claimed cpd has following physical parameter.131: faint yellow non-crystalline state
Ultimate analysis: in C33H40N6O
Calculated value: C, 73.85; H, 7.51; N, 15.66
Measured value: C, 73.66; H, 7.88; N, 15.84
IR(KBr)cm -1：3370，2942，2794，1611，
1560，1506，1431，1352，1160，748
1HNMR(CDCl3)δ：7.46-7.42(3H，m)，
7.33-7.25(4H，m)，7.21-7.13
(2H，m)，6.93(1H，d，J＝7.3)，6.88
(1H，t，J＝7.8)，6.66(2H，d，J＝9.3)，
4.42(2H，s)，3.36(2H，t，J＝6.7)，
2.92-2.90(8H，m)，2.76(3H，s)，
2.42-2.34(3H，m)，2.01-1.93(2H，
m)，1.81(2H，quint，J＝6.8)，1.49-
1.46(4H，m)
MS:536 (M+) 132: yellow non-crystalline state
Ultimate analysis: in C32H37N5O
Calculated value: C, 75.71; H, 7.35; N, 13.80
Measured value: C, 75.54; H, 7.22; N, 13.66
IR(KBr)cm -1：3330，2948，2814，1557，
1506，1433，1352，911，731
1HNMR(CDCl3)δ：7.51(2H，dd，J＝8.5，
1.2)，7.41(1H，dd，J＝7.9，1.2)，
7.32-7.25(4H，m)，7.21-7.13(3H，
m)，7.02-6.85(3H，m)，4.42(2H，
s)，3.36(2H，t，J＝6.7)，2.91(2H，
d，J＝10.4)，2.75(3H，s)，2.41-
2.34(3H，m)，2.31(3H，s)，2.01-
1.92(2H，m)，1.81(2H，quint，J＝
6.8)，1.51-1.45(4H，m)
MS:508 (M+H)+133: colourless non-crystalline state
Ultimate analysis: in C32H37N5O2
Calculated value: C, 73.39; H, 7.12; N, 13.37
Measured value: C, 73.15; H, 7.05; N, 13.11
IR(KBr)cm -1：3302，2948，2812，1601，
1557，1504，1433，1253，787
1HNMR(CDCl3)δ：7.50(2H，dd，J＝8.5，
1.2)，7.41(1H，dd，J＝7.9，1.2)，
7.27(2H，t，J＝7.3)，7.20-7.05(5
H，m)，6.91(1H，d，J＝7.4)，6.86(1
H，t，J＝7.3)，6.69(1H，dd，J＝7.3，
1.8)，4.38(2H，s)，3.75(3H，s)，
3.33(2H，t，J＝6.7)，2.91(2H，d，
J＝10.3)，2.72(3H，s)，2.41-2.34
(3H，m)，1.98-1.92(2H，m)，1.79
(2H，quint，J＝6.8)，1.52-1.49(4
H，m)
MS:523 (M+) 134: white crystals
Fusing point: 198～200.5 ℃
Ultimate analysis: in C33H39N5O0.25 (H2O)
Calculated value: C, 75.32; H, 7.57; N, 13.31
Measured value: C, 75.33; H, 7.53; N, 13.28
IR(KBr)cm -1：3408，2948，1504，750
1HNMR(CDCl3)δ：7.41(1H，dd，J＝7.8，
15)，7.31(2H，m)，7.26(2H，d，J＝
7.8)，7.20(1H，m)，7.18(2H，t，J＝
7.8)，6.98(2H，d，J＝7.8)，6.93(1
H，d，J＝8.3)，6.88(1H，t，J＝7.3)，
4.42(2H，s)，3.36(2H，t，J＝7.3)，
2.93(2H，d，J＝11.7)，2.76(3H，s)，
2.41-2.37(3H，m)，2.32(6H，s)，
2.01-1.92(2H，m)，1.81(2H，quint，
J＝6.8)，1.52-1.43(4H，m)
MS:521 (M+) 135: faint yellow non-crystalline state
Ultimate analysis: in C33H39N5O3
Calculated value: C, 71.58; H, 7.10; N, 12.65
Measured value: C, 71.22; H, 7.25; N, 12.89
IR(KBr)cm -1：3408，2944，1601，1502，
1433，1249，1046，772，756
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.8，
12)，7.21(2H，t，J＝7.8)，7.20(1
H，t，J＝7.3)，7.09(2H，t，J＝2.0)，
7.06(2H，d，J＝7.8)，6.93(1H，d，
J＝8.3)，6.89(1H，t，J＝7.3)，6.71
(2H，dd，J＝7.3，2.0)，4.43(2H，s)，
3.78(6H，s)，3.36(2H，t，J＝6.8)，
2.93(2H，d，J＝11.7)，2.76(3H，s)，
2.41-2.34(3H，m)，1.98-1.92(2H，
m)，1.79(2H，quint，J＝6.8)，1.52-
1.26(4H，m)
MS:554 (M+H) 136; Colourless non-crystalline state
Ultimate analysis: in C33H39N5O
Calculated value: C, 75.97; H, 7.53; N, 13.42
Measured value: C, 76.13; H, 7.38; N, 13.22
IR(KBr)cm -1：3320，2930，1504，1475，
1460，1433，1379，1352，1253，748
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.5)，7.22(1H，t，J＝8.3)，7.48-
7.15(6H，m)，7.12-6.98(2H，m)，
6.96(1H，d，J＝8.3)，6.92(1H，t，
J＝7.8)，4.40(2H，s)，3.40(2H，t，
J＝6.8)，3.15(2H，br)，2.76(3H，
s)，2.58(2H，br.)，1.98(6H，br.)，
240-150(10H，br)
MS:521 (M+) 137: faint yellow non-crystalline state
Ultimate analysis: in C33H39N5O3
Calculated value: C, 71.58; H, 7.10; N, 12.65
Measured value: C, 71.33; H, 7.01; N, 12.88
IR(KBr)cm -1：3496，2944，1504，1487，
1468，1433，1288，1241，1027，754
1HNMR(CDCl3)δ：7.62(2H，d，J＝7.9)，
7.43(1H，dd，J＝7.9，1.8)，7.21(1
H，dt，J＝7.3，1.8)，7.16(2H，dt，
J＝7.9，1.2)，7.05-6.92(3H，m)，
6.88(1H，dt，J＝7.3，1.2)，6.75(2
H，dt，J＝7.9，1.2)，5.23(1H，br.)，
4.41(2H，s)，3.50(6H，s)，3.39(2
H，t，J＝6.7)，2.97(2H，br.)，2.88
(1H，s)，2.77(3H，s)，2.39(2H，
b.r.)，1.96(2H，br.)，1.84(2H，
br.)，1.77(2H，br.)，1.46(2H，
br.)
MS:553 (M+) 138: faint yellow non-crystalline state
Ultimate analysis: in C35H43N5O5
Calculated value: C, 68.49; H, 7.06; N, 11.41
Measured value: C, 68.86; H, 7.27; N, 11.67
IR(KBr)cm -1：3381，2871，1510，1472，
1259，1139，1027，745
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.8，
1.5)，7.19(1H，t，J＝7.3)，7.05
(2H，d，J＝2.0)，6.98-6.87(4H，m)，
6.79(2H，d，J＝8.8)，4.44(2H，s)，
3.85(12H，s)，3.36(2H，t，J＝7.3)，
2.76(3H，s)，2.45-2.32(3H，m)，
2.02-1.90(4H，m)，1.79(2H，quint，
J＝6.8)，1.54-1.46(4H，m)
MS:613 (M+) 139: yellow non-crystalline state
Ultimate analysis: in C27H31N5O3
Calculated value: C, 68.48; H, 6.60; N, 14.79
Measured value: C, 68.11; H, 6.38; N, 14.55
IR(KBr)cm -1：3360，2948，1562，1504，
1475，1433，1352，1147，1009，745
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.8，
1.5)，7.39＝7.38(2H，m)，7.22(1H，
t，J＝7.8)，6.95(1H，d，J＝7.8)，
6.91(1H，t，J＝7.8)，6.37-6.24(4
H，m)，4.40(2H，s)，3.38(2H，t，J＝
7.3)，3.09(2H，br)，2.76(3H，s)，
2.53(2H，br)，2.34(1H，m)，2.14
(2H，m)，1.95(2H，m)，1.67(2H，m)，
1.55(2H，br)
MS：473(M+)
Embodiment 140
4,5-dihydro-1-methyl-5-(3-(4-((3-p-methoxy-phenyl) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3-a) quinoxalines (140)
Figure C9210399101681
The compound of dissolving 1.35g embodiment 133 adds the 5ml concentrated hydrochloric acid then in 5ml ethanol.After 1 hour, cooling with the aqueous sodium carbonate neutralization, is used chloroform extraction then in 100 ℃ of stirrings.After concentrating organic layer, obtain the faint yellow crystalline title compound of 0.89g by the Virahol recrystallize.
Fusing point: 130～132 ℃
Ultimate analysis: in C32H35N5O0.5 (H2O)
Calculated value: C, 74.68; H, 7.05; N, 13.61
Measured value: C, 74.61; H, 6.76; N, 13.86
IR(KBr)cm -1：2954，2834，1605，1578，
1506，1483，1286，1050，745，702
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.9，
1.2)，7.29-7.12(7H，m)，6.96(1H，
d，J＝7.9)，6.90(1H，t，J＝7.3)，
6.76-6.67(3H，m)，4.46(2H，s)，
3.76(3H，s)，3.41(2H，t，J＝7.3)，
2.77(3H，s)，2.49-2.04(10H，m)，
1.87(2H，quint，J＝6.8)
MS:506 (M+H)+embodiment 1414,5-dihydro-1-methyl-5-(3-(4-((4-p-methoxy-phenyl) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxalines (141)
Figure C9210399101691
Carry out the operation same, replace embodiment 101, obtain the title compound of white crystals with the compound of embodiment 114 with embodiment 130.
mp：178～180℃
Ultimate analysis: in C32H35N5O0.25 (H2O)
Calculated value: C, 75.34; H, 7.01; N, 13.73
Measured value: C, 75.37; H, 6.90; N, 13.92
IR(KBr)cm -1：2951，2892，1607，1555，
1510，1421，1247，746，702
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.0)，7.29-6.80(12H，m)，4.44(2
H，s)，3.79(3H，s)，3.41(2H，t，J＝
7.3)，2.77(3H，s)，2.55-2.38(10
H，m)，1.87(2H，quint，J＝6.8)
MS:505 (M+) embodiment 142-165
Below carry out the operation same, replace 133 to obtain 143 with 135, replace 133 to obtain 147 with 134, obtain 164, obtain 165 each compounds with 127 replacements 133 with 129 replacements 133 with embodiment 140.
In addition, carry out the operation same with embodiment 141, replace 114 to obtain 142 with 110, replace 114 to obtain 144 with 111, replace 114 to obtain 145 with 112, obtain 146 with 113 replacements 114, obtain 149, replace 114 to obtain 151 with 116 with 115 replacements 114, replace 114 to obtain 152 with 117, obtain 153 with 118 replacements 114, obtain 154, replace 114 to obtain 155 with 120 with 119 replacements 114, replace 114 to obtain 156 with 121, obtain 157 with 122 replacements 114, the compound with 106 replaces 114 to obtain 158, and the compound with 107 replaces 114 to obtain 159, compound with 108 replaces 114 to obtain 160, compound with 123 replaces 114 to obtain 161, and the compound with 124 replaces 114 to obtain 162, and the compound with 125 replaces 114 to obtain 163 each compounds.
And carry out the operation same with embodiment 46, replace 4-(phenylbenzene methylene radical) piperidines to obtain 147 with 4-(two (3-tolyl) methylene radical) piperidines, (two (4-methoxyphenyl) methylenepiperidines replaces 4 (phenylbenzene methylene radical) piperidines to obtain 148 each compound with 4-.
Figure C9210399101701
Compd A r1 Ar2142 3,4-(MeO) 2-Ph Ph143 3-MeO-Ph 3-MeO-Ph144 2-tolyl 2-tolyl 145 2-MeO-Ph 2-MeO-Ph146 3,4-(MeO) 2-Ph 3,4-(MeO) 2-Ph147 3-tolyl 3-tolyl 148 4-MeO-Ph 4-MeO-Ph149 4-Cl-Ph Ph150 4-Cl-Ph 4-Cl-Ph151 4-CF3-Ph Ph152 4-CF3-Ph 4-CF3-Ph153 4-F-Ph Ph154 3-Cl-Ph Ph155 3-Cl-Ph 3-Cl-Ph156 4-NMe2-Ph Ph157 4-NMe2-Ph 4-NMe2-Ph158 4-tolyl Ph159 4-tolyl 4-tolyls 160 3-tolyl Ph161 2-furyl 2-furyls 162 2-pyridyl Ph163 2-naphthyl Ph164 2-thienyl Ph165 2-thienyl 2-thienyl 142:4, ((4-((3 for 3-for 5-dihydro-1-methyl-5-, the 4-Dimethoxyphenyl) propyl group phenylmethylene) piperidines-1-yl)) (1,2,4) triazolo (4,3, a) quinoxaline 143:4,5-dihydro-1-methyl-5-(3-(4-(two (3-methoxyphenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 144:4,5-dihydro-1-methyl-5-(3-(4-(two (2-tolyl) methylene radical) piperidines-1-yl)-propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 145:4,5-dihydro-1-methyl-5-(3-(4-(two (2-p-methoxy-phenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 146:4, ((4-(two (3 for 3-for 5-dihydro-1-methyl-5-, the 4-Dimethoxyphenyl) (1,2,4) triazolo (4 propyl group piperidines-1-yl methylene radical))), 3, a) quinoxaline 147:4,5-dihydro-1-methyl-5-(3-(4-(two (3-tolyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 148:4,5-dihydro-1-methyl-5-(3-(4-(two (4-p-methoxy-phenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 149:4,5-dihydro-1-methyl-5-(3-(4-((4-chloro-phenyl-) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 150:4,5-dihydro-1-methyl-5-(3-(4-(two (4-chloro-phenyl-) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 151:4,5-dihydro-1-methyl-5-(3-(4-((4-(trifluoromethyl) phenyl) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 152:4,5-dihydro-1-methyl-5-(3-(4-(two (4-trifluoromethyl) phenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a,) quinoxaline 153:4,5-dihydro-1-methyl-5-(3-(4-((4-fluorophenyl) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 154:4,5-dihydro-1-methyl-5-(3-(4-((3-chloro-phenyl-) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 155:4,5-dihydro-1-methyl-5-(3-(4-(two (3-chloro-phenyl-) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 156:4,5-dihydro-1-methyl-5-(3-(4-((4-dimethylamino phenyl) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 157:4,5-dihydro-1-methyl-5-(3-(4-(two (4-dimethylamino phenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 158:4,5-dihydro-1-methyl-5-(3-(4-(phenyl (4-tolyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 159:4,5-dihydro-1-methyl-5-(3-(4-(two (4-tolyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 160:4,5-dihydro-1-methyl-5-(3-(4-(phenyl (3-tolyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 161:4,5-dihydro-1-methyl-5-(3-(4-(two (2-furyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 162:4,5-dihydro-1-methyl-5-(3-(4-(phenyl (2-pyridyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 163:4,5-dihydro-1-methyl-5-(3-(4-((2-naphthyl) phenylmethylene) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 164:4,5-dihydro-1-methyl-5-(3-(4-(phenyl (2-thienyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline 165:4,5-dihydro-1-methyl-5-(3-(4-(two (2-thienyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, a) quinoxaline
Above-claimed cpd has following physics value.Compound spectral analysis data 142: colourless amorphous
Ultimate analysis: C33H37N5O2 meter
Calculated value: C, 73.99; H, 6.96; N, 13.07
Measured value: C, 73.68; H, 6.88; N, 12.98
IR(KBr)cm -1：2902，2772，1506，1461，
1433，1253，1139，1027，750，702
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.0)，7.30-7.12(6H，m)，6.97(1H，
dd，J＝8.3，7.3)，6.90(1H，t，J＝
6.8)，6.79(1H，d，J＝8.3)，6.70-
6.62(2H，m)，4.44(2H，s)，3.86
(3H，s)，3.80(3H，s)，2.77(3H，s)，
251-239(10H，m)，1.86(2H，
quint，J＝6.8).
MS:535 (M+) 143: faint yellow crystallization
mp：125.5～126.5℃
Ultimate analysis: in C33H37N5O2
Calculated value: C, 73.99; H, 6.96; N, 13.07
Measured value: C, 73.92; H, 7.12; N, 12.97
IR(KBr)cm -1：2952，1578，1504，1431，
1286，1048，777，746
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.9，
1.2)，7.29-7.12(7H，m)，6.96(1H，
d，J＝7.9)，6.90(1H，t，J＝7.3)，
6.76-6.67(3H，m)，4.46(2H，s)，
3.76(3H，s)，3.41(2H，t，J＝7.3)，
2.77(3H，s)，2.49-2.04(10H，m)，
1.87(2H，quint，J＝6.8)
MS:536 (M+H)+144: colourless amorphous
Ultimate analysis: in C33H37N5
Calculated value: C, 78.69; H, 7.40; N, 13.90
Measured value: C, 78.47; H, 7.20; N, 14.27
IR(KBr)cm -1：2950，2806，1557，1502，
1475，1429，1377，1346，1247，743，
1HNMR(CDCl3)δ：7.21(1H，t，J＝7.8)，
7.18-7.00(8H，m)，6.96(1H，d，J＝
7.8)，6.96(1H，t，J＝7.8)，6.91
(1H，t，J＝7.8)，4.40(2H，s)，3.41
(2H，t，J＝6.8)，2.76(3H，s)，2.55
(2H，m)，2.31(3H，s)，2.17(3H，s)，
2.45-2.10(8H，m)，1.97(1H，br)
MS:505 (M+) 145: colourless amorphous
Ultimate analysis: in C33H37N5O2
Calculated value: C, 73.99; H, 6.96; N, 13.07
Measured value: C, 74.15; H, 7.12; N, 13.35
IR(KBr)cm -1：2954，1504，1491，1466，
1433，1245，1118，1050，1027，752
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.9，
1.2)，7.24-7.05(6H，m)，6.98(1H，
d，J＝7.9)，6.94-6.82(4H，m)，
4.43(2H，s)，3.88-3.69(6H，br.)，
3.41(2H，t，J＝7.3)，2.77(3H，s)，
2.60-2.10(10H，m)，1.87(2H，br.)
MS:535 (M+) 146: colourless amorphous
Ultimate analysis: in C35H41N5O4
Calculated value: C, 70.56; H, 6.94; N, 11.76
Measured value: C, 70.44; H, 6.88; N, 11.92
IR(KBr)cm -1：2902，2772，1506，1461，
1433，1253，1139，1027，750，702
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.0)，7.30-7.12(6H，m)，6.97(1H，
dd，J＝8.3，7.3)，6.90(1H，t，J＝
6.8)，6.79(1H，d，J＝8.3)，6.70-
6.62(2H，m)，4.44(2H，s)，3.86(3
H，s)，3.80(3H，s)，2.77(3H，s)，
2.51-2.39(10H，m)，1.86(2H，
quint，J＝6.8)
MS:595 (M+) 147: white crystals
mp：151～152℃
Ultimate analysis: in C33H37N5
Calculated value: C, 78.69; H, 7.40; N, 13.90
Measured value: C, 78.43; H, 7.38; N, 13.69
IR(KBr)cm -1：2954，1508，777，748
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.2)，7.21(1H，t，J＝7.3)，7.17
(2H，t，J＝7.8)，7.02-6.88(8H，m)，
4.44(2H，s)，3.41(2H，t，J＝7.3)，
2.77(3H，s)，2.52-2.33(10H，m)，
2.30(6H，s)，1.87(2H，quint，J＝
6.8)
MS:503 (M+) 148: faint yellow crystallization
mp：132～135℃
Ultimate analysis: in C33H37N5O2
Calculated value: C, 73.99; H, 6.96; N, 13.07
Measured value: C, 74.12; H, 7.03; N, 12.85
IR(KBr)cm -1：2952，2838，1607，1510，
1245，1176，1035，835
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.9，
1.2)，7.21(1H，t，J＝7.3)，7.04-
7.01(4H，m)，6.98(1H，d，J＝8.5)，
6.90(1H，t，J＝7.9)，6.83-6.80
(4H，m)，4.44(2H，s)，3.81(6H，s)，
3.43(2H，t，J＝7.3)，2.77(3H，s)，
2.48-2.40(10H，m)，1.86(2H，
quint，J＝6.8)，
MS:535 (M+) 149: faint yellow crystallization
mp：165～167℃
Ultimate analysis: in C31H32N5Cl0.25 (H2O)
Calculated value: C, 72.36; H, 6.37; N, 13.61;
Cl，6.89
Measured value: C, 72.30; H, 6.32; N, 13.51;
Cl，6.85
IR(KBr)cm -1：2960，1684，1611，1557，
1504，1487，1431，756
1HNMR(CDCl3)δ：7.46(1H，dd，J＝7.8，
6.8)，7.31-7.20(7H，m)，7.10-
7.04(3H，m)，6.97(1H，d，J＝8.3)，
6.91(1H，t，J＝8.3)，4.44(2H，s)，
3.41(2H，t，J＝6.8)，2.77(3H，s)，
2.55-2.38(10H，m)，1.87(2H，
quint，J＝6.8)
MS:509 (M+) 150: faint yellow amorphous
Ultimate analysis: in C31H31N5Cl2
Calculated value: C, 68.38; H, 5.74; N, 12.86;
Cl，13.02
Measured value: C, 68.19; H, 5.62; N, 12.55;
Cl，12.85
IR(KBr)cm -1：2938，2806，1555，1504，
1431，1091，818，756
1HNMR(CDCl3)δ：7.46(1H，dd，J＝8.1，
1.5)，7.27-7.21(6H，m)，7.04-
7.01(3H，m)，6.96(1H，d，J＝7.3)，
6.90(1H，t，J＝7.3)，4.44(2H，s)，
3.41(2H，t，J＝6.8)，2.77(3H，s)，
2.48-2.37(10H，m)，1.87(2H，
quint，J＝6.8)
MS:544 (M+H)+151: faint yellow amorphous
Ultimate analysis: in C32H32N5F30.5 (H2O)
Calculated value: C, 69.55; H, 6.02; N, 12.67;
F，10.31
Measured value: C, 69.81; H, 5.86; N, 12.71;
F，10.51
IR(KBr)cm -1：2951，2810，1613，1555，
1504，1431，1325，1067，742，702
1HNMR(CDCl3)δ：7.53(2H，d，J＝8.3)，
7.45(1H，dd，J＝7.8，1.0)，7.38-
7.20(6H，m)，7.11(2H，d，J＝7.3)，
6.97(1H，d，J＝8.3)，6.90(1H，t，
J＝7.8)，4.44(2H，s)，3.41(2H，t，
J＝7.2)，2.77(3H，s)，2.57-2.37
(10H，m)，1.86(2H，quint，J＝6.8)
MS:543 (M+) 152: white crystals
mp?141-143℃
Ultimate analysis: in C33H31N5F6
Calculated value: C, 64.80; H, 5.11; N, 11.45;
F，18.64
Measured value: C, 64.67; H, 5.08; N, 11.17;
F，18.33
IR(KBr)cm -1：2954，1615，1506，1325，
1168，1125，1067，1019，833，746
1HNMR(CDCl3)δ：7.56(4H，d，J＝7.8)，
7.46(1H，dd，J＝7.8，1.0)，7.25-
7.20(5H，m)，6.97-6.89(2H，m)，
4.45(2H，s)，3.41(2H，t，J＝6.8)，
2.78(3H，s)，2.51-2.04(10H，m)，
1.87(2H，quint，J＝6.8)
MS:611 (M+) 153: white crystals
mp：178～180℃
Ultimate analysis: in C31H32N5F0.25 (H2O)
Calculated value: C, 74.75; H, 6.58; N, 14.06;
F，3.81
Measured value: C, 74.62; H, 6.49; N, 14.22;
F，3.83
IR(KBr)cm -1：2886，2821，1603，1555，
1506，1431，1350，1222，745，702
1HNMR(CDCl3)δ：7.46(1H，dd，J＝8.3，
1.5)，7.31-7.19(4H，m)，7.11-
7.06(4H，m)，6.99-6.88(4H，m)，
4.44(2H，s)，3.41(2H，t，J＝7.3)，
2.77(3H，s)，2.56-2.32(10H，m)，
1.86(2H，quint，J＝6.8)
MS:493 (M+) 154: faint yellow crystallization
mp：140～142℃
Ultimate analysis: in C31H32N5Cl0.5 (H2O)
Calculated value: C, 71.72; H, 6.41; N, 13.49;
Cl，6.82
Measured value: C, 71.89; H, 6.43; N, 13.71;
Cl，6.60
IR(KBr)cm -1：2952，2790，1555，1504，
1473，1429，1348，1286，1131，745，
704
1HNMR(CDCl3)δ：7.44(1H，dd，J＝7.9，
1.2)，7.30-7.26(3H，m)，7.23-
7.17(4H，m)，7.10(2H，d，J＝6.7)，
7.02-6.96(2H，m)，6.90(1H，t，
J＝7.3)，4.44(2H，s)，3.41(2H，t，
J＝6.7)，2.77(3H，s)，2.55-2.24
(10H，m)，1.87(2H，quint，J＝6.8)
MS:509 (M+) 155 colourless amorphous
Ultimate analysis: in C31H31N5Cl2H2O
Calculated value: C, 66.19; H, 5.91; N, 12.45;
Cl，12.60
Measured value: C, 66.35; H, 5.89; N, 12.82;
Cl，12.51
IR(KBr)cm -1：2954，2774，1591，1562，
1502，1473，1429，1350，748，714
1HNMR(CHCl3)δ：745(1H，dd，J＝8.3，
1.5)，7.25-7.18(5H，m)，7.10-
7.09(2H，m)，7.03-6.96(4H，m)，
4.44(2H，s)，3.41(2H，t，J＝7.3)，
2.77(3H，s)，2.51-2.36(10H，m)，
1.86(2H，quint，J＝6.8)
MS:543 (M+) 156: white crystals
mp：185～186℃
Ultimate analysis: in C33H38N60.25 (H20)
Calculated value: C, 75.75; H, 7.42; N, 16.06
Measured value: C, 75.56; H, 7.31; N, 15.81
IR(KBr)cm -1：2892，2806，1609，1522，
1510，1352，1129，818，756，708
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.0)，7.28-7.15(5H，m)，7.12(2H，
d，J＝1.5)，7.11-6.97(2H，m)，
6.90(1H，t，J＝7.8)，4.44(2H，s)，
2.93(6H，s)，2.77(3H，s)，2.49-
2.39(10H，m)，1.86(2H，quint，J＝
6.8)
MS:518 (M+) 157: white crystals
mp：189～191℃
Ultimate analysis: in C35H43N70.25 (H2O)
Calculated value: C, 74.23; H, 7.74; N, 17.31
Measured value: C, 74.22; H, 7.73; N, 17.30
IR(KBr)cm -1：2886，2798，1611，1520，
1508，1348，1224，1129，824，746
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.9，
1.2)，7.23(1H，td，J＝8.2，1.2)，
7.00-6.89(6H，m)，6.64(4H，d，J＝
8.8)，4.43(2H，s)，3.42(2H，t，J＝
7.3)，2.93(12H，s)，2.77(3H，s)，
2.49-2.39(10H，m)，1.86(2H，
quint，J＝6.8)
MS:561 (M+) 158: white crystals
mp：187～189℃
Ultimate analysis: in C32H35N50.25 (H2O)
Calculated value: C, 77.77; H, 7.24; N, 14.17
Measured value: C, 77.77; H, 7.21; N, 14.10
IR(KBr)cm -1：2930，2811，1580，1504，
1410，1321，764
1HNMR(CDCl3)δ：7.45(1H，dd，J＝8.3，
1.5)，7.29-6.88(12H，m)，4.44
(2H，s)，3.41(2H，t，J＝7.3)，2.77
(3H，s)，2.56-2.39(10H，m)，2.32
(3H，s)，1.87(2H，quint，J＝6.8)
MS:489 (M+) 159: white crystals
mp：160～162℃
Ultimate analysis: in C33H37N5
Calculated value: C, 78.69; H, 7.40; N, 13.90
Measured value: C, 78.61; H, 7.15; N, 13.85
IR(KBr)cm -1：2952，2798，1611，1551，
1510，1468，1429，1350，1282，820，
745
1HNMR(CDCl3)δ：7.45(1H，dd，J＝8.3，
1.5)，7.21(1H，t，J＝8.3)，7.08(4
H，d，J＝7.8)，7.01-6.97(5H，m)，
6.90(1H，t，J＝8.3)，4.44(2H，s)，
3.43(2H，t，J＝7.3)，2.77(3H，s)，
2.48-2.40(10H，m)，2.32(6H，s)，
1.86(2H，quint，J＝6.8)，
MS:504 (M+H)+160: faint yellow crystallization
mp：169～171℃
Ultimate analysis: in C32H35N50.25 (H2O)
Calculated value: C, 77.77; H, 7.24; N, 14.17
Measured value: C, 77.47; H, 7.13; N, 14.26
IR(KBr)cm -1：2952，2892，2792，1611，
1555，1504，1470，1348，745，708
1HNMR(CDCl3)δ：7.45(1H，dd，J＝7.8，
1.5)，7.30-7.11(7H，m)，7.03-
6.88(5H，m)，4.44(2H，s)，3.41(2
H，t，J＝7.3)，2.77(3H，s)，2.52-
2.33(10H，m)，2.30(3H，s)，1.87
(2H，quint，J＝6.8)
MS:490 (M+H)+161, faint yellow amorphous
Ultimate analysis: in C27H29N5O2
Calculated value: C, 71.19; H, 6.42; N, 15.37
Measured value: C, 71.08; H, 6.22; N, 15.17
IR(KBr)cm -1：2952，2902，1555，1508，
1429，1348，1288，1152，1013，748
1HNMR(CDCl3)δ：7.47(1H，dd，J＝7.82，
0.98)，7.40(2H，d，J＝1.96)，7.24
(1H，d，J＝8.30)，6.99(1H，dd，J＝
8.30，0.98)，6.94(1H，t，J＝7.82)，
6.40(2H，dd，J＝3.42，1.96)，6.15
(2H，d，J＝3.42)，4.42(2H，s)，
3.45(2H，t，J＝6.84)，2.78(3H，s)，
3.10-2.52(10H，m)，2.05(2H，
br.)
MS:455 (M+) 162: faint yellow crystallization
mp：183～185℃
Ultimate analysis: in C30H32N60.25 (H2O)
Calculated value: C, 74.89; H, 6.81; N, 17.47
Measured value: C, 74.81; H, 6.75; N, 17.70
IR(KBr)cm -1：2907，2894，1584，1557，
1508，1451，1429，1348，748，702
1HNMR(CDCl3)δ：8.60(1H，dd，J＝5.5，
1.8)，7.60(1H，td，7.9，1.8)，
7.45(1H，dd，J＝7.9，1.8)，7.32-
7.10(8H，m)，6.98(1H，d，J＝7.3)，
6.89(1H，t，J＝6.7)，4.44(2H，s)，
3.41(2H，t，J＝6.7)，2.77(3H，s)，
2.57-2.41(10H，m)，1.87(2H，
quint，J＝6.8)
MS:476 (M+) 163: faint yellow amorphous
Ultimate analysis: in C35H35N50.25 (H2O)
Calculated value: C, 79.29; H, 6.75; N, 13.21
Measured value: C, 79.09; H, 6.51; N, 13.45
IR(KBr)cm -1：2948，2810，1686，1555，
1504，1473，1431，1350，746，702
1HNMR(CDCl3)δ：7.80-7.73(3H，m)，
7.60-7.58(1H，m)，7.47-7.40(3H，
m)，7.31-7.16(7H，m)，6.98(1H，d，
J＝7.3)，6.90(1H，t，J＝7.9)，4.44
(2H，s)，3.42(2H，t，J＝7.3)，2.77
(3H，s)，2.62-2.43(10H，m)，1.87
(2H，quint，J＝6.8)
MS:526 (M+H)+164: yellow crystal
m.p：185～187℃
Ultimate analysis: in C29H31N5S0.25 (H2O)
Calculated value: C, 71.65; H, 6.53; N, 14.41
Measured value: C, 71.62; H, 6.60; N, 14.20
IR(KBr)cm -1：2952，1504，1429，750，
702
1HNMR(CDCl3)δ：7.46(1H，dd，J＝7.8，
1.5)，7.83(2H，t，J＝1.5)，7.25-
7.20(3H，m)，7.17(2H，d，J＝6.8)，
6.97-6.95(2H，m)，6.90(1H，t，J＝
7.8)，6.79(1H，d，J＝3.4)，4.44
(2H，s)，3.41(2H，t，J＝6.7)，2.77
(3H，s)，2.59-2.32(10H，m)，1.86
(2H，quint，J＝6.8)
MS:481 (M+) 165: yellow crystal
mp：175.5～178℃
Ultimate analysis: in C27H29N5S2
Calculated value: C, 66.50; H, 5.99; N, 14.36
Measured value: C, 66.13; H, 6.07; N, 14.07
IR(KBr)cm -1：2952，2806，1506，1429，
750，704
1HNMR(CDCl3)δ：7.46(1H，dd，J＝8.3，
1.5)，7.25(2H，dd，J＝5.4，1.2)，
7.21(2H，d，J＝7.3)，6.99-6.95(3
H，m)，6.90(1H，t，J＝7.8)，6.85(1
H，d，J＝3.4)，4.44(2H，s)，3.41(2
H，t，J＝6.7)，2.77(3H，s)，2.59-
2.32(10H，m)，1.86(2H，quint，J＝
6.8)
MS:487 (M+) embodiment 1662-(3-methoxy propyl amino) oil of mirbane (166)
Figure C9210399101901
295g ortho position chloronitrobenzene and 417g 3-methoxy propyl amino were stirred 4.5 hours down at 130 ℃.Add ethyl acetate, water extraction, washing, drying.Under reduced pressure distill { 132.5-134.5 ℃ (0.35mmHg) }, obtain the title compound 356g of red oil.
IR(Neat)cm -1：3384，2928，2874，
1622，1574，1516，1421，1352，
1038，745
1HNMR(CDCl3)δ：8.16(2H，dd，J＝8.6，
1.5)，7.42(1H，dt，J＝7.0，1.5)，
6.86(1H，d，J＝8.8)，6.61(1H，td，
J＝7.0，1.5)，3.53(2H，t，J＝5.7)，
3.37(5H，m)，1.98(2H，quint，J＝
6.1)
MS:210 (M)+embodiment 1672-(3-methoxy propyl amino)-4-(trifluoromethyl) oil of mirbane (167)
Except using 2-chloro-4-(trifluoromethyl) oil of mirbane to replace the ortho position chloronitrobenzene among the embodiment 166, according to obtaining (167) of yellow oil with the same method of embodiment 166.
bp：135.5℃(0.66mmHg)
IR(Neat)cm -1：3380，3320，2932，
2880，1638，1576，1541，1439，
1330，1272，1238，1156，1120，
1083
1HNMR(CDCl3)δ：8.60(1H，brs)，8.46
(1H，d，J＝2.2)，7.56(1H，dd，J＝
9.5，2.2)，6.95(1H，d，J＝9.2)，
3.56(4H，m)，3.39(3H，s)，1.56
(2H，quint，J＝7.2)
MS:278 (M)+embodiment 168 2-(3-methoxy propyl amino)-4-methyl-oil of mirbane (168)
Except replace the ortho position chloronitrobenzene among the embodiment 166 with 2-chloro-4-methyl oil of mirbane, according to obtaining (168) of yellow oil with the same method of embodiment 166.
bp：149-150℃(0.7mmHg)
IR(Neat)cm -1：3384，2926，2874，
1634，1570，1526，1408，1350，
1270，1236，1189，1158，1122，922
1HNMR(CDCl3)δ：8.10(1H，brs)，7.96
(1H，m)，7.26(1H，dd，J＝6.4，2.2)，
6.79(1H，d，J＝8.8)，3.60-3.35
(7H，m)，2.26(3H，s)，1.96(2H，
quint，J＝6.3)
MS:224 (M)+embodiment 1694-chloro-2-(3-methoxy propyl amino) oil of mirbane (169)
Figure C9210399101931
Except with 2, the 4-dichloronitrobenzene replaces outside the ortho position chloronitrobenzene among the embodiment 166, according to obtaining (169) of yellow oil with the same method of embodiment 166
bp：141℃(0.12mmHg)
IR(Neat)cm -1：3376，3324，2928，
2876，1615，1568，1524，1495，
1473，1415，1338，1311，1265，
1220，1154，1122，1067，839，750
1HNMR(CDCl3)δ：8.33(1H，brs)，8.11
(1H，d，J＝9.0)，6.87(1H，d，J＝
2.2)，6.66(1H，dd，J＝9.0，2.2)，
3.60-3.30(7H，m)，1.98(2H，
quint，J＝5.4)
MS:244 (M)+embodiment 1702-(3-methoxy propyl amino) aniline (170)
The compound 68g of embodiment 166 is dissolved in 500ml ethanol, in 550ml 10% aqueous sodium hydroxide solution.90 ℃ of one side stirrings down, one side is divided and is added the 129g zinc powder for several times, and then stirs 30 minutes, and residue is filtered.Concentrated filtrate adds ethyl acetate extraction.After washing, the drying, under reduced pressure distill { 140 ℃ (1.2mmHg) }, obtain the title compound of 51g colorless oil.
IR(Neat)cm -1：3390，3342，2928，
2874，1626，1601，1512，1456，
1272，1116，741
1HNMR(CDCl3)δ：6.95-6.80(4H，m)，
3.53(2H，t，J＝5.9)，3.35(3H，s)，
3.22(2H，t，J＝6.6)，1.93(2H，
Quint, J=6.1) embodiment 1712-(3-methoxy propyl amino)-4-(trifluoromethyl) aniline (171)
Figure C9210399101951
Except replace (166) among the embodiment 170 with (167), according to obtaining (171) as colourless crystallization with the same method of embodiment 170.
mp：69～70℃
IR(KBr)cm -1：3374，3258，2950，2874，
1638，1611，1541，1444，1334，
1226，1114，880，737，617
1HNMR(CDCl3)δ：7.07(1H，m)，6.92(1H，
m.)，6.61(1H，d，J＝8.1)，3.55(2H，
t，J＝5.6)，3.37(3H，s)，3.27(2H，
t，J＝6.6)，1.95(2H，quint，J＝6.1)
MS:248 (M)+embodiment 1722-(3-methoxy propyl amino)-4-monomethylaniline (172)
Figure C9210399101952
Except replace (166) among the embodiment 170 with (168), according to obtaining (172) of colourless crystallization with the same method of embodiment 170.
mp：69～72℃
IR(KBr)cm -1：3374，3308，3226，2864，
2840，1589，1518，1294，1230，
1118，791，770
1HNMR(CDCl3)δ：6.56(3H，m)，3.59-
3.11(10H，m)，2.21(3H，s)，1.92
(2H，quint，J＝6.3)
MS:194 (M)+embodiment 1734-chloro-2-(3-methoxy propyl amino) aniline (173)
Figure C9210399101961
Except replace (166) among the embodiment 170 with (169),, obtain (173) of colorless oil according to the method same with embodiment 170
bp：128～136℃(0.1mmHg)
IR(Neat)cm -1：3400，3346，2930，
2876，1623，1599，1512，1274，
1118，650
1HNMR(CDCl3)δ：6.59(3H，s)，3.53(2H，
t，J＝5.8)，3.36(3H，s)，3.19(4H，
t，J＝6.0)，1.92(2H，quint，J＝6.1)
MS:214 (M)+embodiment 1742-hydroxyl-1-(3-methoxy-propyl) benzoglyoxaline (174)
Compound and the 36g urea of 51g embodiment 170 were stirred 5 hours down at 150 ℃, add ethyl acetate and water, extract, after cleaning with 1N hydrochloric acid and salt solution, dry, distilling off solvent by recrystallize in the ethyl acetate, obtain the 49g title compound of colourless crystallization.
mp：102.5℃
Ultimate analysis: in C11H14N2O2
Calculated value: C; 64.06, H; 6.84, N; 13.58
Measured value: C; 64.02, H; 6.82, N; 13.71
IR(KBr)cm -1：3150，1709，1671，1626，
1493，1390，1145，1118，739
1HNMR(CDCl3)δ：10.15(1H，brs)，7.20
-7.00(4H，m)，4.00(2H，t，J＝6.8)，
3.42(2H，t，J＝5.7)，3.34(3H，s)，
2.04(2H，quint，J＝6.5)
MS:206 (M)+embodiment 1752-hydroxyl-1-(3-methoxy-propyl)-6-(trifluoromethyl) benzoglyoxaline (175)
Except replace (170) among the embodiment 174 with (171), according to obtaining (175) as colourless crystallization with the same method of embodiment 174.
mp：83～84℃
IR(KBr)cm -1：3200，2928，2884，1715，
1678，1491，1334，1243，1149，
1135，1118
1HNMR(CDCl3)δ：7.40-7.08(3H，m)，
4.04(2H，t，J＝6.9)，3.41(2H，t，
J＝5.7)，3.34(3H，s)，2.04(2H，
quint，J＝6.0)
MS:274 (M)+embodiment 1762-hydroxyl-1-(3-methoxy-propyl)-6-tolimidazole (176)
Figure C9210399101982
Except replace (170) among the embodiment 174 with (172), according to obtaining (176) of colourless crystallization with the same method of embodiment 174.
mp：118.5～120℃
IR(KBr)cm -1：3160，2964，1702，1665，
1512，1481，1396，1346，1118，803
1HNMR(CDCl3)δ：9.98(1H，brs)，6.91
(3H，m)，3.97(2H，t，J＝6.9)，3.41
(2H，t，J＝5.9)，3.34(3H，s)，2.37
(3H, s), 2.02 (2H, quint, J=6.5) embodiment 1776-chloro-2-hydroxyl-1-(3-methoxy-propyl) benzoglyoxalines (177)
Figure C9210399101991
Except replace (170) among the embodiment 174 with (173), according to obtaining (177) as colourless crystallization with the same method of embodiment 174
IR(KBr)cm -1：3158，3058，2988，2896，
2836，1688，1630，1605，1491，
1400，1388，1375，1114，886，801，
677,555 embodiment 1782-chloro-1-(3-methoxy-propyl) benzoglyoxalines (178)
Figure C9210399102001
In the compound of 49g embodiment 174, add the 100ml phosphorus oxychloride, reflux 30 minutes, pour in the frozen water after the cooling, with 40% aqueous sodium hydroxide solution alkalify, use ethyl acetate extraction, after washing, the drying, distillation { 127.5 ℃ (0.07mmHg) } under reduced pressure obtains the title compound of 33g colorless oil
IR(Neat)cm -1：3060，2930，2876，
1618，1473，1452，1379，1122，
926，745
1HNMR(CDCl3)δ：7.80-7.05(4H，m)，
4.31(2H，t，J＝6.8)，3.33(5H，m)，
2.07(2H，quint，J＝5.7)
MS:224 (M)+embodiment 1792-chloro-1-(3-methoxy-propyl)-6-(trifluoromethyl) benzoglyoxaline (179)
Figure C9210399102002
Except replace (174) among the embodiment 178 with (175), according to obtaining (179) as colourless crystallization with the same method of embodiment 178.
mp：45～53℃
bp：103～106℃(0.02mmHg)
IR(KBr)cm -1：2950，2880，2838，1709，
1630，1473，1462，1379，1365，
1328，1207，1162，1110，1050，928，
890，822
1HNMR(CDCl3)δ：7.98-7.50(3H，m)，
4.36(2H，t，J＝6.7)，3.33(5H，m)，
2.09(2H，quint，J＝5.9)
MS:292 (M)+embodiment 1802-chloro-1-(3-methoxy-propyl)-6-tolimidazole (180)
Figure C9210399102011
Except replace (174) among the embodiment 178 with (176), according to obtaining (180) of colourless crystallization with the same method of embodiment 178.
mp：40～44℃
bp：115～117℃(0.07mmHg)
IR(KBr)cm -1：2926，2828，1475，1456，
1375，1218，1123，789
1HNMR(CDCl3)δ：7.47-7.0(3H，m)，
4.28(2H，t，J＝6.7)，3.32(5H，m)，
2.46(3H，s)，2.06(2H，quint，J＝
6.1)
MS:238 (M)+embodiment 1812,6-two chloro-1-(3-methoxy-propyl) benzoglyoxalines (181)
Figure C9210399102021
Except replace (174) among the embodiment 178 with (177), according to obtaining (181) as colorless oil with 178 same methods.
IR(Neat)cm -1：3074，2928，2878，
1717，1613，1470，1450，1379，
1270，1122，810
1HNMR(CDCl3)δ：7.60(1H，d，J＝8.6)，
7.33(1H，dd，J＝8.6，2.0)，7.19
(1H，d，J＝2.0)，4.28(2H，t，J＝
6.7)，3.37-3.24(5H，m)，2.06(2H，
quint，J＝6.0)
MS:258 (M)+embodiment 1829-(3-methoxy-propyl)-3-methyl-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (182)
Figure C9210399102031
In the compound of 33g embodiment 178, add 350ml ethanol, the water and the thing of 315ml 80% hydrazine, reflux 22 hours.Reaction solution is concentrated dried solid, in residue, add 500ml just-butanols, 70ml triethly orthoacetate, reflux 2 hours, distillation removes and desolvates, with silica gel column chromatography (chloroform: after methyl alcohol=19: 1) refining, use ethyl acetate: hexane=clean at 2: 1 obtains the title compound of 25g colourless crystallization.
mp：74～75℃
IR(KBr)cm -1：3400，2930，1626，1603，
1499，1479，1120，748
1HNMR(CDCl3)δ：7.70-7.05(4H，m)，
4.27(2H，t，J＝6.8)，3.39(2H，t，
J＝5.7)，3.31(3H，s)，2.80(3H，s)，
2.21(2H，quint，J＝5.7)
MS:244 (M)+embodiment 1833-ethyl-9-(3-methoxy-propyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (183)
Except replace the triethly orthoacetate among the embodiment 182 with triethyl orthopropionate, according to obtaining (183) of yellow oil with the same method of embodiment 182.
IR(Neat)cm -1：3400，2980，2940，
2878，1623，1603，1495，1477，
1433，1120，748
1HNMR(CDCl3)δ：7.65-7.0(4H，m)，
4.28(2H，t，J＝6.7)，3.58-3.05
(7H，m)，2.22(2H，quint，J＝6.2)，
1.50(3H，t，J＝7.7)
MS:258 (M)+embodiment 1849-(3-methoxy-propyl)-3-propyl group-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (184)
Figure C9210399102051
Except replace the triethly orthoacetate among the embodiment 182 with of the original acid triethyl, according to obtaining (184) of yellow oil with the same method of embodiment 182.
IR(Neat)cm -1：3400，2966，2934，
2876，1622，1603，1495，1477，
1323，746
1HNMR(CDCl3)δ：7.65-7.10(4H，m)，
4.27(2H，t，J＝6.8)，3.40(2H，t，
J＝5.8)，3.31(3H，s)，3.11(2H，t，
J＝7.6)，2.36-1.8(4H，m)，1.10
(3H，t，J＝7.4)
MS:272 (M)+embodiment 1859-(3-methoxy-propyl)-3-methyl-7-(trifluoromethyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (185)
Figure C9210399102052
Except replace (178) among the embodiment 182 with (179), according to obtaining peachiness crystalline (185) with the same method of embodiment 182
mp：190～195℃
IR(KBr)cm -1：3054，2936，2884，1638，
1586，1504，1330，1296，1276，
1270，1162，1137，1120，1102，
1062
1HNMR(CDCl3)δ：7.82-7.64(2H，m)，
7.43(1H，d，J＝8.6)，4.32(2H，t，
J＝6.7)，3.38(2H，t，J＝5.5)，3.30
(3H，s)，2.84(3H，s)，2.23(2H，
quint，J＝5.8)
MS:312 (M)+embodiment 1863,7-dimethyl-9-(3-methoxy-propyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (186)
Figure C9210399102061
Except replace (178) among the embodiment 182 with (180), according to obtaining peachiness crystalline (186) with the same method of embodiment 182.
mp：113～114℃
IR(KBr)cm -1：3058，2878，1630，1591，
1495，1450，1437，1379，1122，
1019，951，822
1HNMR(CDCl3)δ：7.38-7.2(3H，m)，
4.23(2H，t，J＝6.8)，3.38(2H，t，
J＝5.7)，3.30(3H，s)，2.79(3H，s)，
2.49(3H，s)，2.19(quint，J＝6.0)
MS:258 (M+) embodiment 1877-chloro-9-(3-methoxy-propyl)-3-methyl-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (187)
Except replace (178) among the embodiment 182 with (181), according to obtaining (187) of colourless crystallization with 182 same methods.
mp：136℃
Ultimate analysis: in C13H15N4OCl
Calculated value: C; 56.02, H; 5.42, N; 20.10,
Cl；12.70
Measured value: C; 55.90, H; 5.40, N; 20.03,
Cl；12.60
IR(KBr)cm -1：2926，2872，1626，1603，
1589，1495，1435，1427，1123，826
1HNMR(CDCl3)δ：7.50(1H，d，J＝8.6)，
7.36(1H，d，J＝2.0)，7.18(1H，dd，
J＝8.6，2.0)，4.24(2H，t，J＝6.7)，
3.37(2H，t，J＝5.5)，3.31(3H，s)，
2.78(3H，s)，2.20(2H，quint，J＝
6.3)
MS:278 (M+) embodiment 1882-chloro-3-(3-(4-(diphenyl methyl) piperazine-1-yl) propyl group) benzoglyoxaline (188)
Figure C9210399102081
With 1.9g 2-chloro benzimidazole, 4.3g 1-(3-chloropropyl)-4-(diphenyl methyl) piperazine is dissolved in the 40ml dimethyl formamide, adds 60% sodium hydroxide 0.78g while at room temperature stir, and stirs 8 hours down at 50 ℃, add ethyl acetate, water extraction, washing, drying.Distillation removes and desolvates.With silica gel column chromatography (ethyl acetate: hexane=1: 1) make with extra care, obtain the title compound of 3.3g oily matter.
IR(Neat)cm -1：2962，2814，1470，
1448，1379，1154，1139，1009，745，
706
1NMR(CDCl3)δ：7.66(1H，m)，7.45～
7.15(13H，m)，4.25(2H，t，J＝6.8)，
4.22(1H，s)，2.41(8H，s)，2.35
(2H，t，J＝6.2)，1.97(2H，quint，J＝
6.8)
MS:444 (M)+embodiment 1893-methyl-9-(3-(4-(diphenyl methyl) piperazine-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 2 hydrochlorides (189)
The compound of 33g embodiment 188 is dissolved in 30ml ethanol, adds 1 water and the thing of 18ml hydrazine, reflux 28 hours.Add water, ethyl acetate extraction after drying.Add 1.3g triethly orthoacetate and 40ml dimethylbenzene, stirred 5 hours down at 160 ℃.Distillation removes and desolvates, and is refining with silica gel column chromatography (ethyl acetate～ethanol), obtains 0.67g oily matter.It is dissolved in ethyl acetate, is blown into hydrogen chloride gas, after filtering for crystallizing, the drying, obtain the 0.68g title compound.
Mp:147～157 ℃ embodiment 1902-chloro-3-(3-(4-(diphenyl methyl) piperazine-1-yl) ethyl) benzoglyoxaline (190)
0.81g 2-chloro benzimidazole and 2.1g 1-(2-chloromethyl)-4-(diphenyl methyl) piperazine hydrochloride are dissolved among the 20ml DMF, add 0.46g 60% sodium hydride, at room temperature stirred 1 hour, stirred 2 hours down at 50 ℃, add ethyl acetate, water extraction, after washing, the drying,, obtain the title compound of 1.2g colourless crystallization by recrystallize in the ethyl acetate.
mp：176～178℃
IR(KBr)cm -1：2812，1473，1452，1392，
1156，1009，745，706
1NMR(CDCl3)δ：7.80-7.05(14H，m)，
4.27(2H，t，J＝7.0)，4.19(1H，s)，
2.71(2H，t，J＝7.0)，2.5-2.3(8H，
m)
MS:430 (M+) embodiment 1913-methyl-9-(3-(4-(diphenyl methyl) piperazine-1-yl) ethyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarates (191)
Compound to 0.69g embodiment 190 adds 30ml ethanol, hydrazine water and the thing of 6ml80%.Reflux concentrates after 12 hours and does admittedly, adds ethyl acetate, water extraction, washing, drying.Add the 10ml triethly orthoacetate, after stirring 17 hours under 100 ℃, concentrate, add ethyl acetate, water extraction, washing, drying.With silica gel column chromatography (ethyl acetate～ethyl acetate: ethanol=3: 1) make with extra care, obtain 0.16g3-methyl-9-(3-(4-(diphenyl methyl) piperazine-1-yl) ethyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline.It is dissolved in methyl alcohol, adds the methanol solution of 0.12g fumaric acid, behind the concentrate drying, obtain the 0.27g title compound.
mp：190～194℃
Ultimate analysis: in C28H30N63 (C4H404) H2O
Calculated value C; 58.81, H; 5.43, N; 10.29
Measured value: C; 58.81, H; 5.48, N; 10.04 embodiment 1923-methyl-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumaric acid (192)
Figure C9210399102121
In the compound of 22.6g embodiment 182, add 200ml 30% hydrogen bromide-acetic acid solution, stirred 5 minutes down, stirred 3 hours down at 100 ℃ at 70 ℃.After doing solution concentration admittedly, be dissolved in the 200ml dimethyl formamide, add 21.4g4-(3-indyl) piperidines, 51.1g yellow soda ash, at room temperature stir 30 minutes, 60 ℃ and stirred 1 hour down.Reaction solution is poured in the water, behind ethyl acetate extraction, dry, washing.Distillation removes desolvates, with silica gel column chromatography (ethyl acetate: after ethanol=2: 1) refining, obtain 17.1g oily matter.It is dissolved in the 150ml ethanol, adds the 4.8g fumaric acid is dissolved in solution in the 150ml ethanol.Filter out the colourless crystallization of separating out, obtain the title compound of 19.0g colourless crystallization after the drying.
mp：209～221℃
Ultimate analysis: in C25H28N6C4H4041/2H2O
Calculated value: C; 64.79, H; 6.18, N; 15.63
Measured value: C; 64.60, H; 6.05, N; 15.39 embodiment 193～207
According to the method same, replace 4-(3-indyl) piperidines to obtain compound separately with following compound with embodiment 192.Obtain 195 with 4-(5-chloro-3-indyl) piperidines, obtain 196 with 4-(5-fluoro-3-indyl) piperidines, obtain 197 with 4-(5-methyl-3-indyl) piperidines, obtain 198 with 4-(hydroxyl diphenyl methyl) piperidines, obtain 199 with 4-(hydroxyl two (4-fluorophenyl) methyl) piperidines, obtain 200 with 4-(phenylbenzene methoxy base) piperidines, obtain 201 with 4-(phenylbenzene methylene radical) piperidines, obtain 202 with 4-(two (4-fluorophenyl) methylene radical) piperidines, with 4-(5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 206, with 4-(10,11-dihydro-5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 207 compound separately.Obtain 193, obtain 194, obtain 203, obtain 204, replace 182 to obtain 205 compound separately with 183 replacements 182 with 187 with 186 replacements 182 with 185 replacements 182 with 184 replacements 182.Structural formula of compound 193
Figure C9210399102131
194 195 196 197 198
Figure C9210399102144
199
Figure C9210399102151
200 201 202
Figure C9210399102161
203
Figure C9210399102162
204
Figure C9210399102163
205
Figure C9210399102164
206 207
Figure C9210399102172
193:3-ethyl-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarate 194:3-propyl group-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarate 195:3-methyl-9-(3-(4-(5-chloro-3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 196:3-methyl-9-(3-(4-(5-fluoro-3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 197:3-methyl-9-(3-(4-(5-methyl-3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 198:3-methyl-9-(3-(4-(hydroxyl diphenyl methyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarate 199:3-methyl-9-(3-(4-(hydroxyl two (4-fluoro phenyl) methyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarate 200:3-methyl-9-(3-(4-(phenylbenzene methoxy base) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarate 201:3-methyl-9-(3-(4-(phenylbenzene methylene radical) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumarate 202:3-methyl-9-(3-(4-(two (4-fluoro phenyl) methylene radical) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 203:3-methyl-7-(three fluoro methyl)-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 204:3-methyl-7-methyl-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 205:3-methyl-7-chloro-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline 206:3-methyl-9-(3-(4-(5H-dibenzo (a, d) propyl group piperidines-1-yl suberene-5-subunit)))-9H (1,2,4) triazolo (4,3-a) ((4-(10 for 3-for benzoglyoxaline 207:3-methyl-9-, 11-dihydro-5H-dibenzo (a, d) propyl group piperidines-1-yl suberene-5-subunit)))-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline
The physics value of above-claimed cpd is as follows.Compound spectral analysis data 193: colourless crystallization
mp：173～175℃
Ultimate analysis: in C26H30N61/2 (C4H4O4H2O)
Calculated value: C; 68.13, H; 7.14, N; 17.02
Measured value: C; 68.23, H; 7.05, N; 16.63194: colourless crystallization
mp：150～152℃
Ultimate analysis: in C27H32N61/2C4H4O4H2O
Calculated value: C; 67.42, H; 7.02, N; 16.27
Measured value: C; 67.98, H; 7.29, N; 15.68195: colourless amorphous
mp：138～142℃
Ultimate analysis: in C25H27N6ClC4H4O43/2H2O
Calculated value: C; 59.03, H; 5.80, N; 14.24,
Cl；6.00
Measured value: C; 59.53, H; 5.84, N; 13.59,
Cl; 5.54196: colourless crystallization
mp：192～193℃
Ultimate analysis: in C25H27N6F
Calculated value: C; 69.75, H; 6.32, N; 19.52,
F；4.41
Measured value: C; 69.62, H; 6.28, N; 19.31,
F；4.39
IR(KBr)cm -1：3200，2950，2936，
1624，1605，1495，1477，1466，
1446，1381，1344，1164，938，799，
745
1HNMR(CDCl3)δ：8.30(1H，brs)，7.59
(1H，d，J＝7.9)，7.41-7.35(2H，m)，
7.28-7.19(3H，m)，7.01(1H，d，J＝
2.4)，6.91(1H，td，J＝6.7，2.4)，
4.27(2H，t，J＝6.7)，2.92(2H，m)，
2.80(3H，s)，2.72(1H，m)，2.43
(2H，t，J＝6.7)，2.17(2H，quint，J＝
6.7)，2.06(2H，m)，1.98(2H，m)，
1.70(2H，qd，J＝9.0，3.8)
MS:430 (M+) 197: colourless crystallization
mp：221～224℃
Ultimate analysis: in C26H30N61/2H2O
Calculated value: C; 71.69, H; 7.17, N; 19.29
Measured value: C; 71.87, H; 7.03, N; 19.25
IR(KBr)cm -1：3400，3300，2926，
1626，1603，1499，1477，1444，741
1HNMR(CDCl3)δ：8.03(1H，brs)，7.59
(1H，d，J＝7.8)，7.43-7.35(3H，m)，
7.25-7.18(2H，m)，7.00(1H，dd，
J＝6.8，1.5)，6.93(1H，d，J＝2.0)，
4.27(2H，t，J＝6.8)，2.95(2H，m)，
2.80(3H，s)，2.78(1H，m)，2.45(5
H，m)，2.18(2H，quint，J＝6.8)，
2.11-2.0(4H，m)，1.25(2H，m)
MS:426 (M+) 198: colourless amorphous
mp：130＝135℃
Ultimate analysis: in C30H33N5OC4H4O43/4H2O
Calculated value: C; 67.03, H; 6.37, N; 11.49
Measured value: C; 67.18, H; 6.40, N; 11.15199: colourless amorphous
mp：130～136℃
Ultimate analysis: in C30H31N5OF2C4H4O4H2O
Calculated value: C; 62.86, H; 5.74, N; 10.78,
F；5.85
Measured value: C; 62.72, H; 5.76, N; 10.43,
F; 5.61200: colourless crystallization
mp：119.5～121℃
Ultimate analysis: in C30H33N5OC4H4O41/4H2O
Calculated value: C; 68.04, H; 6.25, N; 11.67
Measured value: C; 67.86, H; 6.24, N; 11.65201: colourless amorphous
mp：103～106℃
Ultimate analysis: in C30H31N5C4H4O43/4H2O
Calculated value: C; 69.08, H; 6.22, N; 11.85
Measured value: C; 69.01, H; 6.16, N; 11.55202; Faint yellow amorphous
IR(KBr)cm -1：3400，2954，1626，
1603，1506，1220，835，746，559
1HNMR(CDCl3)δ：7.59(1H，d，J＝7.8)，
7.38(2H，m)，7.21(1H，m)，7.06-
6.94(8H，m)，4.26(2H，t，J＝6.8)，
2.80(3H，s)，2.45-2.30(10H，m)，
2.15(2H，quint，J＝6.5)
MS:498 (M+H)+203: light peachiness crystallization
mp：173～182℃
IR(KBr)cm -1：3400，3250，2928，
1638，1605，1499，1325，1270，
1160，1118，739
1HNMR(CDCl3)δ：8.06(1H，brs)，7.81
(1H，s)，7.66(1H，d，J＝8.8)，7.62
(1H，d，J＝7.8)，7.53(1H，d，J＝
8.3)，7.36(1H，d，J＝7.8)，7.18
(1H，t，J＝7.6)，7.10(1H，t，J＝
7.6)，6.96(1H，d，J＝2.4)，4.33(2
H，t，J＝6.5)，2.90(2H，m)，2.83(4
H，m)，2.42(2H，t，J＝6.6)，2.19(2
H，quint，J＝6.6)，2.10-2.04(4H，
m)1.70(2H，m)
MS:480 (M+) 204: colourless crystallization
mp：175～175.5℃
IR(KBr)cm -1：3400，2930，1609，
1497，1446，797，743
1HNMR(CDCl3)δ：8.10(1H，brs)，7.63
(1H，d，J＝8.1)，7.39(1H，s)，7.36
(1H，d，J＝8.4)，7.28(1H，d，J＝
8.4)，7.18(2H，m)，7.10(1H，m)，
6.98(1H，d，J＝2.2)，4.24(2H，t，
J＝6.8)，2.95(2H，m)，2.81(1H，m)，
2.79(3H，s)，2.48(3H，s)，2.43(2
H，t，J＝6.8)，2.16(2H，quint，J＝
6.8)，2.1-2.0(2H，m)，1.76(2H，
m)
MS:426 (M+) 205: orange crystallization
mp：214～216℃
Ultimate analysis: in C25H27N6Cl1/4H2O
Calculated value: C; 66.51, H; 6.14, N; 18.61,
Cl；7.85
Measured value: C; 66.75, H; 6.22, N; 18.46,
Cl；7.87
IR(KBr)cm -1：3400，2940，1626，1603，
1497，1444，1342，1067，743
1HNMR(CDCl3)δ：8.11(1H，brs)，7.65
(1H，d，J＝7.8)，7.56(1H，d，J＝
2.0)，7.48(1H，d，J＝7.8)，7.37
(1H，d，J＝7.8)，7.18(2H，m)，7.10
(1H，t，J＝7.8)，7.00(1H，d，J＝
2：0)，4.26(2H，t，J＝6.4)，2.92
(2H，m)，2.83(1H，m)，2.78(3H，s)，
2.37(2H，t，J＝6.4)，2.15(2H，
quint，J＝6.2)，2.11-2.00(4H，m)，
1.80-1.75(2H，m)
MS:447 (M+H)+206: colourless crystallization
mp：240～243℃
Ultimate analysis: in C32H31N5H2O
Calculated value: C; 76.31, H; 6.60, N; 13.90
Measured value: C; 76.52, H; 6.37, N; 13.79
IR(KBr)cm -1：3400，2950，1624，
1593，1499，1477，1435，803，748
1HNMR(CDCl3)δ：7.57(1H，d，J＝7.9)，
7.38-7.30(6H，m)，7.24-7.16
(5H，m)，6.90(2H，s)，4.23(2H，t，
J＝6，7)，2.79(3H，s)，2.46(2H，m)，
2.33(4H，m)，2.10(6H，m)
MS:486 (M+H)+207: colourless crystallization
mp：234～235℃
IR(KBr)cm -1：3400，2946，1624，1593，
1499，1479，1435，1381，779，748
1HNMR(CDCl3)δ：7.58(1H，d，J＝7.8)，
7.40(1H，dd，J＝6.8，1.0)，7.37
(1H，td，J＝7.3，1.0)，7.20(1H，td，
J＝6.8，1.5)，7.15-7.05(8H，m)，
4.26(2H，t，J＝6.6)，3.39(2H，m)，
2.80(2H，m)，2.79(3H，s)，2.58(2
H，m)，2.36(6H，m)，2.13(4H，m)
MS:488 (M+H)+embodiment 2085-(3-methoxy-propyl)-1H-(1,5) benzodiazepine -2,4 (3H, 5H)-diketone (208)
Figure C9210399102261
In 60 ℃ of processes that stir down, in 32 minutes, divide the solution that adds 12.7g N-(3-methoxy-propyl)-O-Phenylene Diamine and 10ml orthodichlorobenzene several times with the solution of 8ml propanedioic acid dichloride and 90ml orthodichlorobenzene.After stirring 1.6 hours under 130 ℃, under hot state, filter, this filtrate is concentrated, refining with silica gel column chromatography (ethyl acetate), the adding normal hexane with crystallization filtration, the drying of separating out, obtains (208) of 9.8g
mp：137～138℃
IR(KBr)cm -1：1696，1676，1417，
1243，748
1HNMR(CDCl3)δ：9.29(1H，s)，7.41(1H，
ABd，J＝7.6，1.8)，7.29(1H，td，J＝
7.3，1.8)，7.25(1H，td，J＝7.3，
1.8)，4.33(1H，m)，3.80(1H，m)，
3.36(1H，s)，3.35(1H，s)，3.33(1
H，m)，3.26(1H，m)，3.19(3H，s)，
1.87 (1H, m), 1.77 (1H, m) embodiment 2095-(3-bromopropyl)-1H-(1,5) benzodiazepine -2,4 (3H, 5H)-diketone (209)
In the compound of 4.9g embodiment 208, add 25ml 30% hydrogen bromide-acetic acid solution, stirred 4.7 hours down, pour in the water, use ethyl acetate extraction, clean after drying with aqueous sodium carbonate, salt solution at 60 ℃.Refining with silica gel column chromatography (ethyl acetate), obtain 3.3g (209).
mp：154～156℃
IR(KBr)cm -1：1711，1661，1504，
1415，1404，1278，754
1HNMR(CDCl3)δ：8.96(1H，s)，7.40-
7.20(4H，m)，4.31(1H，brs)，3.92
(1H，brs)，3.36(2H，s)，3.32(2H，
m)，2.19(2H，brs)
MS:296 (M+) embodiment 2105-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group)-1H (1,5) benzodiazepine -2,4 (3H, 5H)-diketone (210)
In the compound of 2.3g embodiment 209 and 2.6g 1-((4-chloro-phenyl-) phenyl methyl) piperazine and 2.2g salt of wormwood, add the 25ml dimethyl formamide, stirred 4 hours down at 100 ℃.Add 0.35g 1-((4-chloro-phenyl-) phenyl methyl) piperazine, stirred 2.5 hours down at 100 ℃ again.With sedimentation and filtration, concentrated filtrate is with silica gel column chromatography (ethyl acetate: methyl alcohol=9: 1～8: 1) make with extra care, obtain 3.7g (210)
IR(KBr)cm -1：2814，1671，1502，
1398，1091，1011，760
1HNMR(CDCl3)δ：8.89(1H，s)，7.39～
7.31(5H，m)，7.27～7.11(8H，m)，
4.29(1H，brs)，4.15(1H，s)，3.70
(1H，brs)，3.33(1H，s)，3.31(1H，
s)，2.31(9H，brs)，1.82(1H，brs)，
，1.69(2H，brs)
MS:502 (M+) embodiment 2111-methyl-6-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl)-propyl group)-4H (1,2,4) triazolo (4,3-a) (1,5) benzodiazepine leather-5 (6H)-ketone (211)
Figure C9210399102291
Add the 40ml pyridine in the compound of 3.7g embodiment 210 and 1.7g thiophosphoric anhydride, stirred 3.1 hours down at 100 ℃, distillation removes and desolvates, and adds water, chloroform extraction, washing, drying.With silica gel column chromatography (chloroform-2% methyl alcohol), obtain 3.4g 5-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group)-2,3-dihydro-2-sulfo--1H-(1,5) benzodiazepine -4 (5H)-ketone and 5-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group-1H-(1,5) benzodiazepine -2,4 (3H, 5H)-two The mixture of acid.Add the 40ml propyl carbinol to it, on one side-the limit reflux divides five times to add the 1.7g acethydrazide, and reflux 15.8 hours adds water, ethyl acetate extraction, washing, drying.With silica gel column chromatography (ethyl acetate: methyl alcohol=6: 1～4.5: 1) make with extra care, obtain 2.2g (211).
IR(KBr)cm -1：2814，1682，1506，
1427，1044，760
1HNMR(CDCl3)δ：7.55(1H，AB，J＝8.2，
1.5)，7.51(1H，td，J＝7.0，1.5)，
7.38～7.31(5H，m)，7.27～7.21(4H，
m)，7.17(1H，t，J＝7.0)，4.30(1H，
m)，4.15(1H，s)，4.08(1H，AB，J＝
14.0)，3.61(1H，m)，3.36(1H，AB，
J＝14.3)，2.60(3H，d，J＝1.8)，
2.30(4H，brs)，2.26(4H，brs)，2.10
(1H，m)，1.97(1H，m)，1.64(1H，m)，
1.51(1H，m)
MS:540 (M+) embodiment 2121-methyl-6-(3-methoxy-propyl)-4H (1,2,4) triazolo (4,3-a) (1,5) benzodiazepine -5 (6H)-ketone (212)
Figure C9210399102301
The compound that in the dichloromethane solution (30ml) of 1.59g triethyl oxygen Tetrafluoroboric acid ester, adds 1.09g embodiment 208.After at room temperature stirring a night, add aqueous sodium carbonate, organic layer is separated.It is refining with column chromatography to concentrate the back, obtains the 0.60g colorless oil.Add 15ml nBuOH, 0.25g acethydrazide, refluxed 12 hours.Add diethyl ether after distillation removes and desolvates and make its crystallization, obtain the 0.51g title compound.
mp：185～190℃
IR(KBr)cm -1：1665，1541，1510，
1466，1433，1383，1120，791
1HNMR(CDCl3)δ：7.6-7.2(4H，m)，4.6-
4.2(1H，m)，4.09(1H，ABq，J＝
14.3)，3.9-3.4(1H，m)，3.37(1H，
ABq，J＝14.3)，3.3-2.8(2H，m)，
3.10(3H，s)，2.62(3H，s)，1.9-
1.5(2H，m)
MS:286 (M+) embodiment 2131-methyl-6-(3-(4-(4-chloro-phenyl-) phenyl methyl) piperazine-1-yl)-propyl group)-4H (1,2,4) triazolo (4,3-a) (1,5) benzodiazepine -5 (6H)-ketone (211)
Figure C9210399102311
In the compound of 0.23g embodiment 212, add 2ml 47% hydrogen bromide water, stirred 1.5 hours down at 110 ℃.Distillation under reduced pressure removes desolvates, and drying adds 4ml dimethyl formamide, 0.45g yellow soda ash, 0.29g 1-((4-chloro-phenyl-) phenyl methyl) piperazine, stirs 1.5 hours down at 90 ℃.Distillation under reduced pressure removes and to desolvate, add methylene chloride, the water extraction, washing, drying, distillation removes and desolvates, with silica gel column chromatography (ethyl acetate: methyl alcohol=3: 2) refining, by the propyl carbinol recrystallize, obtain the title compound of 0.20g colourless crystallization.Embodiment 2145,6-dihydro-1-methyl-6-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group)-4H (1,2,4) triazolo (4,3-a) (1,5) benzodiazepine (213)
Figure C9210399102321
In the compound of 1.1g embodiment 211, add the 20ml tetrahydrofuran (THF), add the plumbous lithium of 0.17g hydrogenation, reflux 30 minutes.Add the 0.82g lithium aluminum hydride, reflux 20 minutes.Add ethyl acetate, water, behind diatomite filtration, this filtrate is concentrated, with silica gel column chromatography (ethyl acetate: methyl alcohol=7: 1～6: 1) make with extra care, obtain 0.30g (213)
IR(KBr)cm -1：2940，2814，1504，
1152，1011，758
1HNMR(CDCl3)δ：7.39(1H，m)，7.34～
7.31(4H，m)，7.25～7.15(8H，m)，
4.17(1H，s)，3.39(2H，brs)，3.09
(2H，brs)，2.90(2H，brs)，2.47(3H，
s)，2.35(8H，brs)，2.15(2H，t，J＝
7.3)，1.59(2H，quint，J＝7.3)
MS:526 (M+) embodiment 2155,6-dihydro-1-methyl-6-(3-(4-((4-chloro-phenyl-) phenyl methyl) piperazine-1-yl) propyl group)-4H (1,2,4) triazolo (4,3-a) (1,5) benzodiazepine fumarates (214)
Figure C9210399102331
The methanol solution that adds the 59mg fumaric acid in the methanol solution of the compound of 0.26g embodiment 214 concentrates the back and adds Virahol, isopropyl ether, filters, after the drying, obtains 0.11g amorphous (214)
Ultimate analysis: in C31H35N6ClC4.H4O4
Calculated value: C, 65.36; H, 6.11; N, 13.07;
Cl，5.51
Measured value: C, 65.58; H, 6.34; N, 12.86;
Cl，5.77
IR(KBr)cm -1：3390，1678，1504，984，
762,648 embodiment 2163-(4,5-dihydro-1-methyl-(1,2,4) triazolo (4,3-a) quinoxaline-5-yl) methyl propionate
The 10ml DMF solution of 3.75g 1-butoxy potassium is cooled to-18 ℃, splashes into the 37ml DMF solution of 3.13g embodiment 13 compounds.At ambient temperature, and under 40 ℃ of conditions, carry out after 40 minutes stirring in 90 minutes after 10 minutes.After this, under-15 ℃, splash into the 14mlDMF solution of 4.51g 3-bromo propionic acid A ester, after 15 minutes, under 40 ℃, carry out again stirring in 5 hours.Add saturated aqueous ammonium chloride under ice bath reaction is stopped, extracting, clean organic layer, dry, distillation removes and desolvates, and makes with extra care with silica gel column chromatography, obtains the 17.9g white crystals.
mp：91～94℃
Ultimate analysis: in C14H16N4O2
Calculated value: C, 61.75; H, 5.92; N, 20.58;
Measured value: C, 61.73; H, 5.89; N, 20.60;
IR(KBr)cm -1：2958，1734，1504，
1433，1261，1220，1195，748
1HNMR(CDCl3)δ：8.03(1H，d，J＝8.30)，
7.29(1H，t，J＝7.81)，7.04-6.92
(2H，m)，4.51(2H，s)，3.71(3H，s)，
3.71(2H，t，J＝7.33)，2.86(3H，s)，
2.70 (2H, t, J=7.33) embodiment 2173-(4,5-dihydro-1-methyl-(1,2,4) triazolo (4,3-a) quinoxaline-5-yl) propionic acid
The compound of 245mg embodiment 216 is dissolved in the 5ml ethanol, under ice bath, splashes into the 1.35ml potassium hydroxide aqueous solution of 1N, stirred 30 minutes.After it was cleaned with chloroform, modulation pH value was 4, uses chloroform extraction, drying.Distillation removes and desolvates, and by carrying out recrystallize in the 2-propyl alcohol, obtains the title compound 159mg of white crystals.
mp：196～197℃
Ultimate analysis: in C13H14N4O2
Calculated value: C, 60.45; H, 5.46; N, 21.69;
Measured value: C, 60.42; H, 5.45; N, 21.73;
IR(KBr)cm -1：2838，2498，1700，1502，
1435，1267，1207，1015，750
1HNMR(CDCl3)δ：7.46(1H，dd，J＝8.24，
1.43)，7.23(1H，dd，J＝7.91，
1.76)，7.05-(6.80(2H，m)，4.66(2
H，s)，3.75(2H，t，J＝6.38)，2.76
(3H, s), 2 7.2 (2H, t, J=6.38) embodiment 2185-(3-bromo propyl group)-4,5-dihydro-1-methyl (1,2,4) triazolo (4,3-a) quinoxalines
Figure C9210399102361
The compound of 1.51g embodiment 216 is dissolved in the 20ml dry tetrahydrofuran, is cooled to 0 ℃, to wherein adding the 0.3g lithium aluminum hydride and at room temperature stirring 3 hours.After being cooled to 0 ℃ again, adding water and stir.Behind diatomite filtration, distillation removes and desolvates, and uses chloroform extraction.It is refining with silica gel column chromatography to concentrate the back, obtains the 0.86g colourless crystallization.It is dissolved in the 15ml chloroform is cooled to 0 ℃ again.Add the 1ml thionyl bromide.After at room temperature stirring for 1 night, refluxed 2 hours, behind the adding aqueous sodium carbonate, organic layer separation, drying.Distillation is made with extra care with column chromatography after removing and desolvating, and obtains the title compound 0.25g of colourless crystallization.
IR(KBr)cm 1?1502，1431，750
1HNMR(CDCl3)δ：7.47(1H，m)，7.18(1H，
m)，7.02-6.85(2H，m)，4.44(2H，
s)，3.53(2H，t，J＝7.0)，3.49(2H，
t，J＝6.1)，2.78(3H，s)，2.23(2H，
m)
MS：306(M+)
Below, to being illustrated by the PAF antagonistic action of the compound of formula (I) expression and anti-allergy reactivity etc.
1. anti-allergy reactivity test (the PCA reaction of rat)
The anti-allergy reactivity is skin hypersensitivity (the Passivecutaneous anaphylaxis that is subject to processing by rat; PCA) test is studied.As experimental animal, using the Wister of body weight 150～200g is male rat in addition.
The normal saline solution of the monochromatic antibody of 1g E (biological chemistry industry) that contains the small white mouse of anti-dinitrophenyl (DNP) to the rat back subcutaneous injection.After 23 hours, be suspended in test compound in the sweet oil with the oral dose of 50mg/Kg.After 1 hour, the normal saline solution that 0.5ml is contained 2mg/ml DNPization Protalbinic acid and 1%Evansblue is injected by the leg vein.After 30 minutes, cut off carotid artery and make its bloodletting death, peel off skin, cut green grass or young crops and dye part, after in 4ml formaldehyde, frittering, following to 48 hours extraction pigments at 60 ℃.With (1500 * g, 10 minutes) after the skin centrifugation after frittering, the supernatant liquor of removing is measured absorbancy at the 620nm place.Quantitatively go out the amount of pigment that spills to the part by giving the calibration curve of making earlier.With drop under the sweet oil situation amount of pigment in contrast, will drop under the test compound situation, illustrate in the inhibiting rate mode with respect to the ratio of reference examples amount of pigment.The results are shown in table 1.
2. the antagonistic action of histamine
To being suspended in test compound in the sweet oil with the dosage oral administration of 50mg/Kg with 1 same rat.After 1 hour, will contain the physiological saline vein injection of 1%Evans blue with the consumption of 3ml/Kg.Then the histamine solution (50 μ l) of 900 μ M is injected to subcutaneous rat.After 30 minutes, the green grass or young crops of resulting skin is dyed pigment partly with the aforesaid method extraction quantitatively.With drop under the sweet oil situation amount of pigment in contrast, and will drop under the test compound situation, illustrate in the inhibiting rate mode with respect to the amount of pigment of reference examples.The results are shown in table 1.Table 1
The anti-PCA antihistamine of inhibiting rate (%) compound number
4 44 76
45 49 43
46 65 72
49 58 65
52 65 47
75 42 19 189 43 57 192 74 38 199 48 53 214 75 87
Above-mentioned test-results shows that compound and the salt thereof represented with formula (1) have good antihistamine effect and anti-allergy reactivity.
3. stop platelet aggregation test in the test tube
For the antagonistic action of the biologically active pdgf factor (PAF) of measuring material, use in test tube, rabbit thrombocyte PAF brings out the aggegation method.For obtaining being rich in hematoblastic blood plasma, to adopt venous blood by the rabbit ears vein and place the plastics centrifugal separating tube that fills 1.0% sodium citrate solution, blood is 1: 10 to the ratio of sodium citrate solution.The resulting blood that contains Citrate trianion at room temperature with 70 * g (625rpm) centrifugation 20 minutes, is taked the PRP on upper strata in other plastics tubing.Residual lower floor uses 1500 * g (2800rpm) centrifugation 10 minutes again, takes the hematoblastic blood plasma of shortage (ppp) on upper strata.Hematoblastic aggegation uses the aggegation device of two smooth BIOSENS society systems to measure.PRP is injected mensuration respectively with in the cuvette.Be reached for 0.1mM respectively by ultimate density at once, 7mM and 45U/ml add acetylsalicylic acid, creatinine phosphoric acid ester and creatinine phosphokinase.Then add the drug solution that is verified, stirring is after 2 minutes down at 37 ℃, and adding PAF (ultimate density 10ng/ml) brings out platelet aggregation.Agglutinate rate of blood platelet, is calculated from the maximum value of each aggregation curves as maximum aggegation (100% aggegation) with the permeability of PPP.With the aggegation rate under the interpolation normal saline solution situation in contrast, calculate to add respectively and tested the rate that encumbers that the aggegation rate under the compound situation is compared with reference examples, obtain the IC50 value through interpolation technique by figure
Show the result in table 2.Table 2
PAF brings out platelet aggregation PAF and brings out platelet aggregation compound number IC50 (μ g/ml) compound number IC50 (μ g/ml) 4 2.0 52 5.453 1.8 63 4.464 1.6 65 2.066 1.9 73 4.575 0.21 77 0.07278 2.4 80 0.04481 0.6 85 1.4 86 2.2 87 3.1 88 0.86 90 0.56 92 0.66 127 0.23128 1.7 129 0.17130 0.32 131 0.13132 0.036 133 0.063134 0.051 135 0.88138 0.81 140 0.24142 0.51 143 0.22145 0.91 147 0.087148 0.32 149 0.55150 0.51 151 0.76154 0.19 155 1.2156 0.58 160 0.071161 0.54 163 0.32164 0.36 165 0.74189 0.31 193 0.84194 0.045 195 0.14196 0.013 197 0.025198 0.074 199 0.12200 0.023 201 0.16205 2.3 206 2.1214 4.0
Show that by above-mentioned test-results compound and the salt thereof represented by formula (1) have good PAF antagonistic action.
4 use the combination test (paf receptor is in conjunction with test) of (3H)-PAF
Method (Biochemistry according to people such as Hwang; 22; 4756, (1983)), the hematoblastic cytolemma part of modulation rabbit is suspended in this cytolemma part (50mg) in the three times of damping fluids of 10mM that contain 0.25% bovine serum albumin, to wherein adding deuterium-labelled PAF ((3H)-PAF; 0.4nM) and test compound., filter after 60 minutes 25 ℃ of insulations with glass fiber filter paper.This filter paper is transferred in the phial after cleaning for three times with three times of cold damping fluids, adds scintillator, with the energy of liquid flashing counter measuring radiation.The rate that encumbers (bound energy) of test compound is calculated as follows, and the IC50 value is obtained with interpolation technique from figure.
Have, so-called full binding capacity is that so-called non-specific binding capacity is that the PAF of 1 μ M exists down in conjunction with (3H)-PAF radiant at combination (3H-PAF) radiant of test compound in the presence of not again.
The results are shown in table 3, medicine uses disclosed WEB2086 (spy opens clear 6.5-176591 number) to make antagonistic in contrast.Table 3
IC50 ( μg/ml ) IC50 ( μg/ml ) 4 1.0 43 3.0 44 0.80 45 0.32 46 0.18 49 1.7 52 3.5 53 1.5 54 0.5 55 0.37 56 0.48 57 1.2 58 0.28 64 0.46 65 4.8 69 0.36 72 1.9 73 3.1 74 0.23 75 0.41 77 0.097 76 0.13 78 0.059 80 0.33 81 1.5 85 0.11 86 3.00 87 0.10 88 0.34 90 0.99127 0.077 128 0.63129 0.17 130 0.070131 0.045 132 0.026133 0.017 134 0.005135 0.021 138 0.72140 0.006 142 0.087143 0.040 145 0.22147 0.034 148 0.029149 0.105 150 0.083151 0.060 154 0.091155 0.072 156 0.029160 0.097 161 0.16163 0.18 164 0.12165 0.40 189 0.14191 3.2 192 0.69193 2.9 194 1.1195 0.11 196 0.24197 0.032 198 0.21199 0.035 200 0.03201 0.17 205 1.3206 0.88 WEB2086 0.05
Above-mentioned test-results shows that compound and the salt thereof represented by formula (1) have good PAF receptor antagonistic action.
5. use the hyperfunction typical case of tracheae supersensitivity who brings out by PAF of cavy
Animal is to use the male cavy (body weight 300～400g) of Hartley system.
A) the reactive evaluation of tracheae
Anti-mensuration of breathing (Rrs) is not to be fixed on the body plethysmography box under cavy has the situation of anesthesia, is undertaken by succusion.For the animal of this Rrs of METHOD FOR CONTINUOUS DETERMINATION, with the aerocolloidal concentration of vagusstoff (Ach) solution by 31 μ g/ml by doubly being increased to 4000 μ l/ml, and suction 1 minute under each concentration.Obtain the Rrs value and become 1.5cm H 2The suction threshold value of the necessary Ach of O/ml/sec.Moreover the baseline value of Rrs is 0.2～0.5cm H 2O/ml/sec.It is the value that the aerocolloidal situation of Ach that sucked 1000 μ g/ml in 1 minute is calculated as 1 unit that so-called Ach sucks threshold value.The above ANIMALAST (registered trademark) that manipulates CHI STIMAI society system carries out.
B) tracheae supersensitivity is hyperfunction brings out and estimates
According to A) method obtain the tracheae reactivity of cavy, promptly Ach sucks threshold value.Then in 10 minutes, make its aerosol that sucks PAF solution (100 μ g/ml), suck finish 40 minutes after, use A again) method measure the tracheae reactivity. (Ach after PAF sucks sucks threshold value/PAF and sucks preceding Ach suction threshold value the hyperfunction ratio by the Ach suction threshold value that sucks the PAF front and back of tracheae supersensitivity; Back/preceding value) measures.If promptly tracheae supersensitivity is hyperfunction by force, then back/preceding value, then should be worth about 1.0 if not hyperfunction than 1.0 low values.In addition, test compound is suspended in the sweet oil, oral administration administration before 1 hour of beginning PAF suction is compared by the back/preceding value with control group (clothes sweet oil group), estimates and suppresses having or not of effect, behind the results are shown in table 4, in contrast medicine.Use disclosed WEB2086 as the PAF antagonistic. table 4 compound number dosage (mg/Kg)/front contrast 0.57 46 0.3 1.64 46 0.1 1.14 52 1 1.37 73 1 1.18192 1 1.81WEB 2,086 3 0.89
Above-mentioned test-results shows that compound and the salt thereof represented by formula (1) not only have good PAF antagonistic action, also has the hyperfunction effect of the tracheae supersensitivity of inhibition.

Claims (7)

1. the manufacture method of the triazolo derivative of formula (I) expression, In the formula,
R 1Represent hydrogen, low alkyl group,
R 2, represent hydrogen, low alkyl group, lower alkoxy or halogen,
R 3Represent hydrogen,
W represents C=O, CR 4R 5(R 4, R 5Represent hydrogen, low alkyl group respectively),
A represents a straight chain shape or the catenate alkylidene group of carbon number 1-5,
Also can contain a Sauerstoffatom,
L represents 0-2,
N represents 1-3,
Figure C9210399100022
Represent singly-bound or two key,
Y represents N or C,
Z represents C (B) Ar 1Ar 2(B represents hydrogen, hydroxyl or methoxyl group, Ar 1, Ar 2Represent hydrogen, displacement or metathetical aryl not respectively), CAr 1Ar 2(Ar 1, Ar 2Same as described above), O-CHAr 1Ar 2(Ar 1, Ar 2Same as described above) or the condensation aromatic nucleus,
Described method is that the compound of formula (III) expression and the compound of formula (IV) expression are reacted, R in the formula 1, R 2, R 3, R 10, A, W and l be same as described above Y, Z, n and  are same as described above in the formula.
2. the manufacture method of the triazolo derivative of formula (I) expression,
Figure C9210399100033
In the formula, R 1, R 2, R 3, W, A, l, n, The implication of Y and Z is the same, and described method is that the compound of the compound represented by formula V and formula (VI) expression is reacted, R in the formula 1, R 2, R 3, W and l be same as described above,
Figure C9210399100036
In the formula X represent halogen, A, Y, Z, n and
Figure C9210399100041
Same as described above.
3. the manufacture method of the triazolo derivative of formula (I) expression,
Figure C9210399100042
In the formula, R 1, R 2, R 3, W, A, l, n, The implication of Y and Z is the same,
Described method is that the compound of formula (VII) expression and the compound of formula (VIII) expression are reacted,
Figure C9210399100044
In the formula Q represent halogen ,-SH or-OR 11(R wherein 11Represent low alkyl group), R 2, R 3, A, W, Y, Z, l, n,
Figure C9210399100045
Same as described above
R 1CONHNH 2(VIII) R in the formula 1Same as described above.
4. the manufacture method of the triazolo derivative of formula (I) expression, In the formula, R 1, R 2, R 3, W, A, l, n, The implication of Y and Z is the same
Described method is compound and the hydrazine reaction with above-mentioned formula (VII) expression, obtains the compound of formula (IX) expression, R in the formula 2, R 3, A, W, Y, Z, l, n,
Figure C9210399100053
As hereinbefore,
The compound that makes the compound of gained (IX) compound and formula (X) expression or (XI) represent reacts,
R 1C (OR 12) 3(X) R in the formula 12Represent low alkyl group, R 1It is same as described above,
R 1CO 2R in H (XI) formula 1Same as described above.
5. the manufacture method of new triazolo derivative (Ib), R in the formula 1, R 2, R 3, A, G, Y, Z, n, q, As hereinbefore,
Described method is that the compound that formula (XII) is represented is reduced, In the formula, G represents CR 4R 5, q represents 0 or 1, R 1, R 2, R 3, R 4, R 5, A, Y, Z, n,
Figure C9210399100062
As hereinbefore.
6. the manufacture method of triazolo derivative (Ic), Ar in the formula 1, Ar 2, R 1, R 2, R 3, A, W, l, n be same as described above,
Described method is the compound with (XIII) or formula (XIV) expression, with the compound reaction of formula (XV) or formula (XVI) expression,
Figure C9210399100064
R in the formula 13Represent low alkyl group, R 1, R 2, R 3, A, W, l, n as hereinbefore, Ar in the formula 1, R 1, R 2, R 3, A, W, l, n as hereinbefore,
X represents halogen atom in ArMgX (XV) formula, and Ar represents Ar 1And/or Ar 2, Ar 1, Ar 2As hereinbefore,
Ar represents Ar in ArLi (XVI) formula 1And/or Ar 2, Ar 1, Ar 2As hereinbefore,
7. the manufacture method of triazolo derivative (Id),
Figure C9210399100072
Ar in the formula 1, Ar 2, R 1, R 2, R 3, A, W, l, n as hereinbefore,
Described method is that the compound that above-mentioned formula (Ic) is represented is dewatered,
Figure C9210399100073
Ar in the formula 1, Ar 2, R 1, R 2, R 3, A, W, l, n as hereinbefore.
CN 92103991 1991-04-23 1992-04-23 Process for preparing tricyclotriazolo derivatives and their use Expired - Fee Related CN1033327C (en)

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