CN1066849A - Three ring triazolo derivatives, its Manufacturing approach and use - Google Patents
Three ring triazolo derivatives, its Manufacturing approach and use Download PDFInfo
- Publication number
- CN1066849A CN1066849A CN92103991A CN92103991A CN1066849A CN 1066849 A CN1066849 A CN 1066849A CN 92103991 A CN92103991 A CN 92103991A CN 92103991 A CN92103991 A CN 92103991A CN 1066849 A CN1066849 A CN 1066849A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- triazolo
- methyl
- piperidines
- Prior art date
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- Granted
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 25
- 238000013459 approach Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 239000000043 antiallergic agent Substances 0.000 claims abstract description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims abstract description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 494
- -1 methoxyl group Chemical group 0.000 claims description 137
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 94
- 238000006243 chemical reaction Methods 0.000 claims description 81
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 230000002829 reductive effect Effects 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 229910052727 yttrium Inorganic materials 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 229910052721 tungsten Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 4
- XSJMOLCRLLDSFM-UHFFFAOYSA-N 2h-triazolo[4,5-f]quinoxaline Chemical class C1=CC2=NC=CN=C2C2=NNN=C21 XSJMOLCRLLDSFM-UHFFFAOYSA-N 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims 2
- 238000009833 condensation Methods 0.000 claims 2
- 238000006073 displacement reaction Methods 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 384
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- 238000004458 analytical method Methods 0.000 description 120
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- 150000003053 piperidines Chemical class 0.000 description 114
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 95
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- QNSRYVDGWDXBHV-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]quinoxaline Chemical compound C1=CC=C2N3C=NN=C3C=NC2=C1 QNSRYVDGWDXBHV-UHFFFAOYSA-N 0.000 description 70
- 238000002425 crystallisation Methods 0.000 description 59
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- 239000000243 solution Substances 0.000 description 53
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 51
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- 239000002904 solvent Substances 0.000 description 40
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- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
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- 230000001387 anti-histamine Effects 0.000 description 9
- 239000000739 antihistaminic agent Substances 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
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- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
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- 0 C[C@](N(C(C)=N)c1ccccc1N*)[N+]([O-])=O Chemical compound C[C@](N(C(C)=N)c1ccccc1N*)[N+]([O-])=O 0.000 description 7
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 7
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The salt of allowing as the effectively novel three ring triazolo derivatives of anti-inflammatory agent, anti-allergy agent or anti-PAF agent and pharmacology thereof is disclosed, with and manufacture method.Triazolo derivative of the present invention formula (I) expression,
Description
The effect to platelet activity factor (Platelet Activating Factor-is 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, 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 organ transplantation 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 and the relation of PAF (Jpn.J.Pharmacol., 46,55P(1988)).
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 ィ 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 as known anti-PAF agent
Based compound (spy open clear 61-176591, spy open flat 2-256681, the spy opens flat 2-256682).In addition, as the compound that has antihistamine effect and PAF antagonistic action simultaneously, the present known benzocyclohepta pyridine based compound (EP270818 number) that has only.
In addition, as the existing known example of triazolo quinoxaline derivatives, but only (J.Heterocyclic Chem., 27,691(1990)) said and had anti-uneasy acting on to report.
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)).
What in addition, have a synthetic report has a following compound (J.Heterocycl.Chem., 15,1027(1978)).
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.
(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,
Expression 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 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.
(in the formula, R
1, R
2, R
3, R
4And R
5Implication the same, J represent hydrogen or-implication of A-B(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, base etc. just.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
2-
Ar 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.
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
(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
(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 is 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.
(R in the formula
1, R
2, R
3, W, l implication same as above)
(X represents halogen atom in the formula, A, Y, Z, n,
Implication is 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) vulcanize reagent reacts with thiophosphoric anhydride, Lawesson reagent (registered trademark) etc., obtain the compound of (XIXa) formula
(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
(X represents halogen atom in the formula, R
2, R
3, A, W, Y, Z, l, n,
Implication is 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
(R in the formula
11The expression low alkyl group, R
2, R
3, A, W, Y, Z, l, n,
Implication is 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
(R in the formula
2, R
3, A, W, Y, Z, l, n,
Implication is 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 is the same) represented compound can be by making (XII) formula
(R in the formula
1, R
2, R
3, A, G, Y, Z, n, q,
Implication is the same) represented compound and reductive agent reaction and create.
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
(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
(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
(Ar in the formula
1, R
1, R
2, R
3, A, W, l, n, implication be the same) with (XV) compound of formula
ArMgX（XV）
(X represents that halogen atom, Ar represent Ar in the formula
1And/or Ar
2, Ar
1, Ar
2Implication is the same) or (XVI) compound of formula
ArLi（XVI）
(Ar represents Ar 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
(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).
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, in to the not active solvent of reaction (dimethyl formamide, N,N-DIMETHYLACETAMIDE, tetrahydrofuran (THF), diox etc.) and under the situation of mineral alkali (sodium hydride, potassium hydride KH, sodium amide, potassium hydroxide, tert.-butoxy potassium etc.) or organic bases (pyridine, triethylamine etc.) existence, to the solvent for use reflux temperature, carried out 5 minutes to 5 hours 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=0,1 in the formula
(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.
That is, make the compound of (XXVI) formula and (XXVII) compound of formula
(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 can have acetate, hydrochloric acid etc. simultaneously.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
(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.
Make the compound of (XXVI) formula and (XXXIII) compound of formula
(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)
(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.
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
(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.
Make compound of (XXIX) formula and (X.L) formula
(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 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
(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.
Make compound of (XLV) formula and (XLVIII) formula
(E represents OR 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
(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.
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
(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.
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)
(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
(R in the formula
1, R
2, R
3, R
4, R
5Implication is the same) compound and (LVI) formula
LO
2C-A′-X（LVI）
The compound reaction of (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
(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 (trimethylammonium methane amide, 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 separated from reaction mixture 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 during organ 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
The 4-(3-ethoxycarbonyl propyl)-2-hydroxyl-quinoxaline-3(4H)-ketone (1)
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 several times)-O-Phenylene Diamine and 220ml o-dichlorobenzene solution.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 obtain 25.2g(1) the 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
The 4-(3-ethoxycarbonyl propyl)-2-chloro-quinoxaline-3(4H)-ketone (2)
At 22.5g(1) in 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
The 5-(3-ethoxycarbonyl propyl)-4,5-dihydro-1-methyl-(1,2,4) triazolo (4,3-a) quinoxaline-4(5H)-ketone (3)
To 23.3g(2) and the 7.79g acethydrazide in add the 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) quinoxaline-4(5H)-ketone (4)
The aqueous solution of hydrogen bromide of 18ml48% is added to 2.51g(3) in, reflux 2.7 hours.Under reduced pressure heat up in a steamer and desolvate, add 1.96g 4-(diphenylmethylene then) piperidines, 2.33g yellow soda ash, 18ml dimethyl formamide, 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 C31H31N50.1/4H20
Calculated value: C, 75.35; H, 6.43; N, 14.17
Measured value: C, 75.21; H, 6.36; N, 14.27
IR（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) quinoxaline-4(5H)-ketone (5)
Except using the 1-(diphenyl-methyl) piperazine replaces the 4-(diphenylmethylene among the embodiment 4) the piperidines, 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, 17.27
IR（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) quinoxaline-4(5H)-ketone (6)
4-(diphenylmethylene in using 1-((4-chloro-phenyl-) phenyl methyl) piperazine replacement embodiment 4) identical the piperidines with embodiment 4, 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：527（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) quinoxaline-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) quinoxaline-4(5H)-ketone (8)
Except with 1-(4-benzyl chloride base) piperazine replaces the 4-(diphenylmethylene among the embodiment 4) the piperidines, 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 value: C, 64.18; H, 6.26; N, 18.27; Cl, 8.02
IR（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) quinoxaline-4(5H)-ketone (9)
Except using the 4-(3-indyl) piperidines replaces the 4-(phenylbenzene methylene radical among the embodiment 4) identical with embodiment 4 piperidines, obtain colourless amorphous (9).
mp：198～215℃
Ultimate analysis: in C26H28N6O
Calculated value: C, 70.89; H, 6.41; N, 19.08
Measured value: C, 70.68; H, 6.63; N, 18.84
IR（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），7.49（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, the 2-dihydro-quinoxaline-3(4H)-thioketones (10)
The 280ml diglyme is added to 52g1, 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)
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)
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)
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 value: C, 64.34; H, 5.51; N, 29.73
IR（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, 27.91
IR（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)
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, 26.00
IR（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)
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, 27.91
IR（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)
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, 25.92
IR（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
The 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 10g60%, at 0 ℃ of compound that adds 32g embodiment 13 down.Stirred 30 minutes down at 0 ℃, splash into 35g1-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, 20.65
IR（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
The 5-(3-bromopropyl)-4,5-dihydro-1-methyl (1,2,4) triazolo (4,3-a) quinoxalines (19)
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
The N-(3-methoxy-propyl) glycine ethyl ester (20)
MeO（CH
2）
3NHCH
2CO
2Et（20）
Solution 100ml in tetrahydrofuran (THF) immerses in the ice-water bath with the 52g3-methoxy propanamine, 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
The 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)-and the N-(3-methoxy-propyl) glycine methyl ester (22)
With compound, the 3.9g2 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)-and the N-(3-methoxy-propyl) glycine methyl ester (23)
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 replacing 2 with the 2.5-difluoro nitrobenzene, 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
The N-(3-methoxy-propyl)-and the N-(2-nitrophenyl) alanine methyl ester (25)
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) ketone (26) of quinoxaline-3(4H)
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) thioketones (27) of quinoxaline-3(4H)
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.
Compound Y R
2R
3R
4R
5
28??O??7-F??H??H
29??O??6-F??H??H
30??O??H??Me??H
31??S??7-F??H??H
32??S??6-F??H??H
33??S??H??Me??H
28:7-fluoro-1,2-dihydro-1-(3-methoxy-propyl) ketone of quinoxaline-3(4H)
29:6-fluoro-1,2-dihydro-1-(3-methoxy-propyl) ketone of quinoxaline-3(4H)
30:1,2-dihydro-1-(3-methoxy-propyl)-ketone of 2-methyl-quinoxaline-3(4H)
31:7-fluoro-1,2-dihydro-1-(3-methoxy-propyl) thioketones of quinoxaline-3(4H)
32:6-fluoro-1,2-dihydro-1-(3-methoxy-propyl) thioketones of quinoxaline-3(4H)
33:1,2-dihydro-1-(3-methoxy-propyl)-thioketones of 2-methyl-quinoxaline-3(4H)
Above-claimed cpd has following physics value
The 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℃
Ultimate analysis value: in C14H17N4OCl
Calculated value: C, 57.44; H, 5.85; N, 19.14; Cl, 12.11
Measured value: C, 57.68; H, 5.97; N, 19.33; Cl, 12.35
IR（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.
Compound R
1R
2R
3R
4R
5M R
10
35??Et??H??H??H??3??Et
36??Pr??H??H??H??3??Et
37??Me??H??Me??Me??3??Et
38??Me??H??H??H??4??Et
39??Me??7-F??H??H??3??Me
40??Me??8-F??H??H??3??Me
41??Me??H??Me??H??3??Me
35:1-ethyl-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.
The 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 to compound, 0.40g (4-(diphenyl methyl) piperazine-1-yl of 0.13g embodiment 13) in the diethylaluminum monochloride hydrochloride, 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（CDCl3）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 C29H32N61.25C4H4O4
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)
The compound dissolution of 1.12g embodiment 5 in the 20ml dry tetrahydrofuran, is added 10ml(0.5M) stirred 3 hours behind the tetrahydrofuran solution of 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)
In the compound of 0.50g embodiment 19 and 0.52g1-(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)
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 0.92g4-(phenylbenzene methylene radical then) piperidines, 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
-1：3322，1738，1562，1504，1309，1267，1137，681
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)
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)
Except that using the 4-(3-indyl) piperidines replaces 4-(phenylbenzene methylene radical) the 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（1H，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)
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, with 4-(5-methoxyl group-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 54 compound, with 4-(5-chloro-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 55 compound, with 4-(5-bromo-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 56 compound, with 4-(5-fluoro-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 57 compound, with 4-(5-methyl-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 58 compound, with 4-(6-methoxyl group-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 59 compound, with 4-(6-methyl-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 60 compound, with 4-(6-fluoro-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 61 compound, with 4-(2-methyl-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 62 compound, with 4-(1,2,3,6-tetrahydrochysene-4-(3-indyl) piperidines replacement 4-(3-indyl) piperidines obtains 63 compound, with 4-(1-ethyl-3-indyl) piperidines replaces the 4-(3-indyl) piperidines obtains 64 compound, 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.
Compound R
1R
2R
3R
4R
5m
R
7R
8R
9
51??Me??H??H??H??4??-??H??H??H
52??Et??H??H??H??3??-??H??H??H
53??Pr??H??H??H??3??-??H??H??H
54??Me??H??H??H??3??-??H??H??5-MeO
55??Me??H??H??H??3??-??H??H??5-Cl
56??Me??H??H??H??3??-??H??H??5-Br
57??Me??H??H??H??3??-??H??H??5-F
58??Me??H??H??H??3??-??H??H??5-Me
59??Me??H??H??H??3??-??H??H??6-MeO
60??Me??H??H??H??3??-??H??H??6-Me
61??Me??H??H??H??3??-??H??H??6-F
62??Me??H??H??H??3??-??Me??H??H
63??Me??H??H??H??3??＝??H??H??H
64??Me??H??H??H??3??-??H??Et??H
65??Me??7-Cl??H??H??3??-??H??H??H
66??Me??7-F??H??H??3??-??H??H??H
67??Me??8-F??H??H??3??-??H??H??H
68??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 of above-mentioned each compound is shown below
The compound spectroscopic data
51: 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 C27H32N61/4H20
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（1H，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 crystallization
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（6H，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（1H，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（1H，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（4H，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-C4H404）+
65: light yellowish pink crystallization
Fusing point: 203～209 ℃ (decomposition)
Ultimate analysis: in C26H29N6Cl0.9H20
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 the 4-(3-indyl with following compound) the piperidines, according to obtaining each compound with the same operation of embodiment 49.Obtain 69 with 1-((4-chloro-phenyl-) phenyl methyl) piperazine, with 1-(4-benzyl chloride base) piperazine obtains 70, with 1-(1-(1-ethoxyethyl group) benzimidazolyl-2 radicals-yl) piperazine obtains 71, with 1-(1-(1-ethoxyethyl group) benzimidazolyl-2 radicals-yl) high piperazine obtains 72, with 4-(1-(4-luorobenzyl) benzimidazolyl-2 radicals-amino) piperidines obtains 73, with 4-(hydroxy benzophenone base) piperidines gets 74, obtain 75 with 4-(hydroxyl two (4-fluorophenyl) methyl) piperidines, with 4-(phenylbenzene methoxy base) piperidines obtains 76, obtain 77 with 4-(two (4-fluorophenyl) methylene radical) piperidines, with 4-(5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 78, use the 4-(diphenyl methyl) piperidines obtains 79, use 4-(1,2-benzoisoxazole-3-yl) piperidines obtains 80, with 4-(2-ketone group-1-benzimidazoline base) piperidines obtains 81, 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, with 3-(phenylbenzene methylene radical) tetramethyleneimine obtains 85, use the 4-(2-p-methoxy-phenyl) piperazine obtains 86, use 4-(10,11-dihydro-5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 87, use 4-(6,11-dihydro-dibenzo (b, e) oxa-seven ring-11-subunits) piperidines obtains 88, with 4-(2-chlorine Thiaxanthene-9-subunit) piperidines obtains 89.
With 41 replace 18, with 4-(hydroxyl two (4-fluorophenyl) methyl) piperidines replacement 4-(3-indyl) piperidines obtains 90, with 41 replace 18, with 4-(two (4-fluorophenyl) methylene radical) piperidines replacement 4-(3-indyl) piperidines obtains 91, with 35 replace 18, with 4-(phenylbenzene methylene radical) piperidines replacement 4-(3-indyl) piperidines obtains 92, with 41 replace 18, with 4-(phenylbenzene methylene radical) piperidines replaces the 4-(3-indyl) piperidines obtains 93, with 37 replacements 18, with 4-(phenylbenzene methylene radical) piperidines replacement 4-(3-indyl) piperidines obtains 94.
Structural formula of compound
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) benzimidazolyl-2 radicals-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) (1,2,4) 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
The 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（1H，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（2H，m）.
MS：436（M+）
71: colourless non-crystalline state
Ultimate analysis: in C28H36N8 ⊙ 2C4H4O4
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（1H，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），2.65（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
-1：3406，2974，2880，1729，1611，1504，1125，752
73: white crystals
Fusing point: 139～146 ℃ (decomposition)
Ultimate analysis: in C32H35N8F1.5(C4H606H20)
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
-1：3320，1562，1504，1309，1267，748，681，487
74: faint yellow crystallization
Fusing point: 139～142 ℃
Ultimate analysis: in C31H35N5OC4H606H20
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
-1：3324，1562，1502，1433，1307，1265，1069，752，704，681
75: white crystals
Fusing point: 141～144 ℃ (decomposition)
Ultimate analysis: in C31H33N5OF2C4H606H20
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
-1：3322，1603，1506，1307，1265，1220，837，752，681，571
76: white crystals
Fusing point: 191～192 ℃
Ultimate analysis: in C31H35N5OC4H606H20
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
-1：3322，1678，1427，1307，1265，1067，681，485
77: 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（1H，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（5H，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
-1：2948，1611，1555，1508，1433，1352，1236，743
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＝7.1，1.5），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（2H，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 C25H29N7C4H404
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+）
83: 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＝7.1，1.5），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＝7.1Hz），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（1H，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 C30H31N5C4H404
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（2H，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（2H，m），1.85（2H，quint，J＝7.3）
MS：501（M+）
88: white crystals
Fusing point: 148～150 ℃
Ultimate analysis: in C32H33N5O1/2H20
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（2H，t，J＝6.8），2.77（3H，s），2.75-2.57（4H，m），2.40（4H，m），2.26（1H，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（1H，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 C32H33N5F2C4H404
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（KBr）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
-1：2930，1553，1502，1468，1429，1350，750，704
1HNMR（CDCl3）δ：7.46（1H，d，J＝7.8），7.29-7.25（4H，m），7.22-7.16（4H，m），7.12-7.10（3H，m），6.93（1H，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（10H，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＝7.3），1.62（6H，s）
MS：504（M+H）+
Embodiment 95
The 1-(3-chloropropyl)-4-benzoyl piperidines (95)
（95）
In the mixed solvent of forming by 200ml toluene, 64ml 25% aqueous sodium hydroxide solution, add 50.0g4-benzoyl group piperidine hydrochlorate, 69.5g1-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
The 1-(3-chloropropyl)-4-(hydroxyl (4-dimethylamino phenyl) phenyl methyl) piperidines (96)
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
The 1-(3-chloropropyl)-4-oxyethyl group carboxyl piperidines (97)
In the 250ml 2-butanone, add 26.1g isonipecotic acid ethyl ester, 52.5g1-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），2.58-1.61（11H，m），1.25（3H，t，J＝7.0）
Embodiment 98
The 1-(3-chloropropyl)-4-(hydroxyl two (4-dimethylamino phenyl) methyl) piperidines (98)
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.
Compd A r1 Ar2
99 3-tolyl Ph
100??3-MeO-Ph??Ph
101??3，4-（MeO）2Ph??Ph
102 2-Tolyl 2-tolyls
103??2-MeO-Ph??2-MeO-Ph
104??3，4-（MeO）2Ph??3，4-（MeO）2Ph
105 2-furyl 2-furyls
The 99:1-(3-chloropropyl)-4-(hydroxy phenyl (3-tolyl) methyl) piperidines
The 100:1-(3-chloropropyl)-4-(hydroxyl (3-p-methoxy-phenyl) phenmethyl) piperidines
The 101:1-(3-chloropropyl)-4-(hydroxyl (3, the 4-Dimethoxyphenyl) phenmethyl) piperidines
The 102:1-(3-chloropropyl)-4-(hydroxyl two (2-tolyl) methyl) piperidines
The 103:1-(3-chloropropyl)-4-(hydroxyl two (2-p-methoxy-phenyl) methyl) piperidines
The 104:1-(3-chloropropyl)-4-(hydroxyl two (3, the 4-Dimethoxyphenyl) methyl) piperidines
The 105:1-(3-chloropropyl)-4-(hydroxyl two (2-furyl) methyl) piperidines
Above compound has following physical parameter
The 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（2H，m），2.56-2.32（5H，m），2.13-1.38（9H，m）
MS：357（M+）
100: colorless oil
IR（Neat）cm
-1：3500，2950，2814，1736，1601，1489，1448，1251，1050，739，708
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: the 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（2H，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（2H，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（2H，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（2H，br.），2.31（1H，br.），2.04（4H，br.），1.55（4H，br.）
MS：323（M+）
Embodiment 106
The 1-(3-chloropropyl)-4-(phenyl (4-tolyl) methylene radical) piperidines (106)
In 5.3g4-(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
The 1-(3-chloropropyl)-4-(two (4-tolyl) methylene radical) piperidines (107)
At 6.37g4-(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（6H，s），1.98（2H，quint，J＝6.8）
MS：353（M+）
Embodiment 108
The 1-(3-chloropropyl)-4-(phenyl (3-tolyl) methylene radical) piperidines (108)
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, replace 4-(two (4-tolyl) methylene radical) piperidines to obtain 120 compounds with 4-(two (3-chloro-phenyl-) methylene radical) piperidines, 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 Ar2
109??3-MeO-Ph??Ph
110??3，4-（MeO）2-Ph??Ph
111 2-tolyl 2-tolyls
112??2-MeO-Ph??2-MeO-Ph
113??3，4-（MeO）2-Ph??3，4-（MeO）2-Ph
114??4-MeO-Ph??Ph
115??4-Cl-Ph??Ph
116??4-CF3-Ph??Ph
117??4-CF3-Ph??4-CF3-Ph
118??4-F-Ph??Ph
119??3-Cl-Ph??Ph
120??3-Cl-Ph??3-Cl-Ph
121??4-NMe2-Ph??Ph
122??4-NMe2-Ph??4-NMe2-Ph
123 2-furyl 2-furyls
124 2-pyridyl Ph
125 2-naphthyl Ph
The 109:1-(3-chloropropyl)-4-((3-p-methoxy-phenyl) phenylmethylene) piperidines
The 110:1-(3-chloropropyl)-4-((3, the 4-Dimethoxyphenyl) phenylmethylene) piperidines
The 111:1-(3-chloropropyl)-4-(two (2-tolyl) methylene radical) piperidines
The 112:1-(3-chloropropyl)-4-(two (2-p-methoxy-phenyl) methylene radical) piperidines
The 113:1-(3-chloropropyl)-4-(two (3, the 4-Dimethoxyphenyl) methylene radical) piperidines
The 114:1-(3-chloropropyl)-4-((4-p-methoxy-phenyl) phenylmethylene) piperidines
The 115:1-(3-chloropropyl)-4-((4-chloro-phenyl-) phenylmethylene) piperidines
The 116:1-(3-chloropropyl)-and 4-((4-(trifluoromethyl) phenyl) phenylmethylene) piperidines
The 117:1-(3-chloropropyl)-4-(two ((4-trifluoromethyl) phenyl) methylene radical) piperidines
The 118:1-(3-chloropropyl)-4-((4-fluorophenyl) phenylmethylene) piperidines
The 119:1-(3-chloropropyl)-4-((3-chloro-phenyl-) phenylmethylene) piperidines
The 120:1-(3-chloropropyl)-4-(two (3-chloro-phenyl-) methylene radical) piperidines
The 121:1-(3-chloropropyl)-4-((4-dimethylamino phenyl) phenylmethylene) piperidines
The 122:1-(3-chloropropyl)-4-(two (4-dimethylamino phenyl) methylene radical) piperidines
The 123:1-(3-chloropropyl)-4-(two (2-furyl) methylene radical) piperidines
The 124:1-(3-chloropropyl)-4-(phenyl (2-pyridyl) methylene radical) piperidines
The 125:1-(3-chloropropyl)-4-((2-naphthyl) phenylmethylene) piperidines
Above compound has following physical parameter
The compound spectroscopic data
109: colorless oil
IR（Neat）cm
-1：2958，2808，1597，1576，1431，1290，1251，1145，1051，756，704
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
1HNMR（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）cm
-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＝0.4），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（10H，m），1.93（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
1HNMR（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)
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，J＝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: C27H31N5.0S2
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
1HNMR（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: C25H29N50
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: C29H33N50S
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 Ar2
131??4-NMe2-Ph??Ph
132 3-tolyl Ph
133??3-MeO-Ph??Ph
134 3-tolyl 3-tolyls
135??3-MeO-Ph??3-MeO-Ph
136 2-tolyl 2-tolyls
137??2-MeO-Ph??2-MeO-Ph
138??3，4-（MeO）2-Ph??3，4-（MeO）2-Ph
139 2-furyl 2-furyls
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) triazolo (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（5H，m），6.91（1H，d，J＝7.4），6.86（1H，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（4H，m）
MS：523（M+）
134: white crystals
Fusing point: 198～200.5 ℃
Ultimate analysis: in C33H39N5O0.25(H20)
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＝7.8，1.5），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（1H，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＝7.8，1.2），7.21（2H，t，J＝7.8），7.20（1H，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.），2.40-1.50（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（1H，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（2H，dt，J＝7.9，1.2），5.23（1H，br.），4.41（2H，s），3.50（6H，s），3.39（2H，t，J＝6.7），2.97（2H，br.），2.88（1H，s），2.77（3H，s），2.39（2H，br.），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（4H，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)
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(H20)
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 141
4,5-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)
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(H20)
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（2H，s），3.79（3H，s），3.41（2H，t，J＝7.3），2.77（3H，s），2.55-2.38（10H，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, replacing 4-(phenylbenzene methylene radical with 4-(two (3-tolyl) methylene radical) piperidines) piperidines obtains 147, obtains 148 each compound with 4-(two (4-methoxyphenyl) methylenepiperidines replacement 4(phenylbenzene methylene radical) piperidines.
Compd A r1 Ar2
142??3，4-（MeO）2-Ph??Ph
143??3-MeO-Ph??3-MeO-Ph
144 2-tolyl 2-tolyls
145??2-MeO-Ph??2-MeO-Ph
146??3，4-（MeO）2-Ph??3，4-（MeO）2-Ph
147 3-tolyl 3-tolyls
148??4-MeO-Ph??4-MeO-Ph
149??4-Cl-Ph??Ph
150??4-Cl-Ph??4-Cl-Ph
151??4-CF3-Ph??Ph
152??4-CF3-Ph??4-CF3-Ph
153??4-F-Ph??Ph
154??3-Cl-Ph??Ph
155??3-Cl-Ph??3-Cl-Ph
156??4-NMe2-Ph??Ph
157??4-NMe2-Ph??4-NMe2-Ph
158 4-tolyl Ph
159 4-tolyl 4-tolyls
160 3-tolyl Ph
161 2-furyl 2-furyls
162 2-pyridyl Ph
163 2-naphthyl Ph
164 2-thienyl Ph
165 2-thienyl 2-thienyls
142:4,5-dihydro-1-methyl-5-(3-(4-((3, the 4-Dimethoxyphenyl) phenylmethylene) piperidines-1-yl) propyl group) (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
146:4,5-dihydro-1-methyl-5-(3-(4-(two (3, the 4-Dimethoxyphenyl) methylene radical) piperidines-1-yl) propyl group) (1,2,4) triazolo (4,3, 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.
The 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），2.51-2.39（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（3H，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(H20)
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(H20)
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(H20)
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(H20)
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 C31H31N5Cl2H20
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（CDCl3）δ：7.45（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(H20)
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(H20)
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（4H，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(H20)
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（2H，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(H20)
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，J＝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(H20)
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
mp：185～187℃
Ultimate analysis: in C29H31N5S0.25(H20)
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），7.33（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（3H，m），6.90（1H，t，J＝7.8），6.85（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：487（M+）
Embodiment 166
2-(3-methoxy propyl amino) oil of mirbane (166)
295g ortho position chloronitrobenzene and 417g3-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 167
2-(3-methoxy propyl amino)-and the 4-(trifluoromethyl) oil of mirbane (167)
Except using 2-chloro-4-(trifluoromethyl) oil of mirbane replaces 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 169
4-chloro-2-(3-methoxy propyl amino) oil of mirbane (169)
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 170
2-(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 171
2-(3-methoxy propyl amino)-and the 4-(trifluoromethyl) aniline (171)
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 172
2-(3-methoxy propyl amino)-4-monomethylaniline (172)
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 173
4-chloro-2-(3-methoxy propyl amino) aniline (173)
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 174
2-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 175
2-hydroxyl-1-(3-methoxy-propyl)-and the 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 176
2-hydroxyl-1-(3-methoxy-propyl)-6-tolimidazole (176)
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 177
6-chloro-2-hydroxyl-1-(3-methoxy-propyl) benzoglyoxaline (177)
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 178
2-chloro-1-(3-methoxy-propyl) benzoglyoxaline (178)
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 179
2-chloro-1-(3-methoxy-propyl)-and the 6-(trifluoromethyl) benzoglyoxaline (179)
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 180
2-chloro-1-(3-methoxy-propyl)-6-tolimidazole (180)
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 181
2,6-two chloro-1-(3-methoxy-propyls) benzoglyoxaline (181)
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 182
The 9-(3-methoxy-propyl)-3-methyl-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (182)
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 183
3-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 184
The 9-(3-methoxy-propyl)-3-propyl group-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (184)
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 185
The 9-(3-methoxy-propyl)-3-methyl-7-(trifluoromethyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (185)
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 186
3,7-dimethyl-9-(3-methoxy-propyl)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxalines (186)
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 187
7-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 188
2-chloro-3-(3-(4-(diphenyl methyl) piperazine-1-yl) propyl group) benzoglyoxaline (188)
With the 1.9g2-chloro benzimidazole, 4.3g1-(3-chloropropyl)-and the 4-(diphenyl methyl) piperazine is dissolved in the 40ml dimethyl formamide, adds 60% sodium hydroxide 0.78g while at room temperature stir, stirred 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 189
3-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 3.3g 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 190
2-chloro-3-(3-(4-(diphenyl methyl) piperazine-1-yl) ethyl) benzoglyoxaline (190)
With 0.81g2-chloro benzimidazole and 2.1g1-(2-chloromethyl)-the 4-(diphenyl methyl) piperazine hydrochloride is dissolved among the 20ml DMF, add the 0.46g60% 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 191
3-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) H20
Calculated value: C; 58.81, H; 5.43, N; 10.29
Measured value: C; 58.81, H; 5.48, N; 10.04
Embodiment 192
3-methyl-9-(3-(4-(3-indyl) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline fumaric acid (192)
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 ℃.With solution concentration do solid after, be dissolved in the 200ml dimethyl formamide, add the 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 C25H28N6C4H4041/2H20
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
Method according to same with embodiment 192 replaces the 4-(3-indyl with following compound) piperidines obtains compound separately.With 4-(5-chloro-3-indyl) piperidines obtains 195, with 4-(5-fluoro-3-indyl) piperidines obtains 196, with 4-(5-methyl-3-indyl) piperidines obtains 197, use the 4-(hydroxyl diphenyl methyl) piperidines obtains 198, obtain 199 with 4-(hydroxyl two (4-fluorophenyl) methyl) piperidines, with 4-(phenylbenzene methoxy base) piperidines obtains 200, with 4-(phenylbenzene methylene radical) piperidines obtains 201, obtain 202 with 4-(two (4-fluorophenyl) methylene radical) piperidines, with 4-(5H-dibenzo (a, d) suberene-5-subunit) piperidines obtains 206, use 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
193:3-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) suberene-5-subunit) piperidines-1-yl) propyl group)-9H (1,2,4) triazolo (4,3-a) benzoglyoxaline
207:3-methyl-9-(3-(4-(10,11-dihydro-5H-dibenzo (a, d) suberene-5-subunit) piperidines-1-yl) propyl group)-9H-(1,2,4) triazolo (4,3-a) benzoglyoxaline
The physics value of above-claimed cpd is as follows.
The compound spectral analysis data
193: colourless crystallization
mp：173～175℃
Ultimate analysis: in C26H30N61/2(C4H404H20)
Calculated value: C; 68.13, H; 7.14, N; 17.02
Measured value: C; 68.23, H; 7.05, N; 16.63
194: colourless crystallization
mp：150～152℃
Ultimate analysis: in C27H32N61/2C4H404H20
Calculated value: C; 67.42, H; 7.02, N; 16.27
Measured value: C; 67.98, H; 7.29, N; 15.68
195: colourless amorphous
mp：138～142℃
Ultimate analysis: in C25H27N6ClC4H4043/2H20
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; 5.54
196: 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 C26H30N61/2H20
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（5H，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 C30H33N5OC4H4043/4H20
Calculated value: C; 67.03, H; 6.37, N; 11.49
Measured value: C; 67.18, H; 6.40, N; 11.15
199: colourless amorphous
mp：130～136℃
Ultimate analysis: in C30H31N5OF2C4H404H20
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; 5.61
200: colourless crystallization
mp：119.5～121℃
Ultimate analysis: in C30H33N5OC4H4041/4H20
Calculated value: C; 68.04, H; 6.25, N; 11.67
Measured value: C; 67.86, H; 6.24, N; 11.65
201: colourless amorphous
mp：103～106℃
Ultimate analysis: in C30H31N5C4H4043/4H20
Calculated value: C; 69.08, H; 6.22, N; 11.85
Measured value: C; 69.01, H; 6.16, N; 11.55
202: 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（2H，t，J＝6.5），2.90（2H，m），2.83（4H，m），2.42（2H，t，J＝6.6），2.19（2H，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（2H，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 C25H27N6Cl1/4H20
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 C32H31N5H20
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（2H，m），2.36（6H，m），2.13（4H，m）
MS：488（M+H）+
Embodiment 208
The 5-(3-methoxy-propyl)-1H-(1,5) benzodiazepine
-2,4(3H, 5H)-diketone (208)
The solution of 8ml propanedioic acid dichloride and 90ml orthodichlorobenzene in 60 ℃ of processes that stir down, was divided in 32 minutes and adds 12.7g N-(3-methoxy-propyl several times)-solution of O-Phenylene Diamine and 10ml 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（1H，m），3.26（1H，m），3.19（3H，s），1.87（1H，m），1.77（1H，m）
Embodiment 209
The 5-(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 210
5-(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 2.6g1-((4-chloro-phenyl-) phenyl methyl) piperazine and 2.2g salt of wormwood, add the 25ml dimethyl formamide, stirred 4 hours down at 100 ℃.Add 0.35g1-((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 211
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
-5(6H)-ketone (211)
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 3.4g5-(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 reflux divide five times on one side to add the 1.7g acethydrazide, 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
-1：2814，1682，1506，1427，1011，760
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 212
1-methyl-6-(3-methoxy-propyl)-4H (1,2,4) triazolo (4,3-a) (1,5) benzodiazepine
-5(6H)-ketone (212)
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 213
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
-5(6H)-ketone (211)
In the compound of 0.23g embodiment 212, add 2ml47% 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, 0.29g1-((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 214
5,6-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)
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 215
5,6-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
Fumarate (214)
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 C31H35N6ClC4H404
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 216
3-(4,5-dihydro-1-methyl-(1,2,4) triazolo (4,3-a) quinoxaline-5-yl) methyl propionate
The 10ml DMF solution of 3.75g t-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 14ml DMF solution of 4.51g3-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 1.79g 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 217
3-(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（2H，s），3.75（2H，t，J＝6.38），2.76（3H，s），2.72（2H，t，J＝6.38）
Embodiment 218
5-(3-bromo propyl group)-4,5-dihydro-1-methyl (1,2,4) triazolo (4,3-a) quinoxaline
The compound of 1.51g embodiment 216 is dissolved in the 20ml dry tetrahydrofuran, be cooled to 0 ℃ after, add 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
-11502，1431，750
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, the PAF antagonistic action of the compound represented by formula I and anti-allergy reactivity etc. are illustrated.
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 1gE (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%Evans blue 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
Inhibiting rate (%)
The anti-PCA antihistamine of 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) centrifugations 20 minutes, is taked the PRP on upper strata in other plastics tubing.Residual lower floor uses 1500 * g(2800rpm) centrifugations 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, 37 ℃ stir 2 minutes down after, add PAF(ultimate density 10ng/ml) bring 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??5.4
53??1.8??63??4.4
64??1.6??65??2.0
66??1.9??73??4.5
75??0.21??77??0.072
78??2.4??80??0.044
81??0.6??85??1.4
86??2.2??87??3.1
88??0.86??90??0.56
92??0.66??127??0.23
128??1.7??129??0.17
130??0.32??131??0.13
132??0.036??133??0.063
134??0.051??135??0.88
138??0.81??140??0.24
142??0.51??143??0.22
145??0.91??147??0.087
148??0.32??149??0.55
150??0.51??151??0.76
154??0.19??155??1.2
156??0.58??160??0.071
161??0.54??163??0.32
164??0.36??165??0.74
189??0.31??193??0.84
194??0.045??195??0.14
196??0.013??197??0.025
198??0.074??199??0.12
200??0.023??201??0.16
205??2.3??206??2.1
214??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 tritium-labeled 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.
Encumber rate (%)={ 1-(((binding capacity-non-specific binding capacity under the compound existence))/((full binding capacity-non-specific binding capacity))) } * 100
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 to open clear 65-176591 number in contrast) make antagonistic.
Table 3
Receptors bind encumbers receptors bind and encumbers
Compound number IC50(μ g/ml) compound number IC50(μ g/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??0.99
127??0.077??128??0.63
129??0.17??130??0.070
131??0.045??132??0.026
133??0.017??134??0.005
135??0.021??138??0.72
140??0.006??142??0.087
143??0.040??145??0.22
147??0.034??148??0.029
149??0.105??150??0.083
151??0.060??154??0.091
155??0.072??156??0.029
160??0.097??161??0.16
163??0.18??164??0.12
165??0.40??189??0.14
191??3.2??192??0.69
193??2.9??194??1.1
195??0.11??196??0.24
197??0.032??198??0.21
199??0.035??200??0.03
201??0.17??205??1.3
206??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 of manipulating CHISTIMAI 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, compare by back/preceding value with control group (clothes sweet oil group), estimate and suppress having or not of effect, the results are shown in table 4, medicine uses disclosed WEB2086 as the PAF antagonistic in contrast.
Table 4
Compound number dosage (mg/Kg) back/preceding
Contrast 0.57
46??0.3??1.64
46??0.1??1.14
52??1??1.37
73??1??1.18
192??1??1.81
WEB2086??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 (14)
1, the salt that the 3 ring triazolo derivatives of representing with formula I, and pharmacology are allowed
[in the formula, R
1Represent the cycloalkyl of hydrogen, low alkyl group or carbon number 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 a straight chain shape or a saturated or undersaturated alkylidene group of catenate of carbon number 1～5, also can contain heteroatoms.1 represents 0～2, and n represents 1～3,
Represent singly-bound or two key, Y represents N or C, and 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
2Above-mentioned identical), O-CHAr
1Ar
2(Ar
1, Ar
2Same as described above), the condensation aromatic nucleus.]
2, according to claim 1,3 ring triazolo derivatives wherein, and the pharmacology salt of allowing, with formula (Ia) expression,
(in the formula, R
1, R
2, R
3, l, n, Y,
And Z represents 1～4 as above-mentioned, m) integer).
3, the salt of allowing on three ring triazolo derivatives and the pharmacology thereof according to claim 1 or 2 records, wherein following formula (I) or (Ia) in the condensation aromatic nucleus of Z by choosing in the following replacement basic group,
(wherein, R
6Representative replaces or unsubstituted aralkyl or alkoxyalkyl, and P represents 0 or 1, R
7, R
8Represent hydrogen or low alkyl group respectively, R
9Represent hydrogen, low alkyl group, lower alkoxy or halogen,
Represent singly-bound or two key).
4, the dihydro triazolo quinoxaline derivatives of representing with formula (II),
(in the formula, R
1, R
2, R
3, R
4And R
5Same as described above, J be hydrogen or-A-B(wherein: B represent halogen ,-OR
10(R wherein
10Represent the protecting group of alcohol) or-CO
2L(wherein L represents hydrogen or low alkyl group), A is same as described above).
5, the manufacture method of the triazolo derivative of following formula (I) expression wherein is to make by the compound of formula (III) expression and the compound of formula (IV) expression to react,
(R in the formula
1, R
2, R
3, R
10, A, W and l be same as described above)
(Y, Z, n reach in the formula
Same as described above).
6, the manufacture method of the triazolo derivative of following formula (I) expression wherein is that the compound that the compound represented by formula V and formula (VI) are represented reacts,
(R in the formula
1, R
2, R
3, W and l be same as described above,
(in the formula X represent halogen, A, Y, Z, n and
Same as described above.
7, the manufacture method of the triazolo derivative of following formula (I) expression wherein is to make by the compound of formula (VII) expression and the compound of formula (VIII) expression to react,
(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,
Same as described above)
(R in the formula
1Same as described above).
8, the manufacture method of the triazolo derivative of following formula (I) expression, it wherein is the compound that the usefulness formula (IX) that the compound of above-mentioned formula (VII) expression and hydrazine reaction obtain is represented, react with it and with the compound of formula (X) expression or the compound of representing with (XI) again
(R in the formula
2, R
3, A, W, Y, Z, l, n,
Same as described above)
(R in the formula
12Represent low alkyl group, R
1Same as described above)
(R in the formula
1Same as described above).
9, the manufacture method of new triazolo derivative (Ib) wherein is that the compound that formula (XII) is represented is reduced and obtains,
(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,
Same as described above)
(R in the formula
1, R
2, R
3, A, G, Y, Z, n, q,
Same as described above).
10, the manufacture method of triazolo derivative (Ic) wherein is the compound with formula (XIII) or formula (XIV) expression, with the compound reaction of formula (XV) or formula (XVI) expression, and obtains,
(R in the formula
13Represent low alkyl group, R
1, R
2, R
3, A, W, l, n be same as described above)
(Ar in the formula
1, R
1, R
2, R
3, A, W, l, n be same as described above)
Ar??MgX（XV）
(X represents halogen atom in the formula, and Ar represents Ar
1And/or Ar
2, Ar
1, Ar
2Same as described above)
Ar??Li（XVI）
(Ar represents Ar in the formula
1And/or Ar
2, Ar
1, Ar
2Same as described above)
(Ar in the formula
1, Ar
2, R
1, R
2, R
3, A, W, l, n be same as described above).
11, the manufacture method of triazolo derivative (Id) wherein is the compound dehydration with above-mentioned formula (Ic) expression, obtains the triazolo derivative of formula (Id) expression,
(Ar in the formula
1, Ar
2, R
1, R
2, R
3, A, W, l, n be same as described above)
12, a kind of anti-inflammatory agent wherein is that salt that derivative or its pharmacology of each record of claim 1 to 3 are allowed is as effective ingredient.
13, a kind of anti-allergy agent wherein is as effective ingredient with the derivative of each record of claim 1 to 3 or salt that its pharmacology is allowed.
14, a kind of anti-PAF agent wherein is as effective ingredient with the derivative of each record of claim 1 to 3 or salt that its pharmacology is allowed.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP91961/91 | 1991-04-23 | ||
| JP9196191 | 1991-04-23 | ||
| JP14880491 | 1991-06-20 | ||
| JP148804/91 | 1991-06-20 | ||
| JP327541/91 | 1991-12-11 | ||
| JP5741/92 | 1992-01-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1066849A true CN1066849A (en) | 1992-12-09 |
| CN1033327C CN1033327C (en) | 1996-11-20 |
Family
ID=26433388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92103991 Expired - Fee Related CN1033327C (en) | 1991-04-23 | 1992-04-23 | Process for preparing tricyclotriazolo derivatives and their use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1033327C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068201C (en) * | 1992-10-20 | 2001-07-11 | 东丽株式会社 | Inhibitor of intiltration of acidophilic leukocyte |
| CN103619846A (en) * | 2011-06-27 | 2014-03-05 | 詹森药业有限公司 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives |
| US9669035B2 (en) | 2012-06-26 | 2017-06-06 | Janssen Pharmaceutica Nv | Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders |
| CN117050219A (en) * | 2023-09-27 | 2023-11-14 | 桂林理工大学 | Preparation method and application of pyridocycloheptane imine iron complex catalyst |
| TWI913356B (en) | 2020-11-16 | 2026-02-01 | 德商百靈佳殷格翰國際股份有限公司 | Cyclopentathiophene carboxamide derivatives as platelet activating factor receptor antagonists |
-
1992
- 1992-04-23 CN CN 92103991 patent/CN1033327C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1068201C (en) * | 1992-10-20 | 2001-07-11 | 东丽株式会社 | Inhibitor of intiltration of acidophilic leukocyte |
| CN103619846A (en) * | 2011-06-27 | 2014-03-05 | 詹森药业有限公司 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives |
| CN103619846B (en) * | 2011-06-27 | 2016-08-17 | 詹森药业有限公司 | 1-aryl-4-methyl-[1,2,4] triazole [4,3-a] quinoxaline derivant |
| US10604523B2 (en) | 2011-06-27 | 2020-03-31 | Janssen Pharmaceutica Nv | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives |
| US9669035B2 (en) | 2012-06-26 | 2017-06-06 | Janssen Pharmaceutica Nv | Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders |
| TWI913356B (en) | 2020-11-16 | 2026-02-01 | 德商百靈佳殷格翰國際股份有限公司 | Cyclopentathiophene carboxamide derivatives as platelet activating factor receptor antagonists |
| CN117050219A (en) * | 2023-09-27 | 2023-11-14 | 桂林理工大学 | Preparation method and application of pyridocycloheptane imine iron complex catalyst |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1033327C (en) | 1996-11-20 |
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