CN103980289A - Thieno-thiopyrano pyrazole compound and pharmaceutical applications thereof - Google Patents

Thieno-thiopyrano pyrazole compound and pharmaceutical applications thereof Download PDF

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CN103980289A
CN103980289A CN201410213758.3A CN201410213758A CN103980289A CN 103980289 A CN103980289 A CN 103980289A CN 201410213758 A CN201410213758 A CN 201410213758A CN 103980289 A CN103980289 A CN 103980289A
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dihydro
pyrazoles
carbonyl
thiapyran
thiophene
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CN103980289B (en
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胡春
王欣
金辄
刘晓平
黄二芳
孙蕊
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Abstract

The invention belongs to the field of medical technologies, and relates to a thieno-thiopyrano pyrazole compound and pharmaceutical applications thereof. The thieno-thiopyrano pyrazole compound comprises derivatives of the thieno-thiopyrano pyrazole compound and pharmaceutical applicable salts. The thieno-thiopyrano pyrazole compound and salts added by pharmaceutically applicable acids of the compound can be combined with existing drugs or used alone as a lipoxygenase inhibitor, and used for treating related diseases such as chronic dull pains including inflammations, gout, headache, toothache, neuralgia and arthralgia which are relevant to an arachidonic acid metabolizing process.

Description

Thieno-thiapyran pyrazole compound and medical applications thereof
Technical field
The invention belongs to medical technical field, relate to thieno-thiapyran pyrazole compound and as lipoxidase inhibitor application, and preparation method thereof.
Background technology
Inflammation is that body causes tissue injury to various inflammatory stimulus and a kind of basic pathology process of producing, be also body to a kind of defense mechanism infecting, inflammation main manifestations is redness, pain etc.
For the treatment of inflammation, be once widely used in early days glucocorticosteroid AID, also obtained the effect attracting people's attention, but glucocorticoid medicine life-time service can produce dependency, and easily cause the side effects such as adrenal cortex function decline.From 50～sixties of 20th century, occur after the medicines such as Phenylbutazone (Phenylbutazone), indomethacin (Indomethacin) and Ibuprofen BP/EP (Ibuprofen), NSAID (non-steroidal anti-inflammatory drug) (Nonsteroidal Antiinflammatory Drugs, NSAIDs) cause people's concern, and become gradually the emphasis of antiphlogiston research and development.Early 1970s, the mechanism of action that it is found that NSAID (non-steroidal anti-inflammatory drug) is by suppressing cyclooxygenase (Cycloxygenase, COX) or lipoxygenase (Lipoxygenase, LOX) thus the pathways metabolism that suppresses arachidonic acid (Arachidonic Acid, AA) reaches the object of anti-inflammatory.
Inflammation is a complex process, and many factors all can generate " inflammation-causing substance ", and wherein a kind of mechanism is relevant with arachidonic metabolic process.When cytolemma irriate, by phospholipase A 2hydrolysis discharges arachidonic acid with Phospholipase C catalysis cell membrane phospholipid, and arachidonic internal metabolism plays an important role in inflammatory process.Arachidonic acid through discharging can further complete bio-transformation by two approach: (1), under the catalysis at cyclooxygenase, oxidative metabolism becomes prostaglandin(PG) (Prostaglandins, PG) and thromboxane (Thromboxanes, TX) etc.; (2) under the catalysis of lipoxygenase, generate leukotriene (Leukotrienes, LT).Between the meta-bolites of cyclooxygenase and lipoxygenase catalysis, exist certain balance restricting relation, the simple wherein pathways metabolism that suppresses will cause that arachidonic acid enters other pathways metabolisms, thereby cause further developing of inflammation.Since arachidonic acid can produce inflammation-causing substance by cyclooxygenase and two pathways metabolism metabolism of lipoxygenase, the inhibitor of design to cyclooxygenase and lipoxygenase double blocking, to greatly improve anti-inflammatory activity and reduce side effect, therefore to have the inhibitor of double blocking effect be one of focus direction of current antiphlogiston research in exploitation.
Summary of the invention
Technical problem solved by the invention be to provide a kind of suc as formula the compound shown in I or II, its prodrug and pharmaceutical activity metabolite with and pharmacy acceptable salt, and provide its application in the medicine of the preparation prevention disease relevant with treatment lipoxygenase.
The present invention is achieved through the following technical solutions:
Compound involved in the present invention is:
Wherein
N is the natural numbers such as 1,2; Preferably 1,2;
R 1can be H or halogen;
R 2it can be hydrogen or halogen;
R 3for arbitrarily selectively by 1,2 or 3 independently selected from H, halogen ,-OCH 3,-CH 3,-CF 3,-OCF 3the phenyl ring replacing, diphenyl-methyl, 4-chlorobenzhydryl, benzyl;
R 4, R 5respectively independently selected from hydrogen, methyl, ethyl, the tertiary butyl, sec.-propyl, N, N-diethyl, phenyl, furfuryl, benzyl, or R 2, R 3together with the nitrogen-atoms connected with them, form pyrrolidyl, piperidyl, N-methyl piperidine base, morpholinyl, hexamethylene imine basic ring.
The present invention also provides general formula (I) or (II) the described compound application in the medicine of the preparation prevention disease relevant with treatment lipoxygenase.
The present invention be also preferably as follows compound, its prodrug and pharmaceutical activity metabolite with and pharmacy acceptable salt:
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-aminomethyl phenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(diphenyl methyl) piperazine;
N, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-diethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(the chloro-4-fluorophenyl of 3-) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-chloro-phenyl-) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-Trifluoromethoxyphen-l) piperazine; 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-fluorophenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-trimethoxyphenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-phenylpiperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-fluorophenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-methylpiperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-benzyl diethylenediamine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-[(4-chloro-phenyl-) (phenyl) methyl] piperazine;
Bromo-Isosorbide-5-Nitrae-the dihydro-thiophene of the N-tertiary butyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3-bromophenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-ethoxyl phenenyl) piperazine;
4-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) morpholine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) tetramethyleneimine;
Bromo-Isosorbide-5-Nitrae-the dihydro-thiophene of N-sec.-propyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
Bromo-Isosorbide-5-Nitrae-the dihydro-thiophene of N-(2-diethylin) ethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
N, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-dimethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
Bromo-Isosorbide-5-Nitrae-the dihydro-thiophene of N-phenyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also; 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) piperidines;
Bromo-Isosorbide-5-Nitrae-the dihydro-thiophene of N – benzyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
N – (furans-2-methylene) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
N – (pyridine-2-yl) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3,5-, bis-trifluoromethyls) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3,4-difluorophenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-aminomethyl phenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-chloro-phenyl-) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2,5-3,5-dimethylphenyl) piperazine;
1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3-trifluoromethyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(diphenyl-methyl phenyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-chloro-phenyl-) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-[(4-chloro-phenyl-) (phenyl) methyl] piperazine;
The N-tertiary butyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-methylpiperazine;
N, N-diethyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-aminomethyl phenyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-phenylpiperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-Trifluoromethoxyphen-l) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-Trifluoromethoxyphen-l) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-benzyl diethylenediamine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-p-methoxy-phenyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3-trifluoromethyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3-bromophenyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3,4-difluorophenyl) piperazine;
N, N-dimethyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) tetramethyleneimine;
N-sec.-propyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
N-benzyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
N-phenyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
4-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) morpholine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) piperidines;
N-(furans-2-methylene)-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides also;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(the chloro-4-fluorophenyl of 3-) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-aminomethyl phenyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3,5-, bis-trifluoromethyls) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-fluorophenyl) piperazine;
1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-chloro-phenyl-) piperazine;
The N – tertiary butyl-7, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-is [3', 2':5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also;
N, N – dimethyl-7, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-is [3', 2':5,6] thiapyran [4,3-c] pyrazoles-3-acid amides also also.
" the acceptable salt of medicine " has referred to retain biopotency and the character of formula I, II compound, and the conventional acid additive salt or the base addition salt that form with suitable non-toxicity organic or inorganic acid or organic or inorganic alkali.The example of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cipionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrogen chlorate, hydrobromate, hydriodate, 2-isethionate, lactic acid salt, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecylate.Alkali salt comprises ammonium salt, an alkali metal salt, for example sodium and sylvite, alkaline earth salt, for example calcium and magnesium salts, the salt of organic bases, dicyclohexyl amine salt for example, N-methyl-D-glucamine salt, and amino acid whose salt, arginine for example, Methionin etc., and, alkalescence nitrogen-containing group can be quaternized with such reagent, and elementary alkyl halide for example, as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; Sulfuric acid dialkyl, as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide, as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide, as bromide of benzyl and styroyl etc.The acid that is preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable " as pharmaceutically acceptable carrier, excipient, prodrug etc., refers to acceptable on pharmacology and to the essentially no toxicity of the patient of administration particular compound.
" pharmaceutical active metabolite " refers to the meta-bolites of pharmaceutically acceptable and effective formula I, II compound.
The present invention also relates to the medicinal compositions of lipoxygenase inhibitor, said composition contains patent protection compound or derivative or its pharmaceutically applicable acid salt and applicable carrier pharmaceutically.
The term of applying in the present invention " halogen " comprises chlorine, bromine or fluorine.
" replacement ", unless otherwise indicated, refers to that substituting group can exist in one or more positions, and substituting group is independently selected from option particularly.
The compounds of this invention can be taken to patient by diverse ways, for example oral with capsule or tablet, with sterile solution agent or suspensoid administration, and in some cases, can be with the intravenous injection of solution form.Can by free alkali compound of the present invention with its pharmaceutically applicable acid salt form prepare and take.
Compound of the present invention is as the lipoxidase inhibitor of brand new type, can suppress cyclooxygenase-2 activity simultaneously, by block the formation of inflammatory mediator Prostaglandins and Leukotrienes simultaneously, produce collaborative anti-inflammatory action, there is structure type novelty, drug action and existing medicine are quite or be better than the feature of existing medicine, can be used for the chronic dull pains such as treatment or preventing inflammation, gout, headache, toothache, neurodynia and arthrodynia, there is good using value and development prospect.
Embodiment
Flow process 1 has been summarized the synthesis step of preparing the compounds of this invention.
With following example, describe the present invention in detail.But, it should be understood that the following example that the invention is not restricted to concrete narration.
The preparation of embodiment 1:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-aminomethyl phenyl) piperazine (compound number 01)
Steps A: the preparation of 5,6-dihydro-4H-thieno-[2,3-b] thiapyran-4-ketone
4.64g (0.04mol) 2-mercapto-thiophene is added in 80mL tetrahydrofuran (THF), stir the lower 11mL of dropping triethylamine, 3.3mL vinylformic acid, reflux 12h.Slightly cold rear steaming is except tetrahydrofuran (THF).Add 40mL ethyl acetate and 20mL water, add 6mol/L hydrochloric acid to be adjusted to pH=2, collected organic layer.Water is extracted with ethyl acetate, and merges organic phase, anhydrous magnesium sulfate drying.Suction filtration, concentrated, obtain brown oil.Sherwood oil recrystallization obtains white needles solid 6.02g, yield 80.0%, m.p.:43-45 ℃.
3.76g (0.02mol) 3-(thiophene-2-sulfenyl) propionic acid is added in 20mL methylene dichloride, splash into 2 DMF, under nitrogen protection, drip the dichloromethane solution (16mL) of oxalyl chloride (2.2mL), stirring at room 1h.Cryosel is bathed cooling reaction solution to-10 ℃, stirs the lower dichloromethane solution (10mL) that drips tin tetrachloride (1.15mL).After dropping finishes, stir 0.5h at 0 ℃.Add 20mL water, extract organic phase, water washed with dichloromethane, merges organic phase.Successively with saturated solution of sodium carbonate, water and sodium chloride saturated solution washing, anhydrous magnesium sulfate drying.Suction filtration, after concentrated, dry yellow solid.Sherwood oil recrystallization obtains white needles solid 2.59g, yield 76.2%, m.p.:59.0-60.5 ℃.
The preparation of step B:2-oxo-2-(4-oxo-5,6-dihydro-4H-thieno-[2,3-b] thiapyran-5-yl) methyl acetate
Sodium Metal 99.5 (0.46g) is added in 20mL anhydrous methanol, be stirred to sodium solids disappeared, the concentrated methyl alcohol of removing obtains white sodium methylate.In sodium methylate, add dimethyl oxalate (2.36g, 0.02mol), toluene (20mL), 5,6-dihydro-4H-thieno-[2,3-b] thiapyran-4-ketone (1.70g, 0.01mol), after stirring at room 24h, reaction solution is poured in about 100mL frozen water, extracted water.20mL10% sodium hydroxide solution extraction for organic phase.Merge water, with anhydrous diethyl ether washing 3 times, with 6mol/L hydrochloric acid, adjust pH to 1, separate out yellow solid, suction filtration, dry, obtain yellow solid 2.0g, yield 79.8%, m.p.:93.5-95.2 ℃.
The also also preparation of [4,3-c] pyrazoles-3-first carboxylate methyl ester of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of step C:7-
2-oxo-2-(4-oxo-5,6-dihydro-4H-thieno-[2,3-b] thiapyran-5-yl) methyl acetate (0.51g, 2mmol) is added in 10mL Glacial acetic acid, add while stirring hydrazine hydrate (2mL, 3.2mmol), reflux 12h.Under cooling rear stirring, reaction solution is poured in 200mL frozen water, separated out white solid, suction filtration obtains white solid.Glacial acetic acid-aqueous solution recrystallization obtains white solid 0.32g, yield 63.2%, m.p.:94.0-95.7 ℃.
In 100mL round-bottomed flask, add 1,4-dihydro-thiophene is [3' also, 2':5,6] thiapyran [4,3-c] pyrazoles-3-carboxylate methyl ester (2.52g, 0.01mol) also, 50mL Glacial acetic acid and 5mL water, under ice bath cooling and stirring, drip bromine (2.08g, 0.013mol), drip and finish rear room temperature reaction 24h.Reaction solution is poured in 200mL frozen water, separated out white solid, suction filtration, obtains white solid 2.52g, yield 76.0%.
The also also preparation of [4,3-c] pyrazoles-3-carboxylic acid of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of step D:7-
In 100mL round-bottomed flask, add also also [4,3-c] pyrazoles-3-carboxylate methyl ester, 20mL water and 0.4g sodium hydroxide of [3', 2':5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 0.62g (2mmol) 1-, reflux 2h.Reaction solution is adjusted pH to 2 with 18% hydrochloric acid, separates out white solid, and suction filtration obtains white solid 0.57g, yield 90.0%.
Step e: 4,5,6,7-tetramethylene sulfide is the preparation of [2,3-b] thia-4-ketone also
By adding in 120mL dehydrated alcohol under sodium (3.34g, 0.145mol) room temperature, cooling after sodium completely dissolve, add 2-mercapto-thiophene (9.8g, 0.1mol), under room temperature condition, stir 30min left and right, the dimmed redness of reaction solution.Add-butyrolactone (11.53mL, 0.15mol), the about 19h of reflux under nitrogen protection, reaction solution becomes sticky thick.By product underpressure distillation, remove ethanol.With about 100mL sherwood oil, ethyl acetate (V:V=3:1) washing remaining solid.Solid after washing is added in cooling 1N hydrochloric acid, and bottom is separated out garnet oily matter, is extracted with ethyl acetate and with saturated sodium-chloride water solution, washs organic layer afterwards, uses anhydrous magnesium sulfate drying.Filter, concentrate, obtain brown oil.Sherwood oil recrystallization, obtains white crystal 8.08g, yield 40.0%.m.p.:40-42℃。
To the methylene dichloride that adds 4-(thiophene-2-sulfenyl) butyric acid (4.04g, 0.02mol) and 25mL in 250ml three-necked bottle.Under nitrogen protection, drip the dichloromethane solution (25mL) of oxalyl chloride (5.4mL, 0.06mol), the thin out yellow-green colour of reaction solution, drips and stirs 2h.Under nitrogen protection and condition of ice bath, slowly drip the dichloromethane solution (20ml) of tin tetrachloride (2.3mL, 0.02mol), it is blackish green that reaction solution is.Under room temperature condition, stir 24h.Add 50ml hydrochloric acid (V:V=1:1), be stirred to not till having gas to emit.Washing organic layer, becomes orange-yellow to the nearly neutral organic layer of pH.With saturated NaCl solution washing organic layer, anhydrous magnesium sulfate drying.Filter, concentrate to obtain yellow oil.Sherwood oil recrystallization obtains white crystal 0.92g, yield 25%.m.p.:60-62℃。
Step F: the also preparation of [4,5-c] pyrazoles-3-carboxylic acid of 4,5-dihydro-3aH-thieno-[2', 3':2,3] thia
Sodium (0.46g, 0.02mol) is added in anhydrous methanol (20mL), be stirred to sodium solids disappeared, concentrate and obtain white sodium methylate.In sodium methylate, add dimethyl oxalate (2.36g, 0.02mol), 4,5,6,7-tetramethylene sulfide is [2,3-b] thia-5-ketone (1.84g, 0.01mol) and toluene (20mL) also, stirring at room 40h.Reaction solution is poured in the frozen water of about 100mL, water intaking layer, the NaOH aqueous solution extraction organic layer with 10%, combining water layer.Water layer washs with ether.18% hydrochloric acid is adjusted to pH=2, obtains yellow turbid liquid.Cooling standing, separate out red oil, sherwood oil recrystallization obtains red powder 1.62g, yield 60.0%.
(4-oxo-4,5,6,7-tetramethylene sulfide is [2,3-b] thia-5-yl also) acetonic acid methyl esters (0.54g, 2.0mmol) is added in 10mL glacial acetic acid, then add hydrazine hydrate (2mL, 0.032mol), reflux 3h.Reaction solution is poured in frozen water (50g), separated out yellow solid, filter, dry, obtain buff powder 0.40g, yield 75.0%.m.p.:98-100℃。
In 100mL round-bottomed flask, add 4,5-dihydro-3aH-thieno-[2', 3':2,3] thia also [4,5-c] pyrazoles-3-carboxylate methyl ester (5.32g, 20mmol), 300mL water and sodium hydroxide (1g, 25mmol), reflux 2h.Reaction solution is adjusted pH to 2 with 18% hydrochloric acid, separates out white solid, and suction filtration, dry, obtains white solid 4.54g, yield 90.0%.The preparation of step G:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(4-aminomethyl phenyl) piperazine
Logical method: add 7-bromo-1 in the round-bottomed flask of 50mL, 4-dihydro-thiophene is [3' also, 2':5, 6] thiapyran also [4, 3-c] pyrazoles-3-formic acid or 4, 5-dihydro-3aH-thieno-[2', 3':2, 3] thia also [4, 5-c] pyrazoles-3-carboxylic acid (4mmol), 1-substituted-piperazinyl hydrochloride (4.2mmol) or other replacement amine (4.2mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1g, 5mmol), I-hydroxybenzotriazole (0.1g, 0.74mmol) add in 20mL dry methylene chloride, drip 2mL triethylamine, stirring at room 48h, filter, filtrate is used 18% hydrochloric acid successively, saturated sodium carbonate and saturated sodium-chloride water washing.Extract organic phase, anhydrous magnesium sulfate drying.Filter, concentrated, obtain crude product, through the separated (sherwood oil: ethyl acetate=5:1) obtain target compound of silica gel column chromatography.
Synthetic by logical method, obtain white solid 0.77g, yield 35%.m.p.:175-176℃；IR(KBr,cm -1):3420,2921,2851,1607,1451,1384,1262,1154,1027,997,877,831,705； 1H-NMR(600MHz,CDCl 3):2.44(4H,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.19(2H,d,J＝8.4Hz),7.28(4H,dd,J＝7.2Hz,8.4Hz),7.41(4H,d,J＝7.2Hz)；ESI-MS(m/z):551.2[M+H] +。
The preparation of embodiment 2:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(diphenyl methyl) piperazine (compound number 02)
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(diphenyl methyl) piperazine 0.77g, yield 35%.m.p.:175-176℃；IR(KBr,cm -1):3420,2921,2851,1607,1451,1384,1262,1154,1027,997,877,831,705； 1H-NMR(600MHz,CDCl 3):δ2.44(4H,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.19(2H,d,J＝8.4Hz),7.28(4H,dd,J＝7.2Hz,8.4Hz),7.41(4H,d,J＝7.2Hz)；ESI-MS(m/z):551.2[M+H] +。
Embodiment 3:N, the also also preparation of [4,3-c] pyrazoles-3-acid amides (compound number 03) of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-diethyl-7-
Method according to example 1, makes N, and the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-diethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 03) 0.75g also also, yield 50%.m.p.:147-148℃；IR(KBr,cm -1):3212,2958,2917,2849,1735,1583,1535,1508,1485,1461,1375,1215,1159,967,849；? 1H-NMR(600MHz,CDCl 3):δ1.25(6H,m),3.54(4H,m),4.12(2H,s),7.72(1H,s)；ESI-MS(m/z):372.0,374.0[M+H] +。
The preparation of embodiment 4:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(the chloro-4-fluorophenyl of 3-) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-formyl radical)-4-(the chloro-4-fluorophenyl of 3-) piperazine (compound number 04) 0.72g, yield 36%.m.p.:120℃；IR(KBr,cm -1):3233,2924,2853,1745,1609,1586,1502,1464,1382,1223,1154,998； 1H-NMR(600MHz,CDCl 3):δ3.16(4H,t,J＝6.0Hz),3.95(4H,t,J＝6.0Hz),4.26(2H,s),6.79(1H,m),6.95(1H,dd,J＝6.3Hz,J＝2.4Hz),7.05(1H,dd,J＝8.7Hz,J＝9Hz),7.25(1H,s)；ESI-MS(m/z):512.8,514.9,517.0[M+H] +。
The preparation of embodiment 5:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-chloro-phenyl-) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-chloro-phenyl-) piperazine (compound number 05) 0.50g, yield 25%.m.p.:235℃；IR(KBr,cm -1):3159.9,2918.2,2849.7,1740.4,1590.8,1496.6,1480.7,1441.4,1387.7,1234.2,120.6,1151.0,998.1,810.2； 1H-NMR(600MHz,DMSO-d 6):δ3.10(4H,m),3.51(4H,m),4.26(2H,s),7.21(1H,s),7.56(2H,d,J＝5.4Hz),7.58(2H,d,J＝5.4Hz),13.29(1H,s)；ESI-MS(m/z):497.3,495.4,499.2[M+H] +。
The preparation of embodiment 6:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-Trifluoromethoxyphen-l) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-Trifluoromethoxyphen-l) piperazine (compound number 06) 0.92g, yield 42%.m.p.:228-230℃；IR(KBr,cm -1):3240,2919,2850,1730,1605,1532,1510,1475,1386,1368,1327,1272,1153,1028,1004； 1H-NMR(600MHz,DMSO-d 6):δ3.33(8H,m),4.27(2H,s),7.03(2H,d,J＝8.6Hz),7,20(2H,d,J＝8.6Hz),7.56(1H,s),13.84(1H,s)；ESI-MS(m/z):547.0,545.1[M+H] +。
The preparation of embodiment 7:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-fluorophenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-fluorophenyl) piperazine (compound number 07) 0.75g, yield 39%.m.p.:78-80℃；IR(KBr,cm -1):3221,2921,2851,1720,1641,1500,1446,1394,1385,1287,1240,1151,999；? 1H-NMR(600MHz,CDCl 3):δ3.11(4H,t,J＝10.2Hz),4.02(4H,t,J＝10.2Hz),4.24(2H,s),7.02(3H,m),7.23(1H,s),7.38(1H,d,J＝7.8Hz)；ESI-MS(m/z):479.1,481.0[M+H] +。
The preparation of embodiment 8:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-trimethoxyphenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-trimethoxyphenyl) piperazine (compound number 08) 0.87g, yield 44%.m.p.:90℃；IR(KBr,cm -1):2922,1730,1618,1511,1446,1379,1255,1224,1186,1137,1096,1034,992,816；? 1H-NMR(600MHz,CDCl 3):δ3.13(4H,m),3.99(7H,m),4.28(2H,s),6.85(2H,dd,J＝7.2Hz,2.4Hz),6.91(2H,dd,J＝7.2Hz,2.4Hz),7.24(1H,s)；ESI-MS(m/z):491.1,493.2[M+H] +。
The preparation of embodiment 9:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-phenylpiperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-phenylpiperazine (compound number 09) 0.85g, yield 43%.m.p.:112℃；IR(KBr,cm -1):2923,2853,1619,1517,1499,1468,1377,1276,1154,992,832； 1H-NMR(600MHz,CDCl 3):δ3.26(4H,t),4.01(4H,t),4.27(2H,s),6.91(1H,d,J＝7.8Hz),6.96(2H,d,J＝7.8Hz),7,28(2H,dd,J＝7.8Hz,7.8Hz),7.25(1H,s)；ESI-MS(m/z):461.1,463.1[M+H] +。
The preparation of embodiment 10:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-fluorophenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-fluorophenyl) piperazine (compound number 10) 0.67g, yield 35%.m.p.:185-186℃；IR(KBr,cm -1):3443,2922,2852,1605,1507,1443,1384,1225,1116； 1H-NMR(600MHz,CDCl 3):δ3.19(4H,t),4.04(4H,t),4.24(2H,s),7.00(4H,m),7.24(1H,s)；ESI-MS(m/z):479.1,481.0[M+H] +。
The preparation of embodiment 11:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-methylpiperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-methylpiperazine (compound number 11) 0.95g, yield 60%.m.p.:220-222℃；IR(KBr,cm -1):3424.0,2917.8,849.5,1704.1,1465.5,1433.1,1383.9,1296.8,1204.9,940.2； 1H-NMR(600MHz,CDCl 3):δ2.36(3H,s),2.51(4H,t),3.86(4H,t),4.19(2H,s),7.28(1H,s)；ESI-MS(m/z):399.2,401.2[M+H] +。
The preparation of embodiment 12:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-benzyl diethylenediamine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-benzyl diethylenediamine (compound number 12) 0.89g, yield 47%.m.p.:180℃；IR(KBr,cm -1):3422,3206,2918,2850,1730,1601,1509,1446,1384,1266,1126,1029,999； 1H-NMR(600MHz,CDCl 3):δ2.50(4H,t),3.54(2H,s),3.77(4H,t),4.28(2H,s),7.24(1H,s),7.31(5H,m)；ESI-MS(m/z):474.9,477.1[M+H] +。
Embodiment 13:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-[(4-chloro-phenyl-) (phenyl) methyl] preparation of piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-[(4-chloro-phenyl-) (phenyl) methyl] piperazine (compound number 13) 0.89g, yield 38%.m.p.:212-214℃；IR(KBr,cm -1):3442,2920,2851,1602,1452,1384,1126,998； 1H-NMR(600MHz,?CDCl 3):δ2.44(4H,m),3.79(4H,m),4.16(2H,s),4.25(1H,s),7.22(2H,m),7,25(1H,s),7.27(1H,m),7.29(2H,dd,J＝7.8Hz,7.8Hz),7.37(4H,m)；ESI-MS(m/z):584.9,586.8[M+H] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of the embodiment 14:N-tertiary butyl-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 14) 1.12g also of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of the N-tertiary butyl-7-, yield 75%.m.p.:205-207℃；IR(KBr,cm -1):3364,3201,2919,1638,1553,1526,1492,1450,1385,1296,1220,1167,969,863； 1H-NMR(600MHz,CDCl 3):δ1.49(9H,s),4.49(2H,s),7,21(1H,s),7.40(1H,s)；ESI-MS(m/z):372.0,374.2[M+H] +。
The preparation of embodiment 15:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3-bromophenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3-bromophenyl) piperazine (compound number 15) 0.82g, yield 38%.m.p.:150-151℃；IR(KBr,cm -1):3418.7,3217.5,2920.0,2850.7,1590.4,1480.6,1442.9,1384.6,1224.6,1157.9,999.9,938.2,764.3； 1H-NMR(600MHz,CDCl 3):δ3.25(4H,m),4.00(4H,m),4.26(2H,s),6.85(1H,m),7.01(1H,m),7.06(1H,m),7.13(1H,m),7.23(1H,s)；ESI-MS(m/z):538.9,540.8,542.9[M+H] +。
The preparation of embodiment 16:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-ethoxyl phenenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(4-ethoxyl phenenyl) piperazine (compound number 16) 0.89g, yield 44%.m.p.:178-180℃；IR(KBr,cm -1):3443.4,2918.4,2850.2,1618.7,1511.5,1446.0,1384.5,1273.2,1254.0,1224.2,1137.0,1021.6,993.6,834.2,816.7； 1H-NMR(600MHz,CDCl 3):δ1.40(3H,t),3.13(4H,t),3.99(6H,m),4.28(2H,s),6.85(2H,dd,J＝7.2Hz,2.4Hz),6.91(2H,dd,J＝7.2Hz,2.4Hz),7.24(1H,s)；ESI-MS(m/z):505.3,507.3[M+H] +。
The preparation of embodiment 17:4-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) morpholine
According to the method for example 1, make 4-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) morpholine (compound number 17) 0.76g, yield 49%.m.p.:150℃；IR(KBr,cm -1):3444.9,3169.7,2918.2,2850.3,1729.9,1592.2,1441.1,1266.5,1148.2,1113.9,1000.1,969.6,844.0；? 1H-NMR(600MHz,DMSO-d 6):δ3.61(4H,t),3.96(4H,t),4.28(2H,?s),7.42(1H,s),13.59(1H,s)；ESI-MS(m/z):388.2[M+H] +。
The preparation of embodiment 18:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) tetramethyleneimine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) tetramethyleneimine (compound number 18) 0.77g, yield 52%.m.p.:220℃；IR(KBr,cm -1):3442.7,2920.1,2851.2,1606.7,1575.4,1508.2,1454.8,1384.3,1156.9,969.2,844.5； 1H-NMR(600MHz,DMSO-d 6):δ1.81(2H,t),1.87(2H,t),3.46(2H,t),3.84(2H,t),4.37(2H,s),7.42(1H,s),14.57(1H,s)；ESI-MS(m/z):370.1,372.3[M+H] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of embodiment 19:N-sec.-propyl-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 19) 0.99g also of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-sec.-propyl-7-, yield 69%.m.p.:189-190℃；IR(KBr,cm -1):3400.5,3207.5,2974.5,2921.3,1637.4,1556.3,1528.3,1452.1,1384.6,1175.4,967.5,836.5； 1H-NMR(600MHz,DMSO-d 6):δ4.50(1H,m),4.39(2H,s),7.50(1H,s),8.08(1H,s)；ESI-MS(m/z):357.1,359.1[M+H] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of embodiment 20:N-(2-diethylin) ethyl-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 20) 1.06g also of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-(2-diethylin) ethyl-7-, yield 64%.m.p.:165-167℃；IR(KBr,cm -1):3420.4,2968.1,2921.8,1635.0,1556.8,1528.9,1456.6,1384.3,1124.4,968.5,831.9；? 1H-NMR(600MHz,CDCl 3):δ1.07(6H,t),2.68(4H,m),2.77(2H,t),3.55(2H,t),4.43(2H,s),7.21(1H,s),8.05(1H,s)；ESI-MS(m/z):415.3[M+H] +。
Embodiment 21:N, the also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-dimethyl-7-
Method according to example 1, makes N, and the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-dimethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 21) 0.94g also also, yield 68%.m.p.:220℃；IR(KBr,cm -1):3443.5,3205.2,2920.4,1612.5,1536.4,1485.5,1420.6,1384.3,1259.4,1160.8,1101.3,966.7,822.5；? 1H-NMR(600MHz,DMSO-d 6):δ2.97(6H,s),4.26(2H,s),7.43(1H,s),13.54(1H,s)；ESI-MS(m/z):344.2,346.3[M+H] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of embodiment 22:N-phenyl-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 22) 0.47g also of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N-phenyl-7-, yield 30%.m.p.:190-191℃；IR(KBr,cm -1):3443.8,2919.8,2850.5,1730.5,1612.4,1555.1,1441.0,1384.2,1296.2,1114.0,1038.4,778.5； 1H-NMR(600MHz,DMSO-d 6):δ4.42(2H,s),7.40(5H,m),7.42(1H,s),8.82(1H,s),13.64(1H,s)；ESI-MS(m/z):415.3,417.3[M+Na] +。
The preparation of embodiment 23:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) piperidines
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl) piperidines (compound number 23) 0.95g, yield 62%.m.p.:196-198℃；IR(KBr,cm -1):3442.6,2931.0,2852.9,1603.1,1570.1,1538.8,1445.3,1384.3,274.9,1112.4,966.6,851.8；? 1H-NMR(600MHz,CDCl 3):δ1.66(6H,m),3.72(4H,t),4.14(2H,s),7.30(1H,s)；ESI-MS(m/z):384.2,386.3[M+H] +,406.2,408.4[M+Na] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of embodiment 24:N – benzyl-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 24) 0.91g also of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of N – benzyl-7-, yield 56%.m.p.:98-100℃；IR(KBr,cm -1):3421.9,2920.9,2851.7,1629.7,1446.5,1384.2,1274.3,1114.1,850.9； 1H-NMR(600MHz,DMSO-d 6):δ4.40(2H,d),4.42(2H,s),7.40(5H,m),7.42(1H,s),8.82(1H,s),13.64(1H,s)；ESI-MS(m/z):408.3[M+H] +,430.1[M+Na] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of embodiment 25:N – (furans-2-methylene) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 25) 0.62g also of N – (furans-2-methylene) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-, yield 39%.m.p.:89-90℃；IR(KBr,cm -1):3444.2,2921.3,2851.3,16307,1440.4,1384.0,1236.2,1112.3,1089.9,975.6,737.9；? 1H-NMR(600MHz,CDCl 3):δ4.22(2H,s),4.60(2H,d),6.29(1H,d,J＝6Hz),6.33(1H,d,J＝6Hz),7.20(1H,dd,J＝6Hz,6Hz),7.25(1H,s)；ESI-MS(m/z):395.3,397.2[M+H] +,418.3,420.1[M+Na] +。
The also also preparation of [4,3-c] pyrazoles-3-acid amides of [3 ', 2 ': 5,6] thiapyran of embodiment 26:N – (pyridine-2-yl) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-
According to the method for example 1, make also [3 ', 2 ': 5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 26) 0.49g also of N – (pyridine-2-yl) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-, yield 31%.m.p.:83-84℃；IR(KBr,cm -1):3421.0,2921.4,2851.5,1630.3,?1445.7,1384.2,1274.8,1126.2； 1H-NMR(600MHz,CDCl 3):δ4.31(2H,s),.6.50(1H,d,J＝8.2Hz),6.65(1H,m),7.42(2H,m),8.07(1H,d,J＝4.8Hz)；ESI-MS(m/z):395.2[M+H] +。
The preparation of embodiment 27:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3,5-, bis-trifluoromethyls) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3,5-, bis-trifluoromethyls) piperazines (compound number 27) 1.08g, yield 45%.m.p.:220-221℃；IR(KBr,cm -1):3421.2,2918.2,1610.2,1581.2,1485.5,1400.4,1275.0,1175.,1131.4,995.3,963.6,862.4； 1H-NMR(600MHz,DMSO-d 6):δ3.45(4H,t),3.77(2H,t),4.14(2H,t),4.31(2H,s),7.33(1H,s),7.45(1H,s),7.50(2H,s),13.64(1H,s)；ESI-MS(m/z):596.9,599.1[M+H] +,619.1,621.0[M+Na] +。
The preparation of embodiment 28:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3,4-difluorophenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3,4-difluorophenyl) piperazine (compound number 28) 0.88g, yield 44%.m.p.:190-192℃；IR(KBr,cm -1):3444.2,2919.8,1656.7,1560.4,1417.7,1384.3,1276.6,1116.2； 1H-NMR(600MHz,DMSO-d 6):δ3.15(4H,t),3.72(4H,t),4.27(2H,s),6.75(1H,m),7.03(1H,m),7.25(1H,d,J＝9.6Hz),7.45(1H,s)；ESI-MS(m/z):518.9,521.0[M+Na] +。
The preparation of embodiment 29:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-aminomethyl phenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-aminomethyl phenyl) piperazine (compound number 29) 0.91g, yield 48%.m.p.:167-170℃；IR(KBr,cm -1):3442.6,2920.4,2851.6,1621.6,1491.9,1443.3,1384.0,1327.3,1274.9,1224.2,1126.5,1021.8,1000.2,762.3； 1H-NMR(600MHz,CDCl 3):δ2.35(3H,s),2.98(4H,t),3.97(4H,t),4.23(2H,s),7.01(2H,m),7.20(2H,m),7.25(1H,s)；ESI-MS(m/z):475.1,476.4[M+H] +。
The preparation of embodiment 30:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-chloro-phenyl-) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2-chloro-phenyl-) piperazine (compound number 30) 0.73g, yield 37%.m.p.:185-186℃；IR(KBr,cm -1):3444.2,2920.3,2851.4,1610.1,1478.0,1384.4,1265.9,1227.6,1124.4,1022.3； 1H-NMR(600MHz,CDCl 3):δ3.11(4H,t),4.02(4H,t),?4.24(2H,s),7.02(3H,m),7.23(1H,s),7.38(1H,d,J＝7.8Hz)；ESI-MS(m/z):495.1,497.1[M+H] +。
The preparation of embodiment 31:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2,5-3,5-dimethylphenyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(2,5-3,5-dimethylphenyl) piperazine (compound number 31) 0.92g, yield 47%.m.p.:150-152℃；IR(KBr,cm -1):3443.5,2919.6,2850.9,1606.7,1457.4,1384.1,1125.3； 1H-NMR(600MHz,CDCl 3):δ2.29(3H,s),2.30(3H,s),2.95(4H,t),3.96(4H,t),4.27(2H,s),6.82(1H,s),6.84(1H,d,J＝7.2Hz),7.08(1H,d,J＝7.2Hz),7.25(1H,s)；ESI-MS(m/z):489.1,491.1[M+H] +。
The preparation of embodiment 32:1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3-trifluoromethyl) piperazine
According to the method for example 1, make 1-(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-also [3 ', 2 ': 5,6] thiapyran also [4,3-c] pyrazoles-3-carbonyl)-4-(3-trifluoromethyl) piperazine (compound number 32) 0.95g, yield 45%.m.p.:185-186℃；IR(KBr,cm -1):3444.9,3219.1,2918.2,2849.8,1591.1,1444.4,1384.4,1349.9,1319.6,1269.0,1222.1,1163.5,1112.2,1075.2,999.6,946.4,864.1,785.5；? 1H-NMR(600MHz,DMSO-d 6):δ3.31(8H,t),4.27(2H,s),7.09(d,J＝7.7Hz,1H),7.24(d,J＝8.4Hz,1H),7.43(t,J＝8.0Hz,1H),7.50(1H,s)；MS(m/z):427.2,429.0[M-H] +。
The preparation of embodiment 33:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(diphenyl-methyl phenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(diphenyl-methyl phenyl) piperazine (compound number 33) 0.74g, yield 38%.m.p.:138-139℃；IR(KBr,cm -1):3422.1,3207.1,2919.3,2851.1,1617.2,1491.3,1448.8,1384.3,1285.9,1242.7,1142.9,995.3,859.8,747.1,706.2； 1H-NMR(600MHz,CDCl 3):δ2.44(4H,t),3.08(2H,t),3.47(2H,t),3.76(4H,t),5.25(1H,s),7.19(2H,d,J＝7.2Hz),7.22(1H,d,J＝5.4Hz),7.26(1H,d,J＝5.4Hz),7.28(4H,t,J＝7.2Hz),7.41(4H,d,J＝7.2Hz)；MS(m/z):487.2[M+H] +。
The preparation of embodiment 34:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-chloro-phenyl-) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-chloro-phenyl-) piperazine (compound number 34) 0.60g, yield 35%.m.p.:140-141℃；IR(KBr,cm -1):3381.8,2920.9,2850.4,1613.8,1493.2,1440.8,1383.9,1342.3,1270.7,?1230.9,1155.5,1021.5,998.6,883.5,860.0,825.0； 1H-NMR(600MHz,CDCl 3):δ3.10(2H,t),3.21(4H,t),3.47(2H,t),3.94(4H,t),6.90(2H,d,J＝9.0Hz),7.12(2H,d,J＝9.0Hz),7.23(1H,d,J＝5.4Hz),7.26(1H,d,J＝5.4Hz)；MS(m/z):431.1[M+H] +。
Embodiment 35:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-[(4-chloro-phenyl-) (phenyl) methyl] preparation of piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-[(4-chloro-phenyl-) (phenyl) methyl] piperazine (compound number 35) 0.87g, yield 42%.m.p.:142-143℃；IR(KBr,cm -1):3432.2,2919.3,2851.4,1618.6,1488.1,1445.5,1384.4,1286.8,1241.9,1142.8,995.7,860.1,757.4,719.2； 1H-NMR(600MHz,CDCl 3):δ2.32(4H,t),3.02(2H,t),3.38(2H,t),3.68(4H,t),4.16(1H,s),7.12(d,J＝5.4Hz,1H),7.19(d,J＝5.4Hz,1H),7.24(3H,m),7.28(2H,d,J＝5.4Hz),7.33(4H,m)；MS(m/z):521.2[M+H] +。
The embodiment 36:N-tertiary butyl-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
According to the method for example 1, make the N-tertiary butyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 36) 0.64g also, yield 52%.m.p.:170-171℃；IR(KBr,cm -1):3393.2,3253.5,2962.0,2921.2,2851.0,1644.8,1521.4,1484.0,1384.6,1363.0,1258.8,1217.8,1124.6,1053.3,877.9,865.2； 1H-NMR(600MHz,CDCl 3):δ1.47(9H,s),3.10(2H,t),3.69(2H,t),7.21(1H,d,J＝5.4Hz),7.24(1H,d,J＝5.4Hz)；MS(m/z):308.2[M+H] +。
The preparation of embodiment 37:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-methylpiperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-methylpiperazine (compound number 37) 0.60g, yield 45%.m.p.:107-108℃；IR(KBr,cm -1):3429.0,3228.4,2915.6,2792.8,1608.8,1504.8,1439.5,1352.5,1290.1,1253.7,1225.3,1142.0,997.9,861.7,766.6； 1H-NMR(600MHz,CDCl 3):δ2.33(3H,s),2.46(4H,t),3.10(2H,t),3.46(2H,t),3.91(4H,t),7.23(1H,d,J＝5.4Hz,),7.26(1H,d,J＝5.4Hz)；MS(m/z):335.2[M+H] +。
Embodiment 38:N, N-diethyl-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
Method according to example 1, makes N, N-diethyl-4, and 5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 38) 0.69g also, yield 56%.m.p.:183-185℃；IR(KBr,cm -1):3443.6,3200.5,2929.8,1601.5,1509.2,1479.3,1374.1,1284.1,1262.2,1195.5,1127.7,?1092.8,1073.0,1015.8,881.7,859.0； 1H-NMR(600MHz,CDCl 3):δ1.24(6H,t),3.10(2H,t),3.42(2H,t),3.54(4H,m),7.22(1H,d,J＝5.4Hz),7.25(1H,d,J＝5.4Hz)；MS(m/z):308.2[M+H] +。
The preparation of embodiment 39:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-aminomethyl phenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-aminomethyl phenyl) piperazine (compound number 39) 0.71g, yield 43%.m.p.:186-187℃；IR(KBr,cm -1):3124.2,2916.4,1631.5,1579.3,1513.5,1443.3,1384.4,1340.9,1264.6,1236.5,1203.3,1154.1,1016.6,999.2,876.2,811.3； 1H-NMR(600MHz,CDCl 3):δ2.28(3H,s),3.10(2H,t),3.18(4H,t),3.47(2H,t),3.93(4H,t),6.85(2H,d,J＝8.4Hz),7.10(2H,d,J＝8.4Hz),7.23(1H,d,J＝5.4Hz),7.27(1H,d,J＝5.4Hz)；MS(m/z):411.2[M+H] +。
The preparation of embodiment 40:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-phenylpiperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-phenylpiperazine (compound number 40) 0.75g, yield 47%.m.p.:74-75℃；IR(KBr,cm -1):3441.7,3209.2,2920.5,2851.6,1599.6,1495.6,1444.2,1384.1,1260.4,1230.6,1153.3,1016.0,998.3,875.4,759.5； 1H-NMR(600MHz,CDCl 3):δ3.10(2H,t),3.20(1H,t),3.27(4H,t),3.47(1H,t),4.02(4H,t),6.90(1H,m),6.95(2H,m),7.23(1H,d,J＝5.4Hz),7.28(1H,d,J＝5.4Hz),7.29(2H,m)；MS(m/z):397.2[M+H] +。
The preparation of embodiment 41:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-Trifluoromethoxyphen-l) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-Trifluoromethoxyphen-l) piperazine (compound number 41) 0.85g, yield 44%.m.p.:85-86℃；IR(KBr,cm -1):3441.7,3209.2,2920.5,2851.6,1599.6,1495.6,1444.2,1384.1,1260.4,1230.6,1153.3,1016.0,998.3,875.4,759.5； 1H-NMR(600MHz,CDCl 3):δ3.10(2H,t),3.21(4H,t),3.47(2H,t),3.94(4H,t),6.90(2H,d,J＝9.0Hz),7.12(2H,d,J＝9.0Hz),7.23(1H,d,J＝5.4Hz),7.26(1H,d,J＝5.4Hz)；MS(m/z):481.1[M+H] +。
The preparation of embodiment 42:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-Trifluoromethoxyphen-l) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-Trifluoromethoxyphen-l) piperazine (compound number 42) 0.75g, yield 45%.m.p.:195-197℃；IR(KBr,cm -1):3441.9,?2919.7,2851.3,1603.7,1509.0,1444.9,1384.5,1341.8,1263.2,1229.1,1157.7,1017.4,999.5,877.7,817.2； 1H-NMR(600MHz,CDCl 3):δ3.11(2H,t),3.30(4H,t),3.50(2H,t),3.98(4H,t),6.91(2H,dd,J＝9.1Hz,4.2Hz),6.99(2H,dd,J＝9.1Hz,4.2Hz),7.24(1H,d,J＝5.4Hz),7.25(1H,d,J＝5.4Hz)；MS(m/z):415.1[M+H] +。
The preparation of embodiment 43:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-benzyl diethylenediamine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-benzyl diethylenediamine (compound number 43) 0.80g, yield 49%.m.p.:72-73℃；IR(KBr,cm -1):3427.6,3210.5,2918.4,2851.1,2809.1,1613.9,1446.0,1384.2,1347.7,1287.2,1229.1,1143.5,997.1,860.2,740.7,699.1； 1H-NMR(600MHz,CDCl 3):δ2.50(4H,t),3.10(2H,t),3.44(2H,t),3.54(2H,s),3.77(4H,t),7.24(d,J＝4.8Hz,1H),7.26(d,J＝4.8Hz,1H),7.31(5H,m)；MS(m/z):411.2[M+H] +,433.1[M+Na] +。
The preparation of embodiment 44:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-p-methoxy-phenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(4-p-methoxy-phenyl) piperazine (compound number 44) 0.84g, yield 49%.m.p.:156-158℃；IR(KBr,cm -1):3443.8,3196.6,2920.6,2851.1,1611.7,1510.5,1445.2,1384.2,1279.1,1246.5,1225.8,1154.6,1034.6,995.2,859.4； 1H-NMR(600MHz,CDCl 3):δ3.11(10H,m),3.47(2H,t),3.78(3H,s),6.85(2H,J＝9Hz),6.92(2H,d,J＝9Hz),7.24(d,J＝4.8Hz,1H),7.32(d,J＝4.8Hz,1H)；MS(m/z):427.2[M+H] +,449.2[M+Na] +。
The preparation of embodiment 45:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3-trifluoromethyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3-trifluoromethyl) piperazine (compound number 45) 0.80g, yield 43%.m.p.:85-87℃；IR(KBr,cm -1):3444.3,3212.2,2919.3,2851.0,1610.1,1495.4,1445.9,1384.5,1348.8,1232.6,1162.9,1120.8,995.3,860.3； 1H-NMR(600MHz,CDCl 3):δ3.11(2H,t),3.30(4H,t),3.50(2H,t),3.98(4H,t),7.08(1H,d,J＝8.4Hz),7.13(2H,m),7.25(2H),7.38(1H,dd,J＝8.4Hz,8.4Hz),10.26(1H,s)；MS(m/z):465.1[M+H] +。
The preparation of embodiment 46:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3-bromophenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3-bromophenyl) piperazine (compound number 46) 0.76g, yield 40%.m.p.:195-197℃；IR(KBr,cm -1):3443.9,2920.9,2851.1,1589.7,1444.0,1384.1,1236.2,1124.2,994.4,860.0； 1H-NMR(600MHz,CDCl 3):δ3.06(2H,t),3.24(8H,t),3.78(2H,t),6.94(2H,m),7.10(1H,d),7.15(1H,t),7.54(d,J＝5.4Hz,1H),7.56(d,J＝5.4Hz,1H),13.15(1H,s)；MS(m/z):474.4,476.3[M+H] +。
The preparation of embodiment 47:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3,4-difluorophenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3,4-difluorophenyl) piperazine (compound number 47) 0.80g, yield 46%.m.p.:230-232℃；IR(KBr,cm -1):3369.6,3258.9,2920.5,2850.8,1662.4,1629.5,1555.5,1515.3,1434.9,1384.1,1280.9,1222.0,1189.0,1116.2,1004.4,870.1,805.1；? 1H-NMR(600MHz,CDCl 3):δ2.95(4H,t),3.15(2H,t),3.74(2H,t),3.91(4H,t),7.13(1H),7.22(1H,d,J＝5.4Hz),7.24(1H,m),7.28(1H,d,J＝5.4Hz),7.80(1H,m)；MS(m/z):433.2[M+H] +。
Embodiment 48:N, N-dimethyl-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
Method according to example 1, makes N, N-dimethyl-4, and 5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 48) 0.59g also, yield 53%.m.p.:232-233℃；IR(KBr,cm -1):3199.3,3153.2,3055.3,2924.6,1616.9,1524.1,1425.8,1385.1,1144.7,1088.7,1007.5,914.6,861.8,769.0,696.6； 1H-NMR(600MHz,CDCl 3):δ3.10(2H,t),3.16(6H,m),3.45(2H,t),7.24(1H,d,J＝5.5Hz,),7.27(1H,d,J＝5.5Hz,)；MS(m/z):280.0[M+H] +。
The preparation of embodiment 49:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) tetramethyleneimine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) tetramethyleneimine (compound number 49) 0.60g, yield 49%.m.p.:170℃；IR(KBr,cm -1):3263.2,2920.4,2875.7,1595.8,1526.9,1492.2,1470.4,1432.4,1382.8,1339.4,1224.1,1007.6,898.7,861.2,760.5,688.5； 1H-NMR(600MHz,CDCl 3):δ1.82(2H,m),1.93(2H,m),3.11(2H,t),3.37(4H,t),3.59(2H,t),7.23(1H,d,J＝5.5Hz),7.25(1H,d,J＝5.5Hz)；MS(m/z):306.2[M+H] +,328.1[M+Na] +。
Embodiment 50:N-sec.-propyl-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
According to the method for example 1, make N-sec.-propyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 50) 0.66g also, yield 56%.m.p.:214-215℃；IR(KBr,cm -1):3408.8,3256.4,2922.4,1644.1,1543.5,1523.7,1485.7,1446.4,1384.0,1125.5,1007.9,859.5,760.8,692.2； 1H-NMR(600MHz,CDCl 3):δ1.26(6H,d),3.12(2H,t),3.71(2H,t),4.25(1H,m),7.20(1H,d,J＝5.5Hz),7.24(1H,d,J＝5.5Hz)；MS(m/z):294.1[M+H] +。
Embodiment 51:N-benzyl-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
According to the method for example 1, make N-benzyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 51) 0.63g also, yield 46%.m.p.:136-138℃；IR(KBr,cm -1):33401.9,3217.8,2921.8,2851.3,1648.5,1546.9,1452.8,1384.2,1241.6,1128.0,861.8,752.2,698.0,615.7； 1H-NMR(600MHz,CDCl 3):δ3.12(2H,t),3.73(2H,t),4.62(2H,d),7.20(1H,m),7.23(1H,d,J＝5.5Hz),7.28(1H,d,J＝5.5Hz),7.34(4H,m)；MS(m/z):342.1[M+H] +。
Embodiment 52:N-phenyl-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
According to the method for example 1, make N-phenyl-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 52) 0.50g also, yield 38%.m.p.:240℃；IR(KBr,cm -1):3422.8,2921.0,2850.9,1663.2,1596.1,1542.8,1440.4,1384.1,1121.3,861.5,753.4,694.0,618.0；? 1H-NMR(600MHz,CDCl 3):δ3.15(2H,t),3.76(2H,t),7.13(1H,m),7.22(1H,d,J＝5.5Hz,),7.28(1H,d,J＝5.5Hz),7.37(2H,dd,J＝7.9Hz,7.9Hz),7.68(2H,d,J＝7.9Hz)；MS(m/z):328.1[M+H] +。
The preparation of embodiment 53:4-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) morpholine
According to the method for example 1, make 4-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) morpholine (compound number 53) 0.67g, yield 52%.m.p.:176-178℃；IR(KBr,cm -1):3439.5,2920.5,2851.6,1611.7,1434.2,1271.5,1242.1,1194.6,1115.5,1024.6,995.5,861.4,619.7；? 1H-NMR(600MHz,CDCl 3):δ3.11(2H,t),3.48(2H,t),3.75(4H,t),3.81(4H,t),7.22(1H,d,J＝5.4Hz),7.25(1H,d,J＝5.4Hz)；MS(m/z):322.0[M+H] +。
The preparation of embodiment 54:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) piperidines
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also) piperidines (compound number 54) 0.55g, yield 43%.m.p.:76-78℃；IR(KBr,cm -1):3435.9,3229.1,2920.1,2851.2,1607.8,1514.6,1445.3,1384.1,1254.9,1138.8,1027.8,989.4,859.0,774.5,617.9； 1H-NMR(600MHz,CDCl 3):δ1.27(2H,m),1.64(4H,m),3.11(2H,t),3.42(2H,t),3.66(4H,t),7.23(1H,d,J＝5.4Hz),7.24(1H,d,J＝5.4Hz)；MS(m/z):320.1[M+H] +。
Embodiment 55:N-(furans-2-methylene)-4, the also preparation of [4,5-c] pyrazoles-3-acid amides of 5-dihydro-3aH-thieno-[2', 3':2,3] thia
According to the method for example 1, make N-(furans-2-methylene)-4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-acid amides (compound number 55) 0.46g also, yield 35%.m.p.:155-156℃；IR(KBr,cm -1):3408.3,3227.4,2921.6,2850.7,1650.4,1542.9,1523.7,1484.0,1417.8,1384.2,1190.0,1147.0,1003.1,964.7,861.9,747.9,693.0； 1H-NMR(600MHz,CDCl 3):δ3.12(2H,t),3.71(2H,t),4.60(2H,d),6.29(1H,m),6.33(1H,m),7.20(1H,d,J＝5.4Hz),7.25(1H,d,J＝5.4Hz),7.37(1H,m)；MS(m/z):331.6[M+H] +。
The preparation of embodiment 56:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(the chloro-4-fluorophenyl of 3-) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(the chloro-4-fluorophenyl of 3-) piperazine (compound number 56) 0.88g, yield 49%.m.p.:205-206℃；IR(KBr,cm -1):33434.2,3288.2,2919.2,2850.7,1603.4,1503.1,1462.9,1444.8,1384.2,1223.5,1156.2,994.4,945.2,865.3,733.5,688.5； 1H-NMR(600MHz,CDCl 3):δ3.12(2H,t),3.16(4H,t),3.49(2H,t),3.95(4H,t),6.79(1H,m),6.95(1H,dd,J＝6.3Hz,2.4Hz),7.05(1H,dd,J＝9.0Hz,8.7Hz),7.23(1H,d,J＝5.4Hz),7.25(1H,d,J＝5.4Hz)；MS(m/z):449.0,450.8[M+H] +。
The preparation of embodiment 57:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-aminomethyl phenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-aminomethyl phenyl) piperazine (compound number 57) 0.72g, yield 44%.m.p.:192-194℃；IR(KBr,cm -1):3442.6,3264.4,2919.3,2851.2,1601.8,1492.0,1474.7,1442.8,1383.7,1223.1,1152.0,1026.2,995.5,861.7,761.1,691.0； 1H-NMR(600MHz,CDCl 3):δ2.33(3H,s),2.95(4H,t),3.12(2H,t),3.48(2H,t),3.91(4H,t),7.02(2H,m),7.18(2H,m),7.23(1H,d,J＝5.5Hz),7.27(1H,d,J＝5.5Hz)；MS(m/z):409.0[M-H] +。
The preparation of embodiment 58:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3,5-, bis-trifluoromethyls) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(3,5-, bis-trifluoromethyls) piperazines (compound number 58) 0.92g, yield 43%.m.p.:89-91℃；IR(KBr,cm -1):3444.6,2920.4,1618.5,1476.8,1384.9,1277.4,1240.0,1177.9,1130.4,995.0,963.9,861.1,720.5,682.3； 1H-NMR(600MHz,CDCl 3):δ3.12(2H,t),3.38(4H,t),3.51(2H,t),4.01(4H,t),7.23(2H,m),7.27(1H,s),7.24(1H,s),7.34(1H,s)；MS(m/z):533.4[M+H] +。
The preparation of embodiment 59:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-fluorophenyl) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-fluorophenyl) piperazine (compound number 59) 0.66g, yield 40%.m.p.:79-81℃；IR(KBr,cm -1):3439.4,2918.7,1611.8,1500.0,1440.3,1384.7,1342.1,1286.6,1236.6,1201.2,1147.9,998.6,884.5,860.5,747.8； 1H-NMR(600MHz,CDCl 3):δ2.23(2H,t),3.12(4H,t),3.48(4H,t),3.66(2H,t),7.01(1H,m),7.03(1H,m),7.25(2H,m),7.38(1H,m),7.39(1H,m)；MS(m/z):415.3[M+H] +,437.1[M+Na] +。
The preparation of embodiment 60:1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-chloro-phenyl-) piperazine
According to the method for example 1, make 1-(4,5-dihydro-3aH-thieno-[2', 3':2,3] thia is [4,5-c] pyrazoles-3-carbonyl also)-4-(2-chloro-phenyl-) piperazine (compound number 60) 0.66g, yield 38%.m.p.:203-205℃；IR(KBr,cm -1):3441.5,3214.1,2920.0,2851.1,1601.9,1500.3,1477.4,1443.6,1384.1,1336.5,1286.9,1237.1,1202.8,1146.5,1025.4,997.1,861.8,759.2,689.2； 1H-NMR(600MHz,CDCl 3):δ2.23(2H,t),3.12(4H,t),3.48(4H,t),3.66(2H,t),7.02(2H,m),7.25(2H,m),7.38(2H,m)；MS(m/z):431.0,432.9[M+H] +。
The embodiment 61:N – tertiary butyl-7, the also also preparation of [4,3-c] pyrazoles-3-acid amides of [3', 2':5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-
According to the method for example 1, make the N – tertiary butyl-7, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-is [3', 2':5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 61) 0.58g also also, yield 32%.m.p.:224-226℃；IR(KBr,cm -1):3391.7,3075.6,2935.1,1653.5,1544.7,1520.1,1439.2,1366.5,1265.9,1217.1,1018.8,987.3,966.9,858.4,822.7； 1H-NMR(600MHz,CDCl 3):δ1.49(9H,s),4.49(2H,s),7.40(1H,s)；ESI-MS(m/z):450.2,452.2,454.2[M+H] +。
Embodiment 62:N, N – dimethyl-7, the also also preparation of [4,3-c] pyrazoles-3-acid amides of [3', 2':5,6] thiapyran of the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-
Method according to example 1, makes N, N – dimethyl-7, and the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-is [3', 2':5,6] thiapyran [4,3-c] pyrazoles-3-acid amides (compound number 62) 0.76g also also, yield 42%.m.p.:159-160℃；IR(KBr,cm -1):3422.3,2977.2,2933.9,2603.8,1602.2,1476.5,1397.8,1383.3,1271.0,1172.0,1036.7,850.8,807.0； 1H-NMR(600MHz,CDCl 3):δ1.25(6H,m),3.54(4H,m),4.12(2H,s)；ESI-MS(m/z):450.2,452.2,454.2[M+H] +。
The above, be only preferred embodiment of the present invention, is not the present invention to be done to the restriction of other form, and any those skilled in the art may utilize the technology contents of above-mentioned announcement to be changed or be modified as the equivalent embodiment of equivalent variations.But every technical solution of the present invention content that do not depart from, any simple modification, equivalent variations and the remodeling above embodiment done according to technical spirit of the present invention, still belong to the protection domain of technical solution of the present invention.
Pharmacology EXAMPLE Example 63:
The inhibition of representative compound of the present invention to 5-lipoxygenase has been shown, by measuring 5-HETE and LYB in following table 4the inhibition forming, measures 5-lipoxidase inhibitor active, adopts the separated Calcium ionophore (A from rabbit peripheral blood 23187) stimulating neutrophilic leukocyte, research the compounds of this invention suppresses 5-HETE and LYB 4the ability forming.Neutrophilic leukocyte adopts standard method separated, briefly, by piercing through heart, from New Zealand's albinism (NewZealand Albino, NZA) rabbit body, obtains heparinization/calcium chelating blood, by dextran sedimentation at 4 ℃, removes red corpuscle.Centrifugal settling is included in the white corpuscle in supernatant part, and by hypotonic lysis, removes and be mixed with erythrocytic part.After molten born of the same parents and centrifugal red corpuscle, obtain white corpuscle sheet, it is suspended in to Dulbecco ' s PBS again (without Ca 2+/ Mg 2+) and in the upper stratification of 60%Histopaque-1083/40%Histopaque-1119 pad (Sigma Chemical.St.Louis, Missouri, USA.).Then centrifugal Histopaque, and wash gained neutrophilic leukocyte sheet, and be resuspended in 1/25 substance accumulated amount blood.Peek this cell suspending liquid of equal portions and at 37 ℃ with carrier (DMSO) or be dissolved in the test compound pre-treatment in DMSO, in cell suspending liquid, add CaCl immediately 2, and by adding 5 microlitres (μ L) to contain (1- 14c)-arachidonic acid and A 23187dMSO mixture irritation cell.CaCl 2, (1- 14c)-arachidonic acid and A 23187ultimate density be respectively 5.0 mmoles (mM), 52 μ L and 5.0 μ L.At 37 ℃ of incubations, after 3 minutes, add 2 volume acetone termination reactions.Press described in Graff and Anderson and extract and anti-phase (C 18-5 μ) HPLC analyzes (1- 14the arachidonic acid metabolite of C)-mark.
Table 1
FORMULATION EXAMPLE
Following FORMULATION EXAMPLE only illustrates protection scope of the present invention, but forms and limit never in any form.
Embodiment 64: gelatine capsule
The preparation of hard gelatin capsule adopts:
Can improve above-mentioned preparation according to provided reasonable change.
Embodiment 65: tablet
The preparation of tablet adopts
Said components is mixed and be pressed into tablet.
Embodiment 66: tablet
The tablet that contains 2.5-1000mg active ingredient in every is prepared as follows:
Make activeconstituents, starch and Mierocrystalline cellulose by No. 45 mesh sieves of the U.S. and thoroughly mix.Polyvinylpyrrolidonesolution solution is mixed with gained powder, with by No. 14 mesh sieves of the U.S..By the particle generating No. 18 mesh sieves of the dry Bing Jing U.S. at 50-60 ℃.The Xylo-Mucine, Magnesium Stearate and the talcum powder that pass through in advance No. 60 mesh sieves of the U.S. are joined in above-mentioned particle, mix subsequently, on tabletting machine, compacting obtains tablet.
Embodiment 67: suspension
The suspension that every 5ml contains 0.1-1000mg medicine is prepared as follows:
Make medicine through No. 45 mesh sieves of the U.S. and be mixed to form level and smooth paste with Xylo-Mucine and syrup.Benzoic acid solution, correctives and tinting material are also under agitation added to aforesaid paste with some water dilutions.Add subsequently enough water to reach required volume.
Embodiment 68: combined tablet-preparation
Make activeconstituents, starch and Mierocrystalline cellulose by No. 45 mesh sieves of the U.S. and thoroughly mix.Polyvinylpyrrolidonesolution solution is mixed with gained powder, with by No. 14 mesh sieves of the U.S..By the particle generating No. 18 mesh sieves of the dry Bing Jing U.S. at 50-60 ℃.The Xylo-Mucine, Magnesium Stearate and the talcum powder that pass through in advance No. 60 mesh sieves of the U.S. are joined in above-mentioned particle, mix subsequently, on tabletting machine, compacting obtains tablet.
For above-mentioned explanation, those skilled in the art can easily understand essential feature of the present invention, do not deviate from the spirit and scope of the present invention, and the present invention can carry out various changes and improvements to adapt to different application and condition.

Claims (7)

1. thieno-thiapyran pyrazole compound, its prodrug and pharmaceutical activity metabolite with and pharmacy acceptable salt, be selected from:
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-formyl radical)-4-(4-aminomethyl phenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(diphenyl methyl) piperazine;
n,Nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of-diethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(the chloro-4-fluorophenyl of 3-) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(4-chloro-phenyl-) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(4-Trifluoromethoxyphen-l) piperazine; (the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(2-fluorophenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(4-trimethoxyphenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-phenylpiperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(4-fluorophenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-methylpiperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-benzyl diethylenediamine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-[(4-chloro-phenyl-) (phenyl) methyl] piperazine;
nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of-the tertiary butyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(3-bromophenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(4-ethoxyl phenenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 4- c] pyrazoles-3-carbonyl) morpholine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl) tetramethyleneimine;
nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of-sec.-propyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of-(2-diethylin) ethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
n,Nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of-dimethyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of-phenyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl) piperidines;
nbromo-Isosorbide-5-Nitrae-the dihydro-thiophene of – benzyl-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
n– (furans-2-methylene) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
n– (pyridine-2-yl) bromo-Isosorbide-5-Nitrae-dihydro-thiophene of-7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(3,5-, bis-trifluoromethyls) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(3,4-difluorophenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(2-aminomethyl phenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(2-chloro-phenyl-) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(2,5-3,5-dimethylphenyl) piperazine;
(the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 7-is [3 ', 2 ': 5,6] thiapyran [4,3-also also for 1- c] pyrazoles-3-carbonyl)-4-(3-trifluoromethyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(diphenyl-methyl phenyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(4-chloro-phenyl-) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-[(4-chloro-phenyl-) (phenyl) methyl] piperazine;
n-the tertiary butyl-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-methylpiperazine;
n,N-diethyl-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(4-aminomethyl phenyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-phenylpiperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(4-Trifluoromethoxyphen-l) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(4-Trifluoromethoxyphen-l) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-benzyl diethylenediamine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(4-p-methoxy-phenyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(3-trifluoromethyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(3-bromophenyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(3,4-difluorophenyl) piperazine;
n,N-dimethyl-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl) tetramethyleneimine;
n-sec.-propyl-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
n-benzyl-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
n-phenyl-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
4-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl) morpholine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl) piperidines;
n-(furans-2-methylene)-4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-acid amides;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(the chloro-4-fluorophenyl of 3-) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(2-aminomethyl phenyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(3,5-, bis-trifluoromethyls) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(2-fluorophenyl) piperazine;
1-(4,5-dihydro-3a h-thieno-[2', 3':2,3] thia is [4,5-also c] pyrazoles-3-carbonyl)-4-(2-chloro-phenyl-) piperazine;
nthe – tertiary butyl-7, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-is [3', 2':5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides;
n,N– dimethyl-7, the bromo-Isosorbide-5-Nitrae-dihydro-thiophene of 8-bis-is [3', 2':5,6] thiapyran [4,3-also also c] pyrazoles-3-acid amides.
2. a pharmaceutical composition, comprises thieno-thiapyran the pyrazole compound of claim 1, its prodrug and pharmaceutical activity metabolite with and pharmacy acceptable salt and pharmaceutically acceptable carrier or thinner.
3. compound claimed in claim 1 or pharmaceutical composition claimed in claim 2 application in preparation treatment inflammation medicine.
4. following general formula (I) or (II) the described compound application in preparation treatment inflammation medicine,
Wherein
N is the natural numbers such as 1,2; Preferably 1,2;
R 1can be H or halogen;
R 2it can be hydrogen or halogen;
R 3for arbitrarily selectively by 1,2 or 3 independently selected from H, halogen ,-OCH 3,-CH 3,-CF 3,-OCF 3the phenyl ring replacing, diphenyl-methyl, 4-chlorobenzhydryl, benzyl;
R 4, R 5respectively independently selected from hydrogen, methyl, ethyl, the tertiary butyl, sec.-propyl, N, N-diethyl, phenyl, furfuryl, benzyl, or R 2, R 3together with the nitrogen-atoms connected with them, form pyrrolidyl, piperidyl, N-methyl piperidine base, morpholinyl, hexamethylene imine basic ring.
5. according to the application described in claim 3 or 4, it is characterized in that: described inflammation comprises gout, headache, toothache, neurodynia and arthrodynia.
6. application according to claim 5, is characterized in that: described inflammation is that the formation of 5-lipoxygenase blocking-up inflammatory mediator leukotriene produces.
7. according to the application described in claim 3-4, it is characterized in that: wherein said arachidonic acid is the chronic dull pains such as inflammation, gout, headache, toothache, neurodynia and arthrodynia through the relative disease of the catalysis generation leukotriene of 5-lipoxygenase.
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