CN1222153A - Piperidine acetic acid derivatives and their use in treatment of thrombotic disorders - Google Patents
Piperidine acetic acid derivatives and their use in treatment of thrombotic disorders Download PDFInfo
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- CN1222153A CN1222153A CN 97195652 CN97195652A CN1222153A CN 1222153 A CN1222153 A CN 1222153A CN 97195652 CN97195652 CN 97195652 CN 97195652 A CN97195652 A CN 97195652A CN 1222153 A CN1222153 A CN 1222153A
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Abstract
The invention relates to compounds of formula (I) or a salt, solvate, or physiologically functional derivative thereof, in which X represents either CH2-CH2 or CH=CH; Y represents a group (a) or (b); R<0> represents SO2Me or CONH2, and R<1> represents SO2Me, to processes for their preparation, to pharmaceutical compositions containing such compounds and to their use in medicine, particularly in the treatment of thrombotic disorders.
Description
The present invention relates to acetogenin, its preparation method, contain the pharmaceutical composition of this compound and the purposes in medicine thereof.
People are common to think that glycoprotein title complex Gp II b/ III a transmits platelet aggregation and the required adhesive function of thrombosis as the Fibrinogen combining site on the thrombocyte.We have now found that a class non-peptide compound, and they are attached to the fibrinogen deceptor Gp II b/ III a title complex of inferring by the retardance Fibrinogen and suppress the platelet aggregation effect that Fibrinogen relies on.
Disclosed pending application WO 96/20192 and WO96/41803 have described compound, its preparation method and the purposes in medicine thereof of the platelet aggregation function inhibitor that serves as the Fibrinogen dependence after priority date of the present invention.
Therefore the present invention provides a kind of formula I compound
Or its salt, solvate or physiologic function derivative, wherein: X represents CH
2-CH
2Or CH=CH; Y represents group
R
0Represent SO
2Me or CONH
2And R
1Represent SO
2Me.
(I is compound a) to have the present invention further provides a kind of formula
Or its salt, solvate or physiologic function derivative, wherein: X represents CH
2-CH
2Or CH=CH.
The present invention further provides a kind of formula (I b) compound
Or its salt, solvate or physiologic function derivative, wherein: X represents CH
2-CH
2Or CH=CH.
The present invention further provides a kind of formula (I c) compound
Or its salt, solvate or physiologic function derivative, wherein: X represents CH
2-CH
2Or CH=CH.
Being suitable for compound of the present invention comprises: 4-[3-methylsulfonyl-5-(the 2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[3-methylsulfonyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate; And salt, solvate and physiologic function derivative.
Be more suitable for comprising in compound of the present invention: 4-[3-carbamyl-5-(the 2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[3-carbamyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate; And salt, solvate and physiologic function derivative.
Further being suitable for compound of the present invention comprises: 4-[1-methylsulfonyl-6-(the 2-piperidin-4-yl-(E)-vinyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate; 4-[1-methylsulfonyl-6-(2-piperidin-4-yl-ethyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate; And salt, solvate and physiologic function derivative.
The preferred compound of the present invention is { 4-[3-methylsulfonyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate or its salt, solvate or physiologic function derivative.
The preferred compound of the present invention is { 4-[3-carbamyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate or its salt, solvate or physiologic function derivative.
A present invention further preferred compound is { 4-[1-methylsulfonyl-6-(2-piperidin-4-yl-ethyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate or its salt, solvate or physiologic function derivative.
This paper is following all to refer to aforesaid formula I and formula to quoting of " formula I compound " or " The compounds of this invention " (I is a) to (I c) compound and salt, solvate or physiologic function derivative.
Term " physiologic function derivative " refers to the chemical derivative of formula I compound, they with body in the free formula I compound that for example gets by conversion have identical physiological function.According to the present invention, the example of physiologic function derivative comprises the wherein adorned formula I compound of carboxyl, for example becomes carboxylicesters, as C
1-6Alkyl ester.
Be applicable to that gegenion or related solvents are pharmaceutically acceptable in the salt and solvate of formula I compound of medicine.But, have the salt of non-pharmaceutically acceptable gegenion or related solvents and solvate also within the scope of the present invention, can be used as the intermediate of acceptable derivates on preparation formula I compound and pharmacy acceptable salt, solvate and the physiology.
The pharmacy acceptable salt of the formula I compound that is fit to comprises and mineral acid or the formed acid salt of organic acid (for example hydrogen chlorate, hydrobromate, vitriol, phosphoric acid salt, benzoate, naphthoate, Hydroxynaphthoate, tosilate, mesylate, sulfamate, ascorbate salt, tartrate, salicylate, succinate, lactic acid salt, glutarate, glutaconate, acetate, tricarballylic acid salt, Citrate trianion, fumarate and maleate) and inorganic base salts, as an alkali metal salt (for example sodium salt).The hydrogen chlorate of formula I compound is that some administering mode institute is preferred.The salt of other formula I compounds comprises and the formed salt of trifluoroacetic acid.
The pharmaceutically acceptable solvate of the formula I compound that is fit to comprises hydrate.
Term " alkyl " refers to a straight or branched alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl or the tertiary butyl as the part of a group or group.
The present invention has been understood that to contain all isomer and salt, solvate and the physiologic function derivative of formula I compound, comprises all how much, change and optically-active form, and composition thereof (for example racemic mixture).
Term " pharmaceutically acceptable derivates " refers to pharmacy acceptable salt, solvate or the physiologic function derivative of the formula I compound of definition as mentioned ".
Use Born type optics congregation survey meter, (1962 " natures " 194 confirm that 927-929) the formula I compound has the hematoblastic congregation of inhibition for Born, G.V. in the research of being undertaken by the thrombocyte (HRP) to resuspending after people's the washing.
In view of its fibrinogen antagonist agent activity, formula I compound and pharmaceutically acceptable derivates thereof are significant to being used for people and veterinary drug, especially for the treatment thrombotic diseases.The object lesson of thrombotic diseases is known in the art, comprise obliterative vascular disease, as myocardial infarction, heart mortality disease, angina, moment ischemic and thrombus outbreak, arteriosclerosis, vessel wall disease, peripheral vascular disease, ephrosis, retinopathy, postoperative thrombosis, pulmonary infarction, venous thrombosis and retinal vein thrombosis form.Formula I compound and pharmaceutically acceptable derivates thereof also are effectively to being used for prophylactic treatment intra-operative and post-operative complication, as organ transplantation (particularly heart and renal transplantation), coronary bypass-forming operation, peripheral arterial bypass, angioplasty, thrombolysis and endarterectomy.
Formula I compound and pharmaceutically acceptable derivates thereof also can be used for treating other diseases, and these diseases relate to glycoprotein title complex Gp II b/ III a or other integrin receptors.For example, formula I compound and pharmaceutically acceptable derivates thereof can promote wound healing, are used for the treatment of the osteopathia that is caused or caused by bone resorption.The object lesson of osteopathia is known in the art, comprises osteoporosis, malignant hypercalcemia, diostosis are rotten to the corn around the joint in the osteopenia, periodontal disease, hyperparathyroidism, rheumatoid arthritis due to changing, Paget is sick, clamping plate fixedly bring out osteopenia and glucocorticoid therapy.
Formula I compound and pharmaceutically acceptable derivates thereof also can be used for the treatment of some Cancerous disease, for example the transfer of prevention or delay cancer.
Formula I compound or its pharmaceutically acceptable derivates of a kind of people of being used for or veterinary drug have been the present invention further provides, especially for the treatment of thrombotic diseases.
According to another aspect of the present invention, we provide, and a kind of to be used for the treatment of with glycoprotein title complex Gp II b/ III a or other integrin receptors be sick sick the formula I compound and the pharmaceutically acceptable derivates thereof of inducing media.
According to further aspect of the present invention, what we provided a kind of human or animal of treatment is the method for inducing the disease of media with glycoprotein title complex Gp II b/ III a or other integrin receptor, and this method comprises the formula I compound of significant quantity or its pharmaceutically acceptable derivates described curee's administration.
According to another aspect of the present invention, we provide formula I compound or the purposes of its pharmaceutically acceptable derivates in the therapeutical agent of preparation treatment thrombotic diseases.
According to further aspect of the present invention, we provide the method for a kind of human or animal's of treatment thrombotic diseases, and this method comprises the formula I compound of significant quantity or its pharmaceutically acceptable derivates described curee's administration.
Unless clear and definite explanation is arranged in addition, " treatment " speech should be understood that both to have comprised the treatment of determining symptom, also comprise prophylactic treatment.
Self-evident, it is favourable using the uniting of formula I compound and pharmaceutically acceptable derivates thereof and one or more other treatment agent.The example that is suitable for the medicament of adjunctive therapy comprises thrombolytic agent or other stimulate thrombolysis or Fibrinolytic compound and cell toxicity medicaments arbitrarily.The present invention has been understood that to cover the purposes that formula I compound or its pharmaceutically acceptable derivates and one or more other treatment agent are united use.
Formula I compound and pharmaceutically acceptable derivates thereof are comparatively convenient with the form administration of pharmaceutical composition.Therefore in another aspect of this invention, we provide the pharmaceutical composition that contains formula I compound or its pharmaceutically acceptable derivates of a kind of people of being applicable to or veterinary drug.Said composition when using in a usual manner, can be easily with one or more physiology on the form of mixtures of acceptable carrier or excipient exist.
Formula I compound and pharmaceutically acceptable derivates thereof are can be formulated into the preparation of administration in any appropriate manner.For example this compound can be mixed with topical or pass through inhalation, the more preferably formulation of oral administration, transdermal administration or parenteral admin.
Concerning oral administration, this pharmaceutical composition for example can adopt the formulation of tablet, capsule, medicinal powder, solution, syrup or suspension, according to a conventional method with acceptable excipient preparation.
Concerning transdermal administration, this pharmaceutical composition can be in the mode of transdermal patch, and for example transdermal iontophoretic pastes.In preferred mode, the invention provides a kind of iontophoresis releasing unit (for example iontophoresis subsides), this assembly contains formula I compound or its pharmaceutically acceptable derivates, and a kind of pharmacy acceptable salt is advisable with hydrogen chlorate's example.Iontophoresis assembly and system are that prior art is known, for example, WO-A 9116946, WO-A 9116944, WO-A 9116943, WO-A9115261, WO-A 9115260, WO-A 9115259, WO-A 9115258, WO-A9115257, WO-A 9115250, WO-A 9109645, WO-A 9108795, WO-A9004433, WO-A 9004432, WO-A 9003825, EP-A 254965, US4717378, EP-A252732 and GB-A2239803, these all introduce reference of the present invention.
Concerning parenteral admin, this pharmaceutical composition can provide (for example intravenously, intramuscular or subcutaneous) in the mode of injection or lasting transfusion.Said composition can be taked the formulations such as suspension, solution or emulsion in oil or the aqueous carrier, and can contain preparaton, as suspension agent, stablizer and/or dispersion agent.Concerning drug administration by injection, they can take the form of single dose or the form of multiple doses, preferably add a kind of sanitas.
Perhaps, the activeconstituents of parenteral admin can be the powder type with a kind of suitable carrier reorganization.
Formula I compound and pharmaceutically acceptable derivates thereof also can be made into to accumulate preparation.This prolonged action preparation can pass through embedment method (for example subcutaneous or intramuscular) administration, or by the intramuscularly administration.For example, compound and suitable polymkeric substance or lyophobic dust (for example emulsion in a kind of acceptable oil) or ion exchange resin can be prepared, perhaps make restraining property soluble derivative, for example a kind of have restraining property dissolved salt.
As mentioned above, formula I compound and pharmaceutically acceptable derivates thereof also can be used in combination with the other treatment agent.Therefore the present invention further provides a kind of medicine that formula I compound or its pharmaceutically acceptable derivates share with another kind of therapeutical agent (particularly thrombolytic agent) that contains.
Above-mentioned share can be easily in the mode of pharmaceutical preparation, and the pharmaceutical preparation that therefore contains above-mentioned combination and a kind of pharmaceutically acceptable carrier or excipient has constituted the content of the further aspect of the present invention.Each composition in this associating both can sequential administration, also administration simultaneously in the pharmaceutical preparation of isolating or associating.
When the therapeutic activity agent of formula I compound or its pharmaceutically acceptable derivates and second kind of anti-same disease is united when using, the dosage the when dosage of every kind of compound can be different from compound and is used alone.Suitable dosage is that those skilled in the art understand easily.
Concerning people's treatment, suggestion dosage every day of formula I compound is 0.01mg/kg to 30mg/kg, and can divide 1 to 4 administration easily.Used exact dosage desired will depend on patient's age and the state of an illness and route of administration.For example, dosage every day of 0.1mg/kg to 10mg/kg is applicable to the whole body administration.
Formula I compound and salt thereof, solvate and physiologic function derivative can be prepared according to any known process in the compound field of analog structure, for example according to following method.
According to method (A), in the presence of transition-metal catalyst, also at high temperature, make formula II compound or its protected derivative
Wherein the Y definition is as formula I, and R represents a leavings group, as chlorine, bromine or iodine, or one-OSO
2CF
3Group is with formula III compound or its protected derivative
Reaction can make the formula I compound.Suitable transition-metal catalyst comprises palladium catalyst, as palladium triaryl phosphine catalyzer.Suitable temperature, from about 20 ℃ to about 160 ℃, as 80 to 120 ℃, or the reflux temperature of solvent.This reaction should be in the presence of a kind of alkali such as tertiary amine, carry out in a kind of solvent, as a kind of polar solvent, and N for example, dinethylformamide.
According to another kind of method (B), utilize other formula I compounds as precursor, can prepare the formula I compound by tautomerization.
For example, wherein X represents CH
2-CH
2The formula I compound can represent the corresponding formula I compound of CH=CH or its protected derivative to prepare from X wherein by hydrogenation.This hydrogenation can carry out in the presence of a kind of transition-metal catalyst, as Raney nickel or a kind of palladium, platinum or rhodium catalyst.Reaction should be carried out in a kind of solvent, as a kind of alcohol (for example ethanol).
Alternative method is that available chemical process is carried out hydrogenation, for example uses imide.Imide should be on the spot generates from a kind of suitable salt (as diazene dicarboxylic acid, di-potassium), and this reaction should be carried out in the presence of a kind of solvents (for example methyl alcohol) such as a kind of acid such as acetate and alcohol.
Self-evidently for a person skilled in the art be, in the aforesaid method arbitrary steps with molecule in one or more sensitive group protect to prevent that unwanted side reaction from taking place, these all are necessary or need.
Therefore the another kind of method (C) for preparing the formula I compound comprises goes the formula IV compound to protection
Wherein X and Y definition is as the formula I compound, and P ＇ is a carboxyl or protected carboxyl, and P ＂ is hydrogen or an amido protecting group, and its condition is that then P ＂ is not a hydrogen if P ＇ is a carboxyl, if P ＇ is a hydrogen, then P ＂ is not a carboxyl.
The formula IV compound is (A) and (B) preparation according to the method described above, or uses any appropriate means preparation, method as be shown in the examples.
In the detailed embodiment of method (C), the formula I compound can be from the preparation of the protected derivative of the carboxyl of formula I compound, i.e. formula IV compound, and wherein P ＇ is protected carboxyl.In the further embodiment of this method, the formula I compound can be from the amino of formula I compound and/or the protected derivative preparation of carboxyl, i.e. formula IV compound, and wherein P ＂ is the amido protecting group.
The blocking group that is used to prepare the formula I compound can use in the usual way.For example described referring to Theodora W.Green work " blocking group in the organic synthesis " second edition (John Wiley and Sons, 1991), this book has also been described the method for removing these groups.
Detailed protected carboxyl for example comprises carboxylic acid ester groups; as alkyl-carboxylic acid or aralkyl ester, for example the alkyl of this ester functional group or aralkyl moiety are methyl, ethyl, the tertiary butyl, methoxymethyl, phenmethyl, diphenyl-methyl, trityl or p-nitrophenyl methyl.When this ester is a kind of non-branched-chain alkyl (for example methyl) ester, go provide protection both can under the alkaline hydrolysis condition, carry out, for example use lithium hydroxide, also can under the acidic hydrolysis condition, carry out, for example use spirit of salt.The tertiary butyl and trityl ester group can be removed under the acid hydrolysis condition, for example at room temperature with formic acid or trifluoroacetic acid, or with the acetic acid solution of spirit of salt.Phenmethyl, diphenyl-methyl and oil of mirbane methyl ester group can be removed by hydrogenolytic cleavage in the presence of a kind of metal catalyst (for example palladium).
Detailed amido protecting group for example comprises aralkyl, as phenmethyl, diphenyl-methyl or trityl; Acyl group is as N-benzyloxy carbonyl, tert-butoxycarbonyl or trifluoroacetyl group.Can remove acyl group with reference to above-mentioned standard conditions.
The specific isomeric forms of formula I compound if desired; required isomer can separate easily with preparative high performance liquid chromatography (h.p.l.c.); with the ultimate aim compound sample introduction of aforesaid method (A) to (C), or at described method sample introduction before arbitrarily step is protected in final going.
Formula II and formula IV compound or its protected derivative can prepare with any appropriate means, for example the method described in the embodiment.
Above-mentioned some intermediate is novel compound, therefore can be regarded as the content that all novel intermediates of this paper have constituted the further aspect of the present invention.The formula II compound; [4-(5-bromo-3-methylsulfonyl-indazole-1-yl)-piperidines-1-yl]-tert.-butyl acetate and 5-bromo-1-(1-tert-butoxycarbonyl methyl-piperidin-4-yl)-1H-indazole-3-carboxylate methyl ester for example; be crucial intermediate, represent particular aspects of the present invention.The formula IV compound also is an importance of the present invention, comprises 4-{2-[1-(1-tert-butoxycarbonyl methyl-piperidin-4-yl)-3-methylsulfonyl-1H-indazole-5-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester; 1-(1-tert-butoxycarbonyl methyl-piperidin-4-yl)-5-[2-(1-tert-butoxycarbonyl-piperidin-4-yl)-(E)-vinyl]-1H-indazole-3-carboxylate methyl ester; 4-{2-[1-(1-tert-butoxycarbonyl methyl-piperidin-4-yl)-3-carbamyl-1H-indazole-5-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester; and 4-{2-[3-(1-tert-butoxycarbonyl methyl)-piperidin-4-yl)-1-methylsulfonyl-1H-indazole-6-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester.
The compounds of this invention is separated along with making acid salt (for example trifluoroacetate or hydrogen chlorate).The pharmaceutically-acceptable acid addition of The compounds of this invention can prepare from corresponding trifluoroacetate by conventional ion exchange method, for example trifluoroacetate is used such as a kind of alkali neutralizations such as aqueous NaOHs, add a kind of suitable organic or inorganic acid then, for example spirit of salt.Perhaps, go protection, can directly make pharmaceutically-acceptable acid addition by this with suitable organic or inorganic acid (for example spirit of salt).By add a kind of suitable highly basic, as sodium hydroxide, also can make the inorganic base salts of The compounds of this invention from corresponding trifluoroacetate.
The working method of one of aforesaid method step can generate the solvate (for example hydrate) of The compounds of this invention.
The following example illustrates the present invention, but in no case limits the present invention.All temperature are all with a ℃ expression.Tlc (T.I.C.) is carried out on silica-gel plate.Except as otherwise noted, preparative high performance liquid chromatography (h.p.l.c.) uses Dynamax60ACl88 μ M 25cm * 41.4mmi.d. post, wash-out consists of (ⅰ) 0.1% trifluoroacetic acid aqueous solution with solvent mixture, (ⅱ) acetonitrile, this elutriant is expressed as in the solvent mixture percentage that contains (ⅱ), and used flow velocity is per minute 45ml.Except as otherwise noted, analysis mode h.p.l.c. uses Dynamax 60A,Cl8 8 μ M 25cm * 4.6mmi.d. posts, wash-out is with the consisting of of solvent mixture (ⅰ) and (ⅲ) acetonitrile solution of 0.05% trifluoroacetic acid, this elutriant is expressed as in the solvent mixture percentage that contains (ⅲ), and used flow velocity is per minute 1ml.Used following abbreviation: the Me=methyl; The Et=ethyl; The THF=tetrahydrofuran (THF); DMF=N, dinethylformamide; The TR=hplc retention time.Embodiment 1{4-[3-methylsulfonyl-5-(2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-synthetic (ⅰ) 5-bromo-2-nitro-2H-indazole of acetate three (trifluoro-acetate)
In the diacetyl oxide (410ml) that stirs, dripping nitrosonitric acid (8.5ml) under-5 ℃.After 20 minutes, solution is cooled to-15 ℃, and remains on-15 ° of following gradation adding 5-bromo-indazoles
1(7.70g).Mixture stirs 2h down at-15 °.Solid collected by filtration also distributes it between diethyl ether and 5M aqueous NaOH.The waterbearing stratum extracts with diethyl ether, the organic extract liquid drying (Na that has merged
2SO
4) and evaporation in a vacuum, obtain target compound, be an orange solids (7.54g).Chromatogram m/z243 (MH
+) 1 reference: C.Dell ＇ Erba etc., " tetrahedron " 1994,50,3529 (ⅱ) 5-bromo-3-methylsulfonyl-1H-indazole
5-bromo-2-nitro-2H-indazole (3.12g) and the mixture of methyl-sulfinic acid sodium (2.89g) in DMF (20ml) are stirred 5h down at 20 °.Mixture concentrates in a vacuum, and resistates is distributed between methylene dichloride and saturated aqueous sodium bicarbonate.The waterbearing stratum dichloromethane extraction.Organic extract liquid drying (the Na that has merged
2SO
4) and concentrate in a vacuum, obtain target compound, be a yellow solid (1.88g).Mass spectrum m/z 294 (MNH
4 +).(ⅲ) 4-(5-bromo-3-methylsulfonyl-indazole-1-yl)-piperidines-1-carboxylic acid tert-butyl ester
With 5-bromo-3-methylsulfonyl-1H-indazole (1.20g), 4-mesyloxy-piperidines-1-carboxylic acid tert-butyl ester 2 (1.58g), salt of wormwood (1.81g) and the N that stirs, dinethylformamide (20ml) heats 18h down at 100 ℃.Chilled mixture concentrates in a vacuum.Resistates is made with extra care (Merck9385) with silica gel flash chromatography method, uses ethyl acetate: 1: 5 wash-out of hexanaphthene, obtain target compound, and be a butteriness solid (1.37g).Mass spectrum m/z (459) (MH
+).2 references: EP-A-0,560 268 Al (ⅳ) 5-bromo-3-methylsulfonyl-1-piperidin-4-yl-1H-indazole
Trifluoroacetic acid (10ml) solution of 4-(5-bromo-3-methylsulfonyl-indazole-1-yl)-piperidines-1-carboxylic acid tert-butyl ester (1.36g) is stirred 1.5h down at 20 °.In a vacuum except that desolvating and resistates being distributed between methylene dichloride and 0.5M aqueous NaOH.The waterbearing stratum dichloromethane extraction, the organic extract liquid salt water washing that has merged, dry (Na
2SO
4) and concentrate in a vacuum, obtain target compound, be a butteriness solid (0.90g).Mass spectrum m/z360 (MH
+).(ⅴ) [4-(5-bromo-3-methylsulfonyl-indazole-1-yl)-piperidines-1-yl]-tert.-butyl acetate
At N, the mixture in the dinethylformamide (15.0ml) stirs 20h down at 20 ° with 5-bromo-3-methylsulfonyl-1-piperidin-4-yl-1H-indazole (0.90g), bromo-acetic acid tert-butyl (0.390ml) and sodium bicarbonate (0.380g).Mixture concentrates in a vacuum, and resistates is distributed between methylene dichloride and water.The waterbearing stratum dichloromethane extraction, the organic layer that has merged concentrates in a vacuum.Resistates is refining with silica gel flash chromatography method (Merck 9385), with ethyl acetate-hexanaphthene (1: 4 to 1: 3 gradient) wash-out, obtains target compound, is a butteriness solid (0.870g).Mass spectrum m/z 474 (MH
+).(ⅵ) 4-{2-[1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-3-methylsulfonyl-1H-indazole-5-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester
Under nitrogen, with [4-(5-bromo-3-methylsulfonyl-indazole-1-yl)-piperidines-1-yl]-tert.-butyl acetate (0.350g), the 4-vinyl-piperidines-1-carboxylic acid tert-butyl ester that stirs
3(0.177g), triethylamine (0.320ml), acid chloride (II) (0.014g), tri-o-tolyl phosphine (0.037g) and N, the mixture of dinethylformamide (2.50ml) is at 110 ° of heating 16h down.Chilled mixture concentrates in a vacuum, and it is distributed between ethyl acetate and saturated aqueous sodium bicarbonate.The waterbearing stratum ethyl acetate extraction, the organic layer that has merged concentrates in a vacuum.Resistates is refining with silica gel flash chromatography method (Merck9385), uses methylene dichloride: ethanol: 880 ammoniacal liquor (80: 18: 2) wash-out, obtain target compound, and be a white solid (0.270g).Mass spectrum m/z603 (MH
+) 3 with reference to PCT/EP 95/05043 (ⅶ) { 4-[3-methylsulfonyl-5-(2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-acetate trifluoroacetate
With 4-{2-[1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-3-methylsulfonyl-1H-indazole-5-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester (0.270g) is dissolved in trifluoroacetic acid (10ml), and mixture stirs 5h down at 20 °.Mixture concentrates in a vacuum, and resistates is by making with extra care with the method for diethyl ether development.Filtering and collect gained solid and dry in a vacuum, obtain target compound, is a butteriness solid (0.170g).Mass spectrum: m/z447 (MH
+) analysis measured value: C, 42.0; H, 3.9; N, 6.8; S, 3.9C
22H
30N
4O
4S.3.2CF
3CO
2H requires: C, 42.0; H, 4.1; N, 6.9; S, 3.95% embodiment 2{4-[3-methylsulfonyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-the synthetic method A of acetate trifluoroacetate
Under room temperature and pressure; will [4-[3-methylsulfonyl-5-(2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-acetate three (trifluoro-acetate) (0.782g) carries out hydrogenation; 10% palladium carbon (50% is used in reaction; stick with paste; 0.20g), and at water: ethanol carries out 6h in 70: 30.Leach catalyzer, evaporating solvent obtains a yellow oil (0.577g) in a vacuum.(gradient scope 10-75% (ⅱ) 20 minutes, 250nM detects, RT 10.3 minutes) is refining with preparation HPLC, and the gained jelly is developed with anhydrous diethyl ether, obtains target compound, is a white solid (0.180g).Mass spectrum m/z449 (MH
+) analysis measured value: C, 44.6; H, 5.2; N, 7.8; S, 4.3C
22H
32N
4O
4S.2.4CF
3COOH requires: C, 44.6; H, 4.8; N, 7.8; S, 4.4 method B (a) 4-bromo-(2-methylthiomethyl) aniline
Under 0 to-5 ℃, in methylene dichloride (3750ml) solution of the N-chloro-succinimide (139.7g) that stirs, drip dimethyl sulphide (105ml), the gained suspension is cooled to-20 ℃.To the methylene dichloride that wherein drips 4-bromaniline (150.0g) (300ml) solution, suspension stirs 0.5h down at-20 ℃, and reaction mixture dilutes with triethylamine (292ml).Reaction mixture stirs 58h at ambient temperature, and water, 2N spirit of salt, 8%w/w contain the sodium bicarbonate washing, dry (Na
2SO
4) and evaporation in a vacuum, obtain target compound, be a faint yellow solid (162.0g).Mass spectrum m/z232.9 (MH
+) (b) 5-bromo-3-methyl sulfane base (sulfanyl)-1H-indazole
Under 10-15 ℃, in water (815ml) solution of 4-bromo-(2-methylthiomethyl) aniline (163.0g) that stirs and fluoroboric acid (230ml, the 48% w/w aqueous solution), drip water (100ml) solution of sodium cyanide (48.4g).The yellow suspension of gained stirs 1h at ambient temperature, and the filtering separation solid with this solid water and diethyl ether washing, is suspended in the chloroform (4000ml) at last.The suspension that stirs is handled with potassium acetate (138.0g) and hexaoxacyclooctadecane-6-6 (9.30g), and stirs 2h at ambient temperature.Reaction mixture is filtered, and filtrate is washed with 2N sodium hydroxide, dry (Na
2SO
4) and evaporation in a vacuum, obtain target compound, be a faint yellow solid (147.7g).Mass spectrum m/z243.9 (MH
+) (c) 5-bromo-3-methylsulfonyl-1H-indazole
Gradation adds oxone TM (182.2g) in the methyl alcohol (450ml) of the 5-bromo-3-methyl sulfane base-1H-indazole (36.0g) that stirs and water (135ml) suspension.Reaction mixture stirs 3h at ambient temperature, concentrates in a vacuum, and gained oily matter is distributed between ethyl acetate and water.Separate this two-phase mixture, contain the water ethyl acetate extraction, the organic phase that has merged is with 8%w/w aqueous carbonic acid hydrogen sodium and water washing, dry (Na
2SO
4) and evaporation in a vacuum, obtain target compound, be an incomplete white solid (38.8g).Mass spectrum m/z293.9 (MNH
4 +) (d) 4-[3-methylsulfonyl-5-{1-(1-tertiary butyloxycarbonyl ylmethyl-2-piperidin-4-yl-ethyl)-1H-indazole-1-yl]-the 1-pyridylacetic acid(HPAC) tert-butyl ester
In the ethanol (77ml) of 10% Pd/C of pre-hydrogenation (115.5g) and water (19ml) suspension, add 4-{2-[1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-3-methylsulfonyl-1H-indazole-5-yl]-(E)-vinyl }-ethanol (760ml) solution of the 1-Piperidineacetic acid tert-butyl ester (77.0g), the suspension that gained stirs is hydrogenation 26h at ambient temperature.Reaction mixture filters by hyflo, the resistates washing with alcohol, and the filtrate that will merge is evaporated in a vacuum, obtain a light green oily matter, refining with the Biotage chromatography, use ethyl acetate: hexanaphthene (1: 1) wash-out, obtaining target compound, is a colloidal solid (46.8g).Mass spectrum m/z 605.3 (MH
+) (e) two hydrochloric acid 4-[3-methylsulfonyl-5-(2-piperidin-4-yl-ethyl)-1H-indazole-1-yls]-the 1-Piperidineacetic acid
With 4-[3-methylsulfonyl-5-{1-tertiary butyloxycarbonyl ylmethyl-2-piperidin-4-yl-ethyl) }-1H-indazole-1-yl]-trifluoroacetic acid (250ml) solution of the 1-Piperidineacetic acid tert-butyl ester (25.0g) stirs 4h at ambient temperature.Reaction mixture evaporates in a vacuum, resistates is refining with preparation HPLC, water: acetonitrile: trifluoroacetic acid wash-out (90: 10: 0.1 to 25: 75: 0 gradients, 20 minutes, 260nm detected, RT13 minute), obtain a white solid, it is dissolved in 2N hydrochloric acid, and evaporation in a vacuum, a white solid obtained.The dissolving with hydrochloric acid step repeats twice.This white solid is developed with acetone (100ml), and suspension evaporates in a vacuum.Solid is used acetone (100ml) development once more, and suspension stirs 0.5h and filtering separation solid at ambient temperature, is dried to constant weight with washing with acetone and in 45 ℃ of following vacuum, obtains target compound, is a white crystals shape solid (10.03g).Analyze measured value: C, 46.9; H, 6.8; N, 9.9C
22H
32N
4O
4S.2HCl.2H
2O requires: C, 47.3; H, 6.8; N, 10.0% embodiment 3{4-[3-carbamyl-5-(2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-synthetic (a) 5-bromo-1-(1-tertbutyloxycarbonyl-piperidin-4-yl)-1H-indazole-3-carboxylate methyl ester of acetate trifluoro-acetate
To contain 4-mesyloxy-piperidines-1-carboxylic acid tert-butyl ester 2 (40.9g, 5-bromo-1H-indazole-3-carboxylic acid 153mmol)
4(15.75g 140mmol) handles, and stir 24h under nitrogen, reflux conditions anhydrous THF (400ml) solution of methyl esters (35.8g) with potassium tert.-butoxide.After the cooling, mixture evaporates in a vacuum, and resistates is handled with moisture saturated ammonium chloride (400ml).The mixture ethyl acetate extraction, merging, dry (Na
2SO
4) after organic extract liquid be evaporated on the silica gel in a vacuum.As silica gel flash distillation column packing, use hexanaphthene with silica obtained: ethyl acetate (19: 1 to 3: 1 gradients) wash-out, obtain a kind of isomer earlier, be target product (22.8g) then.T.l.c.SiO
2(hexanaphthene: EtOAc, 7: 3), Rf 0.29
4Reference: G.A.Bistrocchi etc. " Farmaco.Ed.Sci. " 1981,36,315 (b) 5-bromo-1-piperidin-4-yl-1H-indazole-3-carboxylate methyl ester two (trifluoro-acetate)
Under 23 °, last 1 minute, in 5-bromo-1-(1-tertbutyloxycarbonyl-piperidin-4-yl)-1H-indazole-3-carboxylate methyl ester (22.75g), add trifluoroacetic acid (100ml).Behind the 1h, mixture evaporate in a vacuum and with the methylene dichloride coevaporation, obtain target product (28.05g), be a light yellow solid.T.l.c.SiO
2(CH
2Cl
2: EtOH:880NH
3, 89: 10: 1), Rf0.18 (c) 5-bromo-1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-3-carboxylate methyl ester
Under nitrogen, 23 °, while stirring 5-bromo-1-piperidin-4-yl-1H-indazole-3-carboxylate methyl ester two (trifluoro-acetate) (28.05g) is handled with diisopropyl ethyl amine (25.9ml) with bromo-acetic acid tert-butyl (7.3ml) DMF (500ml) solution, and kept 4 days.Further add bromo-acetic acid tert-butyl (1.4ml), be diisopropyl ethyl amine (5.0ml) and continue to stir 2h then.Mixture evaporates in a vacuum, handles with moisture saturated sodium bicarbonate (400ml), and uses ethyl acetate extraction.Merging, dry (Na
2SO
4) after organic extract liquid evaporate in a vacuum, resistates is crystallization from ethyl acetate, obtains target product (13.43g).T.l.c.SiO
2(hexanaphthene: EtOAc, 7: 3) .Rf0.17 (d) 1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-5-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl)-(E)-vinyl]-1H-indazole-3-carboxylate methyl ester
With 5-bromo-1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-3-carboxylate methyl ester (13.43g), 4-vinyl-piperidines-1-carboxylic acid tert-butyl ester (6.90g), acid chloride (II) (666mg), tri-o-tolyl phosphine (1.81g), triethylamine (12.4ml, 89.1mmol), and the mixture of DMF (200ml) stirs 15h under 120 °, nitrogen.After the cooling, mixture evaporates in a vacuum, handles with moisture saturated sodium bicarbonate (200ml), and uses ethyl acetate extraction.Merging, dry (Na
2SO
4) after organic extract liquid evaporate in a vacuum, resistates is refining with silica gel flash chromatography method.Use methylene dichloride: ethanol: 880 ammoniacal liquor gradient elutions (989: 10: 1 to 978: 20: 2 gradients), obtain target compound, be a light orange foam, (8.94g).T.l.c.SiO
2(CH
2Cl
2: EtOH: 880NH
3, 978: 20: 2) and Rf0.14 (e) 4-{2-[1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-3-carbamyl-1H-indazole-5-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester
With 1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-5-[2-(1-tertbutyloxycarbonyl-piperidin-4-yl)]-(E)-vinyl]-solution of 1H-indazole-3-carboxylate methyl ester (600mg) in using the satisfied methyl alcohol of ammoniacal liquor (20ml) heating 50h under 80 °.Cooled solution is evaporated in a vacuum, and resistates is refining with silica gel flash chromatography method.Use methylene dichloride: ethanol: 0.88 ammoniacal liquor gradient elution (989: 10: 1 to 967: 30: 3 gradients) obtains target product, with a white foam (373mg).T.l.c.SiO
2(CH
2Cl
2: EtOH: 880NH
3, 978: 20: 2) Rf 0.08 (f) 4-[3-carbamyl-5-(the 2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-the acetate trifluoro-acetate
With 4-{2-[1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-3-carbamyl-1H-indazole-5-yl]-(E)-vinyl }-trifluoroacetic acid (6ml) solution of piperidines-1-carboxylic acid tert-butyl ester (292mg) keeps 2h down at 23 °.Solution evaporates in a vacuum, with water (3ml) coevaporation, and with the diethyl ether development, obtains target product, is a white solid (311mg).Mass spectrum m/z412 (MH
+) analysis measured value: C, 45.0; H, 4.8; N, 9.4C
22H
29N
5O
3, 2.8CF
3CO
2H requires: C, 45.4; H, 4.4; N, 9.6% embodiment 4{4-[3-carbamyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate trifluoro-acetate method A
Add in water (10ml) suspension of 10% palladium on the activated carbon (70mg) of pre-hydrogenation { 4-[3-carbamyl-5-(2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-water (40ml) solution of acetate trifluoro-acetate (100mg), and under hydrogen, stir 4h.Leach catalyzer, washing, filtrate is handled with trifluoroacetic acid (2).Solution evaporates in a vacuum, and resistates is developed with ether, obtains target product, is a pure white crystallization (74mg).Mass spectrum m/z414.1 (MH
+) analysis mode HPLC RT analysis in 9.2 minutes measured value: C, 45.7; H, 4.9; N, 9.9C
22H
31N
5O
3, 2.65CF
3CO
2H requires: C, 45.8; H, 4.7; N, 9.8% method R (a) 5-bromo-3-formyl radical-1H-indazole
Under 20-25 °, last 0.5h to 5-bromo indole (100g) and 1 of sodium cyanide (350g), the stable 3N spirit of salt (18L) that adds makes it be acidified to pH2.5 in 4-dioxane (3.5L) and water (18vol) solution.Mixture stirs 0.75h, uses ethyl acetate extraction then.The organic extract liquid that has merged dilutes with ethyl acetate (IL) and washes with water.The water washing ethyl acetate extraction that has merged.Organic layer washes with water, and the organic extract liquid merging evaporation with main obtains a black dull-brown solid.This solid filters with ethyl acetate (200ml) development 1h, and filter cake obtains target compound with ethyl acetate washing and dry, is a reddish-brown solid (60.8g).Mass spectrum m/z223,225[M-H
+]
-(b) 5-bromo-3-cyano group-1H-indazole
The suspension of 5-bromo-3-formyl radical-1H-indazole (143g) is heated 16h down at 65-70 ° in water (1.4L) solution of oxyamine-0-sulfonic acid (93.4).Last 1h mixture is cooled to 20 °, filter, filter cake washes with water and is dry under 45 ℃, obtains a solid (146g).This solid is reflux 1h and filtration under 90 ℃ in toluene (3.65L).The filtrate reheat obtains a solution, stirs and be cooled to 10 ℃.Filter this suspension, filter cake obtains target compound with toluene wash and dry, is a light brown solid (111g).Mass spectrum m/z220,222[M-H
+]
-(c) 4-(5-bromo-3-cyano group-1H-indazole-1-yl)-piperidines-1-carboxylic acid tert-butyl ester
5-bromo-3-cyano group-1H-indazole (111g), 1-tertbutyloxycarbonyl-4-methylsulfonyl-piperidines (168g) and the suspension of salt of wormwood (193g) in DMF (1.1L) are heated 6h down at 105-110 °; be evaporated to driedly, and orange residue distributed between methylene dichloride and water.Contain water and use dichloromethane extraction once more, the organic phase that has merged washes with water, and evaporation obtains an orange residue (130g).(6: 1,1.04L) development 1h filtered the mixture of this resistates usefulness hexanaphthene and ethyl acetate.Filter cake washs with the mixture of hexanaphthene and ethyl acetate, and drying obtains target compound, is a pale yellow powder (125g).Mass spectrum m/z405,407[MH
+] (d) 5-bromo-1-piperidin-4-yl-1H-indazole-3-carboxylic acid amides
Under 20-30 °, last 1h gradation in the vitriol oil (620g) and add 4-(5-bromo-3-cyano group-1H-indazole-1-yl)-piperidines-1-carboxylic acid tert-butyl ester (62g), suspension stirs 2h.Mixture is poured on the ice (1.24kg), lasts 1.5h and alkalize to pH12 with 5N sodium hydroxide (2.44L) under 20-30 °, water (300ml) dilution is filtered.Filter cake washes with water and is dry, obtains target compound, is an incomplete white solid (51.5g).Mass spectrum m/z323,325[MH
+] (e) 4-(5-bromo-3-aminocarboxyl-1H-indazole-1-yl)-1-Piperidineacetic acid tert-butyl ester
Under 20-30 °, in DMF (1L) solution of 5-bromo-1-piperidin-4-yl-1H-indazole-3-carboxylic acid amides (100g) and triethylamine (43.3ml), add bromo-acetic acid tert-butyl (60.4g) carefully, mixture stirs 2h.Last 1h and drip water (1.5L) under＜25 ° in mixture, suspension stirs 1h, filters.Filter cake washes with water, and drying obtains target compound, is a faint yellow solid (121g).Mass spectrum m/z437,439[MH
+] (f) 4-{2-[3-aminocarboxyl-1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-5-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester
4-(5-bromo-3-aminocarboxyl-1H-indazole-1-yl)-1-Piperidineacetic acid tert-butyl ester (120g), 4-(E)-vinyl-piperidines-1-carboxylic acid tert-butyl ester (60.8g), triethylamine (114.6ml), tri-o-tolyl phosphine (16.7g), acid chloride (6.2g) and the mixture of harborlite J2 flocculating aids (60g) in DMF (2.4L) are heated 14h down at 105-110 °.Mixture is cooled to about 35 °, adds charcoal (30g), and mixture stirs 1h down at about 35 °, is cooled to envrionment temperature then.Mixture filters, filter bed N, dinethylformamide and hexanaphthene washing.Filtrate water (240ml) dilution that has merged, generation is separated, N, dinethylformamide/water extract washs with hexanaphthene, concentrates to obtain a red jelly.This jelly stirs 1h in water (600ml), further add entry (1.8L), and suspension stirs 0.5h, filters.Filter cake washes with water, and drying obtains target compound (153g), is an orange/yellow solid.Mass spectrum m/z568[MH
+] (g) 4-{2-[3-aminocarboxyl-1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-5-yl]-ethyl }-piperidines-1-carboxylic acid tert-butyl ester
To 4-{2-[3-aminocarboxyl-1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-5-yl]-(E)-vinyl }-add 10% palladium carbon catalyst (73.5g) in tetrahydrofuran (THF) (2.94L) solution of piperidines-1-carboxylic acid tert-butyl ester (147g), and under hydrogen, envrionment temperature, stir 5h.For the second time add 10% palladium carbon catalyst (73.5g) and tetrahydrofuran (THF) (200ml), suspension further stirs 18h under hydrogen, add catalyzer (73.5g) and tetrahydrofuran (THF) (200ml) then for the third time, and suspension stirs 20h in addition under hydrogen.Mixture filters, and with the tetrahydrofuran (THF) washing, and evaporation obtains an aterrimus oily matter.This oily matter is refining with the Biotage silica gel chromatography, uses eluent ethyl acetate again with ethyl acetate-hexanaphthene (1: 1) earlier, obtains target compound, is white crystals (32.65g).Mass spectrum m/z570[MH
+] (h) 4-[3-carbamyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-the acetate trifluoro-acetate
In trifluoroacetic acid (330ml), divide two equal portions to add 4-{2-[3-aminocarboxyl-1-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-5-yl]-ethyl]-piperidines-1-carboxylic acid tert-butyl ester (32.65g), solution stirs 3h at ambient temperature.It is heavy that mixture is concentrated into 100g, and make with extra care with preparation HPLC (KromsilC8,10 μ m, anti-phase), and water-acetonitrile-trifluoroacetic acid 90: 10: 25: 75 (B) wash-outs of 0.1%v/v (A) and water-acetonitrile obtain a white solid (26g).This solid (23.6g) is dissolved in hplc grade water (60ml), and under 20-30 °, lasts 0.5h and add 880 ammonia solns (20ml), transfer to pH10.The oyster white suspension stirs 1.5h down at 20 °, filters.Filter cake washes with water, and between twice washing vacsorb 10 minutes, 40 ° down behind the dry 10h under envrionment conditions balance 4h, obtain target compound, be a white powder (12.05g).Mass spectrum m/z414[MH
+] embodiment 5{4-[1-methylsulfonyl-6-(2-piperidin-4-yl-(E)-vinyl)-1H-indazole-3-yl]-piperidines-1-yl }-synthetic (a) 1-[4-(2,4-two bromo-benzoyls)-piperidines-1-yl of acetate]-ethyl ketone (ethanone)
In hydrochloric acid 1-ethanoyl-piperidines-4-carboxyl chlorine 5 (21.8g) that stirs and aluminum chloride (III) mixture (34.5g), add 1,3-dibromobenzene (65ml), mixture heats 1.5h down at 95-100 °.After the cooling, in this mixture impouring ice-water mixture (50ml), use ethyl acetate extraction.Merging, dry (Na
2SO
4) after organic extract liquid evaporate in a vacuum, resistates is refining with silica gel flash chromatography method (Merck9385).With ether-ethanol gradient elution (99: 1 to 90: 10 gradients), obtain target compound, be an orange (16.7g).T.l.c.SiO
2(Et
2O-EtOH, 9: 1) Rf=0.235 reference: EP-A-0 428 437 (b) hydrochloric acid (2,4-two bromo-phenyl)-piperidin-4-yl-ketone
With 1-[4-(2, the 4-two bromo-benzoyls)-piperidines-1-yl that stirs]-ethane ketone (11.00g) heats 7h with the mixture of moisture 5M spirit of salt (60ml) in refluxed under nitrogen.Mixture evaporates in a vacuum, obtains target compound, is a white solid (10.8g).T.l.c.SiO
2(CH
2Cl
2-EtOH-880NH
3, 89: 10: 1) and Rf=0.17 (c) (2,4-two bromo-phenyl)-piperidin-4-yl-methylene radical-hydrazine
Hydrochloric acid (2, the 4-two bromo-phenyl)-piperidin-4-yl-ketone (7.04g), the hydrazine (6.0ml) that stir are heated 16h with the solution of ethanol (150ml) in refluxed under nitrogen.Chilled solution evaporates in a vacuum, handles with moisture 1M yellow soda ash (50ml), use extracted with diethyl ether, and will merge, drying (Na
2SO
4) after organic extract liquid evaporate in a vacuum.Resistates is refining with flash chromatography method (Merck 9385), with dichloromethane-ethanol-880 ammoniacal liquor wash-out (89: 10: 1 to 835: 150: 15 gradients), obtains target compound, is a butteriness solid (5.71g).T.l.c.SiO
2(CH
2Cl
2-EtOH-880NH
3, 78: 20: 2) and (d) hydrochloric acid 6-bromo-3-piperidin-4-yl-1H-indazole of Rf=0.13 (less important) and Rf=0.16 (mainly)
The mixture of (2, the 4-two bromo-phenyl)-piperidin-4-yl-methylene radical-hydrazine (5.64g), sodium hydride (1.25g, 60% oily dispersed system) and the dry DMF (150ml) that stir is heated 6.5h under 105 °, nitrogen.Further add sodium hydride (200mg) and continue heating 2h.Mixture evaporates in a vacuum, adds moisture 2M hcl acidifying to pH1, adds moisture 1H yellow soda ash then and alkalizes to pH8.The mixture extracted with diethyl ether, merging, dry (Na
2SO
4) after organic extract liquid evaporate in a vacuum.Resistates is refining with flash chromatography method (Merck 9385), with dichloromethane-ethanol-880 ammoniacal liquor (89: 10: 1 to 78: 20: 2 gradients) wash-out, obtains target compound, is a yellow butteriness solid (2.50g).T.l.c.SiO
2(CH
2Cl
2-EtOH-880NH
3, 78: 20: 2) and Rf=0.6 (e) [4-(6-bromo-1H-indazole-3-yl)-piperidines-1-yl]-tert.-butyl acetate
With hydrochloric acid 6-bromo-3-piperidin-4-yl-1H-indazole (500mg), bromo-acetic acid tert-butyl (0.29ml), sodium bicarbonate (150mg, 1.87mmol) and the mixture of DMF (10ml) under 23 °, nitrogen, stir 18h.Mixture evaporates in a vacuum, handles with moisture saturated sodium bicarbonate (25ml), and extracts with ethyl acetate (50ml).Dry (Na
2SO
4) after organic layer at the tool evaporative air to silica gel (Merck 7734).Refining with flash chromatography method (Merck9385), with dichloromethane-ethanol-880 ammoniacal liquor (967: 30: 3 to 945: 50: 5 gradients) wash-out, obtain target compound, be a pure white crystallization (347mg).T.l.c.SiO
2(CH
2Cl
2-EtOH-880NH
3, 945: 50: 5) and Rf=0.27 (f) 4-{2-[3-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-6-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester
With [4-(6-bromo-1H-indazole-3-yl)-piperidines-1-yl]-tert.-butyl acetate (1.34g), 4-vinyl-piperidines-1-carboxylic acid tert-butyl ester (0.75g), triethylamine (1.4ml), acid chloride (ⅱ) (0.050g) and the mixture of three (o-tolyl) phosphine (0.210g) in DMF (60ml) under 120 °, nitrogen, stir 16h.Mixture evaporates in a vacuum, and refining with flash chromatography method (Merek 9385), elutriant is an ethyl acetate: hexanaphthene: triethylamine (50: 50: 2 to 100: 0: 2), obtain target compound, and be a yellow solid (1.18g).T.l.c.SiO
2(CH
2Cl
2: EtOH: 880NH
395: 5: 0.5) Rf=0.32 (g) 4-{2-[3-(1-tertiary butyloxycarbonyl ylmethyl-piperidines 4-yl]-1-methylsulfonyl-1H-indazole-6-yl]-(E)-vinyl }-piperidines-1-carboxylic acid tert-butyl ester
With 4-{2-[3-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl]-1H-indazole-6-yl]-(E)-vinyl-DMF (10ml) solution of piperidines-1-carboxylic acid tert-butyl ester (0.211g) is with sodium hydride (60% oil suspension, 0.019g) handle, under 23 ℃, nitrogen, stir 0.5h.Add methylsulfonyl chloride (0.03ml), mixture further stirs 40h.Evaporating solvent distributes resistates between water (20ml) and ethyl acetate in a vacuum.Extraction liquid drying (Na
2SO
4), dry in a vacuum, refining with silica gel flash chromatography method, elutriant is a hexanaphthene: ether: triethylamine 50: 50: 2, obtain target compound, and be a colourless jelly (0.141g).Mass spectrum m/z603 (MH
+) (h) 4-[1-methylsulfonyl-6-(the 2-piperidin-4-yl-(E)-vinyl)-1H-indazole-3-yl]-piperidines-1-yl }-the acetate trifluoro-acetate
With 4-{2-[3-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl]-1-methylsulfonyl-1H-indazole-6-yl]-(E)-vinyl-piperidines-1-carboxylic acid tert-butyl ester (0.138g) handles with trifluoroacetic acid (3ml), stirs 2h down at 22 ℃.Evaporating solvent in a vacuum, resistates is with preparation HPLC refining (gradient scope 20-70% (ⅱ) 18 minutes, Rf12.5 minute).With the ether development, obtain target compound, be a white crystals shape solid (0.114g).Mass spectrum m/z 447.2 (MH
+) analysis measured value: C, 44.5; H, 4.7; N, 7.7C
22H
30N
4O
4S.2.4C
2HF
3O
2Require: C, 44.7; H, 4.5; N, 7.8% embodiment 6{4-[1-methylsulfonyl-6-(2-piperidin-4-yl-ethyl)-1H-indazole-3-yl]-piperidines-1-yl }-the synthetic method A of acetate
Add in water (30ml) suspension of the 10% palladium carbon (600mg) that stirs { 4-[1-methylsulfonyl-6-(2-piperidin-4-yl-(E)-vinyl)-1H-indazole-3-yl]-piperidines-1-yl }-water (90ml) solution of acetate trifluoro-acetate (690mg), mixture stirs 6h under 23 °, nitrogen.Leach catalyzer, filtrate is evaporated in a vacuum, obtains target compound, is pure white crystallization (420mg).Mass spectrum m/z449 (MH
+) analysis measured value: C, 42.6; H, 4.9; N, 7.2C
22H
32N
4O
4S.3C
2HF
3O
2.0.3C
4H
10O requires: C, 42.4; H, 4.6; N, 6.8% method B (a) 4-{2-[1-methylsulfonyl-3-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-6-yl]-ethyl }-piperidines-1-carboxylic acid tert-butyl ester
At ambient temperature, to 4-{2-[3-(1-tertiary butyloxycarbonyl ylmethyl-piperidin-4-yl)-1H-indazole-6-yl that stirs]-ethyl }-piperidines-1-carboxylic acid tert-butyl ester (40.1g) and 4-N, drip methylsulfonyl chloride (7.6ml) in pyridine (280ml) solution of N-Dimethylamino pyridine (0.96g).The gained brown solution stirs 18h at ambient temperature, and water (400ml) dilution is with methylene dichloride (400ml) extraction.The organic extract liquid that has merged evaporates in a vacuum, brown resistates with ethanol (400ml) dilution after evaporation in a vacuum, obtain a brown oil.This oily matter with ethanol (400ml) development, is evaporated to about 200ml in a vacuum, obtains a suspension.Filtering separation gained solid is used washing with alcohol, and is dry in 45 ℃ of vacuum, obtains target compound, is an incomplete white solid (37.6g).Mass spectrum m/z605 (MH
+) (b) 4-[1-methylsulfonyl-6-(2-piperidin-4-yl-ethyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate;
With 4-{2-[1-methylsulfonyl-3-(1-tertiary butyloxycarbonyl ylmethyl-piperidines-4-may-1H-indazole-6-yl]-ethyl-(5N hydrochloric acid (200ml) solution of 20g stirs 5h to piperidines-1-carboxylic acid tert-butyl ester at ambient temperature.Reaction mixture extracts with Virahol with saturated potassium carbonate (300ml) neutralization.The organic extract liquid that has merged evaporates in a vacuum, obtains an oily matter, with ethanol (300ml) dilution, concentrates with the rotary evaporation method, obtains a white solid.Should make with extra care with flash chromatography method (Merck9385) by incomplete white solid, use ethanol: methylene dichloride: 0.88 ammoniacal liquor (15: 3: 1 to 15: 3: 1.5 gradients) wash-out, obtain target compound, be a white solid (10.1g).Analyze measured value: C, 56.3; H, 7.7; N, 11.0% (C
22H
32N
4O
4S.0.80H
2O 0.83 C
2H
6O) * 0.984 require:
C, 55.8; H, 7.6; N, 11.1% embodiment, 7 tablets
(a) The compounds of this invention 5.0mg
Lactose 95.0mg
Microcrystalline Cellulose 90.0mg
Cross-linked polyvinylpyrrolidone 8.0mg
Magnesium Stearate 2.0mg
Pressing weight 200.0mg
The compounds of this invention, Microcrystalline Cellulose, lactose and cross-linked polyvinylpyrrolidone by 500 tm screen, are mixed in a kind of suitable mixing machine.Magnesium Stearate by 250 tm screen, is mixed with activated mixture.With suitable stamping machine in flakes with the mixture compacting.
B) The compounds of this invention 5.0mg
Lactose 165.0mg
Pregelatinized Starch 20.0mg
Cross-linked polyvinylpyrrolidone 8.0mg
Magnesium Stearate 2.0mg
Pressing weight 200.0mg
The compounds of this invention, lactose and pregelatinized Starch are mixed together back water granulation.Moist wood drying, levigate.Magnesium Stearate and cross-linked polyvinylpyrrolidone are passed through 250 tm screen, mix with particle.The gained mixture is with suitable tabletting machine compressing tablet.Embodiment 8 capsules
A) The compounds of this invention 5.0mg
Pregelatinized Starch 193.0mg
Magnesium Stearate 2.0mg
Filling weight 200.0mg
The compounds of this invention and pregelatinized Starch are passed through 500 microns hole sizers, be mixed together, lubricated with Magnesium Stearate (by 250 tm screen).Mixture is inserted in the hard capsule of appropriate size.
B) The compounds of this invention 5.0mg
Lactose 177.0mg
Polyvinylpyrrolidone 8.0mg
Crosslinked polyethylene tetramethyleneimine 8.0mg
Magnesium Stearate 2.0mg
Filling weight 200.0mg
The compounds of this invention is mixed with lactose, use the polyvinylpyrrolidonesolution solution granulation.Moist wood drying, levigate.Magnesium Stearate and cross-linked polyvinylpyrrolidone are passed through 250 tm screen, mix with particle.The gained mixture is inserted in the hard capsule of appropriate size.Embodiment 9 syrup
A) The compounds of this invention 5.0mg
The hydroxyl third methylcellulose gum 45.0mg
Nipasol 1.5mg
Butoben 0.75mg
Soluble saccharin 5.0mg
Sorbitol solution 1.0ml
Suitable buffer reagent is an amount of
Suitable correctives is an amount of
Pure water is to 10ml
HPMC and hydroxybenzoate are dispersed in the pure water of certain proportion heat, make solution be cooled to envrionment temperature.In bulk solution, add soluble saccharin correctives and sorbitol solution.The compounds of this invention is dissolved in a certain proportion of all the other water, joins in the bulk solution.Can add suitable buffer reagent and regulate pH in the scope that keeps maximum stable.Solution is supplemented to volume required, filters, in the appropriate containers of packing into.Embodiment 10 injections
％w/v
The compounds of this invention 1.00
Water for injection (British Pharmacopoeia) is to 100.00
Can add sodium-chlor come regulator solution tension force, with diluted acid or alkali or add suitable buffering salt can be with pH regulator to maximum stable and/or promote of the present inventionization thing dissolved value.Also can add antioxidant and metal-chelating salt.Solution purification, water are supplemented to final volume, measure and regulate pH in case of necessity once more, obtain the formula I compound of 10mg/ml.
Can be in the injection packing with filled with solution, for example can is in being sealed in ampoule, bottle or syringe.Ampoule, bottle or syringe can sterile filling (for example can carry out filtration sterilization to solution, the aseptic ampoule of packing under aseptic condition) and/or last sterilizations (for example using an acceptable cycle to heat in autoclave).Can under inert nitrogen, carry out the solution packing.
The ampoule of preferably solution being packed into, glass melting sealing, sterilization at last.
Further contain 0.5,2.0 and the sterile preparation of 5%w/v formula I compound by similar approach preparation, thereby obtain 5,20 and the formula I compound of 50mg/ml respectively.The thrombocyte of biological data 1. people washing is measured
Measure the restraining effect of The compounds of this invention according to following method to platelet aggregation.Obtain whole blood (1 part of 3.8%w/v trisodium citrate of Citrated on one's body from the volunteer; 9 parts of blood), the volunteer did not accept pharmacological agent at least in 10 days before donating blood.Blood is handled centrifugal then (1400g, 4 minutes, 20 ℃) with Asprin (0.1mM) and prostacyclin (0.06 μ M).Separate and be rich in hematoblastic blood plasma (PRP) supernatant liquor, further centrifugal (1400g, 10 minutes, 20 ℃) settle down thrombocyte.Abandoning supernatant is suspended in modulated physiological salt solution to pH6.4 (HEPES5mM, NaHCO once more with the thrombocyte piller
312mM, NaCl, 140mM, KH
2PO
40.74mM, D-glucose 5.6mM and KCl 2.82mM) in.This thrombocyte suspension centrifugal (1400g, 8 minutes, 20 ℃) is suspended in gained thrombocyte piller modulated to the physiological salt solution of pH7.4 once more.The washed platelet transfusion of dilution gained, obtaining final platelet count is 3 * 10
8/ l.With purified human fibrin matter (Knight, L.C. etc. 1981 " thrombosis hemostatic method " 46 (3) 593-596), Ca
2+Mg
2+Be added back in the washed platelet transfusion, obtain ultimate density and be respectively 0.5mg/ml, 1mM and 0.5mM.With the hematoblastic gathering of turbidometer quantitative measurment.Test compound and washed thrombocyte constant temperature (37 ℃) 5 minutes add 1 μ M platelet aggregation agonist U-46619 (a kind of stable thromboxane A then
2Simulant).The inhibition of test compound is tired with IC
50Value representation, it is defined as and suppresses the required compound concentration of 50% platelet aggregation.Obtain the IC of following The compounds of this invention
50Value: table 1
| The embodiment numbering | ????IC 50(nm) |
| ????1 | ????100 |
| ????2 | ????53 |
| ????3 | ????＜100 |
| ????4 | ????＜100 |
| ????5 | ????＜100 |
| ????6 | ????＜100 |
Claims (13)
1. formula I compound
Or its salt, solvate or physiologic function derivative, wherein: x represents CH
2-CH
2Or CH=CH; Y represents a group
R
0Represent SO
2Me or CONH
2R
1Represent SO
2Me.
2. (I is compound a) according to the formula of claim 1
Or its salt, solvate or physiologic function derivative, wherein: x represents CH
2-CH
2Or CH=CH.
3. according to formula (1b) compound of claim 1
Or its salt, solvate or physiologic function derivative, wherein: x represents CH
2-CH
2Or CH=CH.
4. according to formula (1c) compound of claim 1
Or its salt, solvate or physiologic function derivative, wherein: x represents CH
2-CH
2Or CH=CH.
5.{4-[3-methylsulfonyl-5-(the 2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[3-methylsulfonyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[3-carbamyl-5-(the 2-piperidin-4-yl-(E)-vinyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[3-carbamyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[1-methylsulfonyl-6-(the 2-piperidin-4-yl-(E)-vinyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate; 4-[1-methylsulfonyl-6-(2-piperidin-4-yl-ethyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate; Or its salt, solvate and physiologic function derivative.
6.{4-[3-methylsulfonyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[3-carbamyl-5-(2-piperidin-4-yl-ethyl)-indazole-1-yl]-piperidines-1-yl }-acetate; 4-[1-methylsulfonyl-6-(2-piperidin-4-yl-ethyl)-1H-indazole-3-yl]-piperidines-1-yl }-acetate; Or its salt, solvate or physiologic function derivative.
7. according to each compound in the claim 1 to 6, be a kind of hydrochloride.
8. pharmaceutical composition, said composition contain in the with good grounds claim 1 to 7 each compound or its pharmaceutically acceptable derivates, and mix with acceptable carrier or excipient on one or more physiology.
9. be used for people or veterinary drug according to each compound or its pharmaceutically acceptable derivates of claim 1 to 7.
10. according to each compound or the purposes of its pharmaceutically acceptable derivates in the therapeutical agent of preparation treatment thrombotic diseases in the claim 1 to 7.
11. suffer from glycoprotein title complex Gp II b/ III a or other integrin receptors is the methods of treatment of human or animal body of the disease of media, this method comprise to described patient use significant quantity according to each compound or its pharmaceutically acceptable derivates in the claim 1 to 7.
12. according to the method for claim 11, wherein this disease is a thrombotic diseases.
13. the preparation method of each defined compound in the claim 1 to 7, this method comprises:
(A) make formula II compound or its protected derivative
Wherein the y definition is with the formula I compound, and R represents a leavings group, with the formula III compound
Or its protected derivatives reaction; Or
(B) carry out tautomerization with formula I compound or its protected derivative as precursor; And/or
(C) make the formula IV compound go protection,
Wherein x and y definition is with the formula I compound; P ' is carboxyl or protected carboxyl; P " be hydrogen or amido protecting group; its condition is if P ' is a carboxyl; P then " not hydrogen; if P ' be hydrogen, then P " not carboxyl, and/or can or not be converted into its pharmaceutically acceptable derivates with the conversion of gained formula I compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97195652 CN1222153A (en) | 1996-06-21 | 1997-06-19 | Piperidine acetic acid derivatives and their use in treatment of thrombotic disorders |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9613017.4 | 1996-06-21 | ||
| GB9613095.0 | 1996-06-21 | ||
| GB9613018.2 | 1996-06-21 | ||
| CN 97195652 CN1222153A (en) | 1996-06-21 | 1997-06-19 | Piperidine acetic acid derivatives and their use in treatment of thrombotic disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1222153A true CN1222153A (en) | 1999-07-07 |
Family
ID=5179293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 97195652 Pending CN1222153A (en) | 1996-06-21 | 1997-06-19 | Piperidine acetic acid derivatives and their use in treatment of thrombotic disorders |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1222153A (en) |
-
1997
- 1997-06-19 CN CN 97195652 patent/CN1222153A/en active Pending
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