CN1161040A - Bicyclic tetrahydro pyrazolopyridines and their use as medicaments - Google Patents
Bicyclic tetrahydro pyrazolopyridines and their use as medicaments Download PDFInfo
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- CN1161040A CN1161040A CN95195743A CN95195743A CN1161040A CN 1161040 A CN1161040 A CN 1161040A CN 95195743 A CN95195743 A CN 95195743A CN 95195743 A CN95195743 A CN 95195743A CN 1161040 A CN1161040 A CN 1161040A
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Abstract
Compounds of formula(I) wherein R<1>, R<2>, R<3> and X are as defined. The compounds of formula(I) and the pharmaceutically acceptable salts thereof are useful in inhibiting phosphodiesterase(PDE) type IV and the production of tumor necrosis factor(TNF) and in the treatment of asthma, arthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory diseases, AIDS, septic shock and other diseases involving the production of TNF.
Description
The present invention relates to a series of bicyclic tetrahydro pyrazolopyridines (bicyclic tetrahydro pyrazolo-pyridines), they are phosphodiesterase (PDE) IV type or the selective depressant that produces tumour necrosis factor (hereinafter being called TNF), and with regard to this point, they can be used for the treatment of asthma, sacroiliitis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis and other inflammatory conditions and acquired immune deficiency syndrome (AIDS), septic shock and other relates to the disease that TNF produces.
The invention still further relates to the method for the above-mentioned illness of utilizing this compounds for treating Mammals (especially human), and relate to the useful pharmaceutical composition of these compounds.
Since recognizing that cyclic amp (Cyclic AMP) is intracellular second messenger [E.W.Sutherland, and T.W.Rall, " pharmacology comment " (Pharmacol.Rev) 1960,12,265], thus suppressing phosphodiesterase has become and has relaxed and therapeutic is interfered the target of some pathologies.Recently, have recognized that the PDE[J.A.Beavo and the D.H.Reifsnyder of different properties type, TiPS, 1990,11,150] and optionally suppress these enzymes and made pharmacotherapy be improved [C.D.Nicholson, R.A.Challiss and M.Shahid, TiPS, 1991,12,19].More detailed is, have recognized that suppressing PDE IV type can make the release of inflammatory mediator be suppressed [people such as M.W.Verghese, " molecule and cell Cardiology magazine " (J.Mol.Cell Cardiol.), 1989,12 (supplementary issue II), S61], and [T.J.Torphy is referring to " new anti-asthma medicine guide " to suppress airway smooth muscle loose, eds S.R.O ' Dnnell and C.G.A.Persson, 1988,37, Birkhauser-Verlag].Therefore, suppress PDE IV type, but to the compound of the PDE action effect difference of other type, can be when not causing cardiovascular or antiplatelet effect, suppress that inflammatory mediator discharges and airway smooth muscle is loose.
Generally acknowledged TNF relate to a lot of infectivity and autoimmune disease [W.Friers, " European biological chemistry association federation communication " (FEBS Letters), 1991,285,199).In addition, proved that TNF is basic medium (people such as C.E.Spooner, " clinical immunology and immunopathology " (Clinical Immunology and Immunopathology), 1992 of the Inflammatory response seen in Sepsis and the septic shock, 62, S11).
The present invention relates to have the compound and the pharmaceutically useful salt thereof of following formula:
R wherein
1Be hydrogen, (C
1-C
3) alkyl, (C
2-C
3) alkenyl, (C
3-C
5) cycloalkyl or methylene radical (C
3-C
5) cycloalkyl, wherein each alkyl or alkenyl can be randomly by 2 (C of as many as
1-C
2) alkyl or trifluoromethyl or replaced by maximum three halogens (atom);
X is oxygen or 2 hydrogen atoms;
R
2With R
3Independently be selected from following group respectively: hydrogen; (the C that randomly replaces by halogen or cyano group
1-C
4) alkyl; (C
1-C
14) alkyl sulphonyl; (C
1-C
14) alkoxyl group; Naphthyl; (C
2-C
7) alkenyl; (C
3-C
7) cycloalkyl; (C
1-C
4) alkyl (C
3-C
7) cycloalkyl; (C
3-C
7) cycloalkyl (C
1-C
4) alkyl; (C
4-C
7) heterocyclic radical, wherein contain oxygen, sulphur, SO
2Or NR
5, R wherein
5Be hydrogen or (C
1-C
4) alkyl; (C
4-C
7) Heterocyclylalkyl-(W)
d, (C wherein
4-C
7) Heterocyclylalkyl contains one or more Sauerstoffatom, sulphur atom, SO
2Or NR
5, R wherein
5For hydrogen or randomly by halogen or (C
1-C
4) (the C that replaces of alkyl
1-C
4) alkyl, d be 0 or 1 and W be (C
1-C
4) alkyl, CO or alkylsulfonyl; CONR
10R
11, R wherein
10With R
11All independent is hydrogen or (C
1-C
4) alkyl; (C
1-C
5) alkyl-carbonyl; (C
1-C
5) alkoxy carbonyl; (C
1-C
5) alkyl-carbonyl (C
1-C
5) alkyl, (C
1-C
5) alkoxy carbonyl (C
1-C
5) alkyl; (C
1-C
5) alkoxyl group (C
1-C
5) alkyl; R
12R
13N (C
1-C
5) alkyl, wherein R
12With R
13All independent is hydrogen or (C
1-C
5) alkyl;
Or have a group of following structural formula:
Wherein, a is the integer of 0-5, and b and c are 0 or 1, R
4Independently be selected from hydrogen, hydroxyl, (C
1-C
5) alkyl, (C
2-C
5) alkenyl, (C
1-C
5) alkoxyl group, (C
3-C
6) cycloalkyloxy, halogen, trifluoromethyl, CO
2R
6, CONR
6R
7, NR
6R
7, CONHOH, CN, NO
2Or SO
2NR
6R
7, R wherein
6With R
7All independent is hydrogen or (C
1-C
4) alkyl; Wherein Y is (C
1-C
4) alkyl, (C
2-C
5) alkylidene group or randomly by maximum 2 (C
1-C
7) alkyl or (C
3-C
7) (the C of cycloalkyl substituted
2-C
6) alkenyl; And Z is oxygen, sulphur, CO, SO
2Or NR
8, R wherein
8Be hydrogen or (C
1-C
4) alkyl;
Or be the group of the following structural formula of tool:
Wherein p is the integer of 1-3; W is a hydroxyl; R
9Be (C
1-C
3) alkyl; Wherein each described alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic radical can be selected from (C by 1-14, preferred 1-5 arbitrarily
1-C
2) gene of alkyl, trifluoromethyl or halogen replaces;
Or have a group of following structural formula:
Wherein m, n and p are 1 or 2;
Or group with following structural:
Wherein Q is hydroxyl or the group with following structural formula:
Prerequisite is: at R
1Be ethyl and R
2During for the 4-aminomethyl phenyl, R
3Can not be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl; At R
2Be 4-aminomethyl phenyl and R
3During for the 4-fluorophenyl, R
1Can not be phenyl, methyl or n-propyl; At R
1Be ethyl and R
2During for phenyl, R
3Can not be 4-chloro-phenyl-, 4-fluorophenyl or 4-tolyl; At R
1Be ethyl and R
2During for the 4-methoxyphenyl, R
3Can not be the 4-fluorophenyl; And when W was CO or alkylsulfonyl, d was 1;
Following situation also is prerequisite: R
2And R
3Can not all independently be selected from hydrogen; (C
1-C
4) alkyl; (C
1-C
14) alkoxyl group; (C
2-C
7) alkenyl; (C
4-C
7) heterocyclic radical, wherein contain aerobic, sulphur, SO
2Or NR
5, R wherein
5Be hydrogen or (C
1-C
4) alkyl; Or group with following structural:
Wherein a is the integer of 1-5; B and c are 0 or 1; R
4Be hydrogen, hydroxyl, (C
1-C
5) alkyl, (C
2-C
5) alkenyl, (C
1-C
5) alkoxyl group, (C
3-C
6) cycloalkyloxy, halogen, trifluoromethyl, CO
2R
6, CONR
6R
7, NR
6R
7, NO
2Or SO
2R
6R
7(R wherein
6With R
7All independent is hydrogen or (C
1-C
4) alkyl); And Y is (C
1-C
5) alkylidene group or at random by maximum 2 (C
1-C
7) alkyl or (C
3-C
7) (the C of cycloalkyl substituted
2-C
6) alkenyl; Or group with following structural:
Wherein, p is the integer of 1-3, and W is oxo or hydroxyl, R
9Be (C
1-C
3) alkyl; Wherein each described alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic radical can be at random by 1-14, preferred 1-5 (C
1-C
2) alkyl, trifluoromethyl or halogen replace.
Above restricted condition increase is come in, just rejected the theme among the PCT/IB/94/00156 of former submission.
In one embodiment, the present invention relates to a kind of compound in structural formula I that has, wherein R
1Be (C
1-C
3) alkyl and R
3Be (C
3-C
7) cycloalkyl, contain SO
2(C
4-C
7) heterocyclic group or have the group of following structural formula:
Wherein, a is integer and the R of 1-5
4Independently be selected from hydrogen, hydroxyl, (C
1-C
5) alkyl, (C
1-C
5) alkoxy or halogen.
In another embodiment, the present invention relates to have compound in structural formula I, wherein, R
1Be ethyl or sec.-propyl; R
2Be phenyl; the 2-tolyl; the 3-tolyl; the 2-methoxyphenyl; the 3-methoxyphenyl; the 2-hydroxyphenyl; the 3-hydroxyphenyl; the 4-hydroxyphenyl; the cyclopropyl methyl; benzyl; isobutyl-; isobutenyl; 2-ethylbenzene base; naphthalene thiazolinyl (naphthalenyl); the 2-chloro-phenyl-; the 3-methyl butyl; formyl-dimethylamino; the 1-methyl-benzyl; sec.-propyl; the 1-picolyl; the 2-picolyl; the 3-picolyl; 2-methyl-5-chloro phenyl; 2-chlorothiophene-5-base-methyl; 2-hydroxy-5-methyl base phenyl; 3; 5-dimethyl-isoxazole-4-bases-methyl; 3-benzyl chloride base; thiophene-2-base-methyl; 2-hydroxyl-5-chloro-phenyl-; thiophene-2-carbonyl; tetrahydrofurfuryl; 3-cyano group benzyl; morpholine-4-carbonyl; the sec.-propyl alkylsulfonyl; 4-methoxyphenyl alkylsulfonyl or 3-fluoroform phenyl, and R
3Be cyclobutyl, cyclopentyl, cyclohexyl, 3-tetramethylene sulfone base, 4-fluorophenyl or 3,4-dichlorophenyl.
The invention still further relates to the pharmaceutical composition that is used to suppress phosphodiesterase (PDE) IV type and tumour necrosis factor (TNF) generation, and relate to and be used for the treatment of the pharmaceutical composition that asthma, sacroiliitis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory conditions, acquired immune deficiency syndrome (AIDS), septic shock and other relate to the disease that TNF produces, this pharmaceutical composition is made up of compound and a kind of pharmaceutically useful carrier of the claim 1 of pharmacy effective dose.
The invention still further relates to and be used for suppressing the method that phosphodiesterase (PDE) IV type and tumour necrosis factor (TNF) produce, comprise having compound in structural formula I and pharmaceutically useful salt thereof to patient's administration effective dose.
The invention further relates to the method for the mammiferous inflammatory conditions of treatment, this method comprises to the formula I compound of described Mammals administration anti-inflammatory dosage and its pharmaceutically useful salt.
The invention still further relates to treatment or prophylactic method, described disease is selected from asthma, sacroiliitis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory conditions, acquired immune deficiency syndrome (AIDS), septic shock and other relates to the disease that TNF produces; This method comprises to the formula I compound of patient's administration effective dose and its pharmaceutically useful salt.
Unless otherwise noted, used " halogen " speech comprises chlorine, fluorine and bromine in the literary composition.
Unless otherwise noted, the alkyl of being mentioned in the literary composition, alkoxyl group and alkenyl can be straight chains, perhaps, by 3 or a plurality of carbon when forming, can be straight chain, side chain, cyclic, perhaps are the combination of part cyclic and side chain or straight chain.
According to the present invention, treatable " inflammatory conditions " includes but not limited to asthma, chronic obstructive pulmonary disease, bronchitis and sacroiliitis.
Unless otherwise noted, to R used in the literary composition
1, R
2And R
3With reference to eliminant I definition as above.
Following reacting flow chart illustrates but does not limit preparation compound of the present invention.
Schema 1
Schema 2
In the reaction 1 in the schema 1, when having copper powder and salt of wormwood to exist, by with the reaction of pure aryl halide, it is N-(aryl)-2-Pyrrolidone that the compound 2-Pyrrolidone of tool structural formula IV is changed into corresponding compounds V, wherein " aryl " is the group of tool structural formula II.Suitable aryl halide comprises 1-iodo-or 1-bromo-4-methoxy benzene, 3-methoxy benzene, 2-methoxy benzene, 3-toluene, 4-toluene, 2-toluene, 3-phenylfluoroform, 2-phenylfluoroform, 3,4-dimethoxy-benzene or 3-cyclopentyloxy-4-methoxy benzene.Under the inert reaction condition, temperature of reaction generally in about 110 ℃-117 ℃ scope, is preferably about 150 ℃; Reaction times is about 14-22 hour, preferably approximately 18 hours.
In the reaction 2 of schema 1, in the suspension that magnesium forms, add R in anhydrous aprotic solvent
1Halogenide.The reacting by heating mixture makes it to reflux, and all is consumed until magnesium, then reaction mixture is cooled to temperature and is approximately-15 ℃～15 ℃, 0 ℃ of preferably approximately.Add compound N-(aryl)-2-Pyrrolidone of tool structural formula V again, be heated to room temperature in stirred reaction mixture, the time is about 1.5-2.5 hour, and preferably approximately is 2 hours.Suitable alkyl halide comprises monobromethane, monobromethane or N-PROPYLE BROMIDE.Preferred anhydrous aprotic solvent is an anhydrous diethyl ether.When reaction is finished, can separate required intermediate product in a usual manner, the organism that for example first water and salt water washing merge is again in dry on the sodium sulfate, filtration and concentrated under reduced pressure, the white solid precipitation that is reclaimed easily.
By above precipitation being distributed in the mixture of proton inert non-polar solvent and alkali, with precipitation be converted into corresponding formula VI 1,2,5, the 6-5,6-tetrahydropyridine compounds.During vigorous stirring, just add the ethyl oxalyl chloride, and the reaction mixture heating is made it to reflux, the time is about 1.5-4.5 hour, preferably approximately 3.0 hours.Preferred proton inert non-polar solvent is a benzene, and preferred alkali is sodium hydroxide.Remove and to desolvate, and the resistates of the solution-treated generation that in ethanol, forms with sodium alkoxide.The about 1-3 of reflux hour, preferably approximately was after 1.5 hours, enriched mixture under reduced pressure, and with hcl acidifying to pH=3.
In the reaction 3 of schema 1, by the reaction mixture heating that the compound of tool structural formula VI and 3-methyl isophthalic acid-right-the toluene triazene forms in aprotic solvent is made it to reflux, the compound of wushu VI is converted into compound 3-methoxyl group-1,2,5, the 6-tetrahydropyridine of corresponding formula VII.Reaction times is about 30-120 minute, preferably approximately 45 minutes.
In the reaction 1 of schema 2, by compound and formula R with formula VIII
3HNNH
2Hydrazine reaction, with the compound 1,2,5 of formula VIII, 6-tetrahydropyridine (R wherein
5Be hydrogen or methyl) compound that is converted into corresponding formula IX promptly 4,5,6,7 ,-tetrahydrochysene-7-oxo-1H-pyrazoles [3,4-c] pyridine.Two kinds of derivatives of the compound of formula VIII, promptly 3-hydroxyl and 3-methoxy derivatives can be used as the starting materials under the set condition in three groups of different conditions.
Under a group reaction condition, compound by in anhydrous polar proton inert solvent, making formula VIII and hydrazine hydrochloride and sodium alkoxide reaction, with the compound of formula VIII promptly 1,2,5, the 6-tetrahydropyridine is converted into the compound of corresponding formula IX.Preferred sodium alkoxide is a sodium methylate, and preferred anhydrous polar proton inert solvent is a dehydrated alcohol.The reacting by heating mixture makes it to reflux about 9-15 hour, preferably approximately 12 hours.
Under the second group reaction condition, compound by in anhydrous polar proton inert solvent (being preferably ethanol), making formula VIII and hydrazino-benzoic acid reaction, with the compound of formula VIII promptly 1,2,5, the 6-tetrahydropyridine is converted into the compound of corresponding formula IX.The reacting by heating mixture makes it to reflux about 16-24 hour, preferably approximately 20 hours.Can in polar proton inert solvent (being preferably ethanol), react about 15-45 minute (preferred 30 minutes) by compound with formula IX with sodium alkoxide, the compound of the formula IX that forms is as stated above further reacted compound 1-(4-benzamide)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3, the 4-c] pyridine that generates correspondence.Under decompression, remove polar proton inert solvent, solid residue is suspended in the proton inert non-polar solvent (being preferably benzene), and under decompression, remove this proton inert non-polar solvent subsequently.The solid suspension of doing that generates in cold ether, is handled with oxalyl chloride and N, dinethylformamide, and stirred about 30-90 minute, be preferably 60 minutes.Remove then and desolvate, thick resistates is dissolved in the anhydrous tetrahydrofuran (THF).Approximately-10 under ℃-10 ℃ of (preferred 0 ℃) temperature the solution that forms is dropwise being joined in the ammoniacal liquor that had stirred.
Under the 3rd group reaction condition, by compound and the hydrazine hydrochloride reaction that in polar proton inert solvent (being preferably methyl alcohol), makes formula VIII, the compound that the compound 1,2,5 of wushu VIII, 6-tetrahydropyridine are converted into corresponding formula IX.Reacting by heating mixture to temperature is about 70 ℃-110 ℃ under the condition that gentle stream of nitrogen gas is arranged, and is preferably about 90 ℃, until solvent is all removed.Be about 120-180 ℃ with purified mixture heating up to temperature again, be preferably about 150 ℃, be about 30-90 minute heat-up time, is preferably 60 minutes.
By approximately-15～15 ℃, be preferably under about 0 ℃ temperature, make the formula IX that generates by above method at polar proton inert solvent, be preferably the solution that forms in the acetonitrile and the reactant aqueous solution of cerous nitrate (IV) ammonium, compound that can wushu IX is converted into corresponding compounds 6-R
2-4,5,6,7-tetrahydrochysene-7-oxo-1H-pyrazoles [3,4-c] pyridine, wherein R
2Be not the group of formula II, the reaction times is about 20-50 minute, preferably approximately 35 minutes.When reaction finishes, the dilute with water mixture, and use the ethyl acetate extracting.Again with saturated sodium bicarbonate, the organism that merges with S-WAT washing then.Be dissolved in polar proton inert solvent with the sodium hydride processing, be preferably the compound by above method generation in the tetrahydrofuran (THF), heating makes it to reflux, and stirs about 30-60 minute, is preferably 45 minutes.It is about 20-30 ℃ that reaction mixture is cooled to temperature, is preferably about 25 ℃.Add a kind of formula R
2Halid alkyl halide wherein defines R
2Group with reference to formula I rather than formula II.Stirred reaction mixture, heating makes it to reflux about 12-20 hour, is preferably 16 hours.
In the reaction 2 of schema 2, by at the nonpolar aprotic inert solvent, be preferably the compound and the reductive agent that make formula IX in the ether, be preferably the lithium aluminum hydride reaction, with the compound of formula IX is that 2-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine are converted into the compound of corresponding formula X.Reaction mixture was stirred about 12-20 hour preferred 16 hours.Add entry and alkali again, be preferably sodium hydroxide, reaction mixture was stirred about 1.5-2.5 hour, preferred 2 hours, refilter.Concentrated filtrate obtains white solid.
By following analyzed in vitro, illustrate that these compounds or its pharmaceutically useful salt suppress phosphodiesterase IN (PDE
4), thereby and show the ability of validity of its treatment inflammatory conditions.
Biological analysis
(people's lung PDE
IV)
The human lung tissue of 30-40 gram is put into Tris/ phenylmethylsulfonyl fluoride (PMSF)/sucrose damping fluid of the pH7.4 of 50ml, and use Tekmar Tissumizer
(Tekmar company, 7143KemperRoad, Cincinati, Ohio 45249) at full speed following homogenate 30 seconds.Under 4 ℃ of temperature in 48, the centrifugal homogenate of 000xg 70 minutes.With 0.22 μ m filter membrane supernatant liquid filtering 2 times, and be added to (Pharmacia LKB Biotechnology on Mono-Q fast protein liquid chromatography (FPLC) post, 800Centennial Avenue, Piscataway, New Jersey 08854), the FPLC post carried out pre-equilibration with the Tris/PMSF damping fluid of pH7.4.The flow velocity of sample upper prop is 1ml/ minute, then again with 2ml/ minute flow velocity drip washing and wash-out.Increase (concentration) NaCl and pH7.4 Tris/PMSF buffer solution elution sample with the gradient segmentation.Collect the 8ml component.Analyze each component, with [
3H] mark cyclic amp ([
3H] cAMP) hydrolysis and a kind of known PDE
IVInhibitor (as rolipram) is measured special PDE to the inhibition ability of this hydrolytic action
IVActive.Suitable component is merged, spent glycol dilution (2ml ethylene glycol/5ml enzyme), and under-20 ℃ of temperature, be saved to when using.
Concentration with 10mM is dissolved in dimethyl sulfoxide (DMSO) (DMSO) with each compound, with 1: 25 ratio in water, dilute (compound of 400 μ M, 4%DMSO).Further serial dilution in 4%DMSO is to reach required various concentration.DMSO final concentration in the analyzer tube is 1%.In repeated experiments, in the Glass tubing of a 12 * 75mm, be sequentially added into following composition (all given concentration are the final concentration in the analyzer tube):
I) 25 μ l compounds or DMSO (1%) with comparing and blank assay
The ii) pH7.5 Tris damping fluid of 25 μ l
iii)[
3H]cAMP(1μM)
The iv) PDE of 25 μ l
IVEnzyme (when being used for blank assay) with enzyme preincubation 5 minutes in boiling water
Shake reaction tubes, and be placed in the water-bath (37 ℃) 20 minutes, came termination reaction in 4 minutes by each pipe being put into boiling water bath when the time comes.To place each pipe on the ice bath add drip washing damping fluid (0.5ml, 0.1M 4-(2-hydroxyethyl)-1-piperazine-ethyl sulfonic acid (HEPES)/0.1MNaCl, pH8.5).The content of every pipe be added to use drip washing damping fluid pre-equilibration in advance Affi-Gel (Affi-Gel) 601 posts on (Biorad laboratories, P.O.Box 1229,85A Marcus Drive, Melville, New York11747) (borate Affi-Gel, 1ml column volume).With the drip washing of 2 * 6ml drip washing damping fluid [
3H] cAMP, use again 4ml 0.25M acetate wash-out [
3H] 5 ' AMP.Behind vortex, in the 3ml scintillation solution of containing in suitable tubule, add the 1ml elutriant, vortex and to [
3H] counting.
IC
50Be defined as and make [
3H] the cAMP specificity be hydrolyzed to [
3H] reaction of 5 ' AMP is suppressed 50% o'clock compound concentrations.
(TNF)
By following analyzed in vitro, thereby illustrate that the pharmaceutically useful salt of each compound or its suppresses TNF and produces and show that its treatment relates to the ability of the validity of the illness that TNF produces:
Collect human volunteer's peripheral blood (100ml), blood is dissolved in the ethylenediamine tetraacetic acid (EDTA) (EDTA).Can (Ficoll, soluble poly sucrose)/Hypaque separating monocytic cell with phenanthrene, and washing three times in incomplete balanced salt solution (HBSS).Cell is resuspended to the RPMI (containing 5% foetal calf serum, glutamine, Pen/Step and nystatin) of preheating.With 1 * 10
6The density of individual cell/ml is laid on monocyte on the flat board of 24-hole.In incubation (5% carbonic acid gas) cell under 37 ℃ of temperature made in 2 hours its attached to flat board on, slowly the cell that does not adhere to is removed in drip washing then.With 3-4 kind concentration test compound (10 μ l) is added in the cell culture again, and incubation 1 hour.(10 μ l) adds in the suitable hole with lipopolysaccharides (LPS).Dull and stereotyped under 37 ℃ of temperature, be incubated overnight (18 hours).Enzyme-linked immunosorbent assay (ELISA) (R﹠amp by sandwich-type when incubation period finishes; D Quantikine Kit) analyzes TNF.Come each compound is carried out IC according to linear regression analysis
50Measure.
The pharmaceutically useful acid salt class of compound of the present invention includes, but are not limited to those salts that forms with following acid: HCl, HBr, HNO
3, H
2SO
4, H
3PO
4, CH
3SO
3H, p-CH
3C
6H
4SO
3H, CH
3CO
2H, glyconic acid, tartrate, toxilic acid and succsinic acid.R wherein
4Be CO
2R
6And R
6For the pharmaceutically useful positively charged ion salt of the compound of the formula I of the present invention of hydrogen including, but not limited to those salts that forms with following positively charged ion: sodium, potassium, calcium, magnesium, ammonium, N, N '-dibenzyl-ethylenediamin, N-methylglucosamine (Mai Geluming), thanomin and diethanolamine.
As for inflammatory conditions is treated with preventive treatment in to people's administration, for common adult patients (70kg), the oral dosage of the compound of formula I and its pharmaceutically useful salt (hereinafter also they being called active compound of the present invention) is usually in 0.1-100mg/ days scope.Therefore for typical adult patients, single agent tablet or capsule contain the 0.1-50mg active compound in suitable pharmaceutically useful vehicle or carrier.The dosage that is used for intravenous administration is generally in the scope of the 0.1-10mg/ agent of stipulating.Be used for nose dosage interior or inhalation and generally be made into 0.1-1% (w/v) solution.The doctor can determine for the only actual dose of individual patient in practice, and this actual dose can change with age, body weight and the reaction of particular patient.Above dosage all is example generally speaking, still, the individual cases that should give higher or lower dosage range is arranged certainly, and all these dosage all are within the scope of the present invention.
For suppressing TNF to people's administration, can use all comprise oral, without intestines and partial conventional route.Usually, oral or be about 0.1-25mg/ per kilogram weight in patients every day without the dosage of enteral administration active compound, be preferably about 0.3-5mg/ per kilogram weight in patients.But, should make some dosage according to the curee's who is treating healthy state changes.Under any circumstance, the people of responsible administration should be identified for indivedual curees' suitable dose.
When the human, active compound of the present invention can be individually dosed, but consider the pharmacy practice of predetermined route of administration and standard, can come administration with the mixture that is made into selected medicinal diluent or carrier usually.For example, active compound can contain the tablet form of the vehicle of starch for example or lactose, perhaps be made into the form of the capsule or the ovales of mixture separately or with vehicle, perhaps with the elixir that contains seasonings or tinting material or the form oral administration administration of suspension.These active compounds also can be without enteral administration, as intravenously, intramuscular or subcutaneous.For without enteral administration, active compound preferably uses with the form of aseptic aqueous solution.This aseptic aqueous solution can contain other material, as salt or the glucose that solution etc. is opened.
Therefore on the other hand, the invention provides pharmaceutical composition, these pharmaceutical compositions contain compound, its pharmaceutically useful salt and acceptable diluents or the carrier of formula I.
The present invention will be described by the following example, but the present invention is not limited to the particular case of embodiment.
Embodiment 1
1-cyclohexyl-3-ethyl-6-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
Under the situation that has mild stream of nitrogen gas to exist, the 3-methoxyl group-1-that in methyl alcohol (15ml), is made into (3-methoxyphenyl)-2-oxo-4-propionyl-1,2,5,6-pyridine (0.80g, 2.8mmole) and cyclohexyl hydrazine hydrochloride (0.54g, 3.6mmole) solution be heated to 90 ℃, until removing all solvents.Extremely about 150 ℃ of following purified mixture heating up of condition that has nitrogen to exist, the time is 1 hour then.After being cooled to room temperature, mixture is dissolved in ether, uses 1N hydrochloric acid, use the salt water washing again, and dry on sodium sulfate, under reduced pressure, filter again and concentrate.Chromatography on silica gel is made elutriant with 1: 1 ethyl acetate/hexane, obtains the title compound of the yellow oil of 0.47g.1H nucleus magnetic resonance (250MHz, CDCl
3): 1.20-1.52 (m, 6H comprised t at 1.23 o'clock, J=7.6Hz, 3H), 1.64-1.74 (m, lH), 1.80-2.06 (m, 6H), 2.67 (q, J=7.6Hz, 2H), 2.87 (t, J=6.7Hz, 2H), 3.82 (s, 3H), 3.97 (t, J=6.7Hz, 2H), 5.13 (tt, J=4.3 and 11.3Hz, 1H), 6.79-6.93 (m, 3H), 7.31 (t, J=8.1Hz, 1H); Calculate C with high resolution mass spectrometry assay method (HRMS)
21H
27N
3O
2[M+] is: 353.2103, and actual measurement: 353.2094.
Experimental example 2-16
Take to be similar to the method for embodiment 1, suitable hydrazine hydrochloride and the 4-chain triacontanol base-2-methoxyl group-2-oxo-1,2,5 that needs, the reaction of 6-tetrahydropyridine generate the compound with following formula IX.
| Embodiment # | ??R 1 | ??R 2 | ??R 3 | Fusing point ℃ (M.p. ℃) | Mass spectrum or analysis (calculating gained) %C, %H, %N | Mass spectrum or analysis (actual recording) %C, %H, %N |
| ??2 | Ethyl | 2-methoxyl group-phenyl | Cyclobutyl | ??123-4 | ??70.13，7.12，12.91 | ??69.93，7.09，12.81 |
| ??3 | Ethyl | 2-methyl-phenyl | 3-methyl-cyclopentyl | Oil | ??[M+]337.46 | ??MS(m/z)338 |
| ??4 | Ethyl | 2-ethyl-phenyl | Cyclobutyl | Oil | ??[M+]323.44 | ??MS(m/z)324 |
| ??5 | Ethyl | 2-ethyl-phenyl | Cyclopentyl | ??106-7 | ??[M+]337.46 | ??MS(m/z)337 |
| ??6 | Ethyl | The 1-naphthalene | Cyclopentyl | ??188-90 | ??[M+]359.47 | ??MS(m/z)360 |
| ??7 | Ethyl | 1-naphthalene (1-naph-thalene) | Cyclohexyl | ??199-201 | ??[M+]373.5 | ??MS(m/z)372 |
| ??8 | Ethyl | 2-chloro-phenyl | Cyclopentyl | ??100-3 | ??66.37，6.45，12.22 | ??66.65，6.61，11.92 |
| ??9 | Ethyl | 2-chloro-phenyl | Cyclohexyl | Oil | ??[M+]357.88 | ??MS(m/z)358 |
| ??10 | Ethyl | 2-methyl-phenyl | Two the ring [2.2.1] heptan-the 2-base | ??141-2 | ??75.61，7.79，12.02 | ??75.74，7.84，11.85 |
| ??11 | Ethyl | 2-methoxy-5-methyl-phenyl | Cyclopentyl | ??94-6 | ??71.36，7.70，11.89 | ??71.88，7.71，11.43 |
| ??12 | Ethyl | 5-fluoro-2-methyl-phenyl | Cyclopentyl | ??109-11 | ??67.12，6.76，11.74 | ??67.30，7.02，11.21 |
| ??13 | Ethyl | 5-chloro-2-methyl-phenyl | The 4-fluorophenyl | ??90-2 | ??[M+]383.85 | ??MS(m/z)384 |
| ??14 | Ethyl | 5-chloro-2-methyl-phenyl | Cyclobutyl | ??135-7 | ??66.37，6.45，12.22 | ??67.17，6.81，11.78 |
| ??15 | Ethyl | 5-chloro-2-methoxyl group-phenyl | The 4-fluorophenyl | ??129-30 | ??63.08，4.79，10.51 | ??63.08，4.86，10.41 |
| ??16 | Ethyl | The 2-chloro-phenyl- | The 4-THP trtrahydropyranyl | Oil | ??[M+]359.85 | ??MS(m/z)360 |
The recrystallize solvent:
aEthyl acetate/pentane,
bDiethyl ether/pentane,
cIsopropyl ether/pentane,
dEthyl acetate/petroleum ether,
eEthyl acetate,
fEthyl acetate/hexane
Embodiment 17
3-ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
In the 50ml ether, be made into 3-ethyl-6-(4-fluorophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-four oxygen-1H-pyrazoles [3,4-c] pyridine (0.3g, 0.82mmole) solution, in this solution that stirred, add lithium aluminum hydride (33mg, 0.86mmole).Stir and add entry (0.5ml) after 16 hours, add 3N sodium hydroxide (1ml) again.Behind the restir 2 hours, by the diatomite filtration white precipitate, and under reduced pressure concentrated filtrate.On silica gel, carry out chromatography, as elutriant, obtain the title compound of the yellow powder of 0.12g with 1: 3 ethyl acetate/hexane.
1HNMR(250MHz，CDCl
3)，1.28(t，J＝7.6Hz，3H)，2.66(q，J＝7.6Hz，2H)，2.71(t，J＝5.7Hz，2H)，3.49(t，J＝5.7Hz，2H)，3.84(S，3H)，4.23(S，2H)，6.84-6.99(m，6H)，7.36(d，J＝9.0Hz，2H)；MS?m/z[m+]352。
Embodiment 18
To be similar to the method for embodiment 17, suitable 7-oxo-2,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine and lithium aluminum hydride react, and generate the compound of following formula IX.
| Embodiment # | ?R 1 | ??R 2 | ??R 3 | Fusing point ℃ (M.p. ℃) | Molecular weight (Mol.Weight) | Mass spectrum ([M +]) (actual recording) |
| ??18 | Ethyl | Isobutyl- | Cyclopentyl | Oil | ????275.44 | ??MS(m/z)276 |
Embodiment 19
1-cyclopentyl-3-ethyl-6-benzyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
Sodium hydride (32mg with 60%, 0.77mmoles) (in mineral oil) handle 1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] (0.12g 0.51mmoles) is dissolved in dimethyl formamide (DMF, 5ml) solution of Xing Chenging to pyridine.After stirring 1 hour at ambient temperature, and the adding bromotoluene (0.22g, 1.29mmoles).After 4 hours, water (50ml) diluted mixture thing, and use the ethyl acetate extracting.The organic layer that water and salt water washing merge, dry on sodium sulfate, and under reduced pressure, concentrate.Chromatography on silica gel with 1: 4 ethyl acetate/hexane wash-out, obtains the title compound of 0.13g colorless oil.MS?m/z[M+]324。
Embodiment 20-68
To be similar to the method for embodiment 19,1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine and sodium hydride (in DME) reaction add essential electrophilic reagent again, generate the compound of following formula IX, wherein R1=ethyl and R3=cyclopentyl.
| Embodiment # | Electrophilic reagent | R 2 | Fusing point ℃ (Mp ℃) | Mass spectrum/analysis (calculated value) %C, %H, %N | Mass spectrum/analysis (survey) %C, %H, %N |
| ????20 | Cyclopropyl-methyl-bromide | The cyclopropyl methyl | Oil | [M+]287.41 | MS(m/z)288 |
| ????21 | Cyclopentyl bromination thing | Cyclopentyl | Oil | [M+]301.43 | MS(m/z)302 |
| ????22 | Isobutyl-bromination thing | Isobutyl- | Oil | [M+]289.42 | MS(m/z)290 |
| ????23 | Methylallyl bromination thing | Methylallyl | Oil | [M+]287.41 | MS(m/z)288 |
| ????24 | Isopentyl-bromide | The 3-methyl butyl | Oil | [M+]303.45 | MS(m/z)304 |
| ????25 | Ethyl-2-bromo-butyrates | 1-oxyethyl group-carbonyl-propyl group | Oil | [M+]347.46 | MS(m/z)348 |
| ????26 | Dimethyl-formamyl | Dimethyl-formamyl | Oil | [M+]304.39 | MS(m/z)305 |
| ????27 | The neo-pentyl bromide | Neo-pentyl | Oil | [M+]303.45 | MS(m/z)304 |
| ????28 | Ethyl-4-bromo-butyrates | 3-oxyethyl group-carbonyl-propyl group | Oil | [M+]347.46 | MS(m/z)348 |
| ????29 | 1-bromo-2-diphenylphosphino ethane | 2-phenyl-ethyl | Oil | [M+]337.47 | MS(m/z)338 |
| ????30 | 1-bromo-1-phenyl-ethane | 1-phenyl-ethyl | ?70-1 | 74.74，8.06，12.45 | 74.66，8.22，12.47 |
| ????31 | N, N-dimethylated methylene ammonium chloride | N, the N-dimethylaminomethyl | Oil | [M+]290.41 | MS(m/z)291 |
| ????32 | Sec.-propyl bromination thing | Sec.-propyl | Oil | [M+]275.40 | MS(m/z)276 |
| ????33 | Acetylfluoride | Ethanoyl | Oil | [M+]275.35 | MS(m/z)276 |
| ????34 | 2-brooethyl-1, the 3-dioxolane | 1,3-dioxolane-2-base-methyl | ?52-3 | [M+]319.41 | MS(m/z)320 |
| ????35 | 3-picolyl chlorination thing | The 3-picolyl | Oil | [M+]324.43 | MS(m/z)325 |
| ????36 | 2-picolyl chlorination thing | The 2-picolyl | Oil | [M+]324.43 | MS(m/z)325 |
| ????37 | 4-picolyl chlorination thing | The 4-picolyl | Oil | [M+]324.43 | MS(m/z)325 |
| ????38 | Benzene sulfonyl chloride | Benzenesulfonyl | Oil | [M+]373.48 | MS(m/z)374 |
| ????39 | The sec.-propyl SULPHURYL CHLORIDE | Different third alkylsulfonyl | ?117-9 | 56.61，7.42，12.38 | 56.78，7.43，12.33 |
| ????40 | 2-chloro-5-(chloro-methyl) thiophene | 2-chloro-thiophene-5-base-methyl | Oil | [M+]363.91 | MS(m/z)364 |
| ????41 | 3-chloro-methyl-methyl-phenoxide | The 3-methoxybenzyl | Oil | [M+]353.47 | MS(m/z)354 |
| ????42 | 4-chloro-methyl-3,5-dimethyl-isoxazoles | 3,5-dimethyl-isoxzzole-4-base-methyl | ?98-9 | 66.64，7.65，16.36 | 66.46，7.79，16.33 |
| ????43 | 3-chloro-benzyl-bromide | The 3-chlorophenylmethyl | Oil | [M+]357.89 | MS(m/z)358 |
| ????44 | 2-chloro-bromotoluene | 2-benzyl chloride base | ?68-9 | 67.12，6.76，11.74 | 67.13，7.03，11.90 |
| ????45 | Thiophene-2-SULPHURYL CHLORIDE | Thiophene-2-alkylsulfonyl | Oil | [M+]379.50 | MS(m/z)380 |
| ????46 | The 4-chlorobenzene sulfonyl chloride | 4-methoxy benzenesulfonyl | Oil | [M+]407.92 | MS(m/z)408 |
| ????47 | Methylsulfonyl chloride | Methylsulfonyl | ?55-60 | [M+]311.40 | MS(m/z)312 |
| ????48 | 4-methoxy benzene sulfonyl chloride | The true acyl group of 4-methoxy benzene | ?118-126 | [M+]403.50 | MS(m/z)404 |
| ????49 | 3-chlorobenzene sulfonic acid fluoride | 3-chlorobenzene alkylsulfonyl | ?89-94 | [M+]407.92 | MS(m/z)408 |
| ????50 | The 2-chloromethyl thiophene | Thiophene-2-base-methyl | Oil | [M+]329.47 | MS(m/z)330 |
| ????51 | 2, the 5-two chloro phenylsulfonyl chloride | 2,5-dichlorobenzene alkylsulfonyl | Oil | [M+]442.37 | MS(m/z)442 |
| ????52 | Thiophene-2-carbonyl acyl fluorides | Thiophene-2-carbonyl | ?77-8 | 62.95，6.16，12.23 | 62.87，6.25，12.35 |
| ????53 | Isobutyryl chloride | Isobutyryl | Oil | [M+]303.40 | MS(m/z)303 |
| ????54 | Tetrahydrochysene glycosyl muriate | Tetrahydrofurfuryl | Oil | [M+]317.43 | MS(m/z)318 |
| ????55 | Benzoyl chloride | Benzoyl | ?72-4 | [M+]337.42 | MS(m/z)338 |
| ????56 | Different nicotinoyl chlorine | Different nicotinoyl | Oil | [M+]338.41 | MS(m/z)339 |
| ????57 | Nicotinoyl chlorine | Nicotinoyl | ?103-5 | [M+]338.41 | MS(m/z)339 |
| ????58 | 2-bromo-ethyl-methyl ether | The 2-methoxyethyl | Oil | [M+]291.39 | MS(m/z)292 |
| ????59 | 3-(bromo-methyl) benzonitrile | 3-cyano group benzyl | Oil | 72.39，6.94，16.08 | 72.19，6.98，15.75 |
| ????60 | The methyl chloride formate | Methoxycarbonyl | Oil | 61.84，7.26，14.42 | 61.34，7.47，14.23 |
| ????61 | 2-(brooethyl) benzonitrile | 2-cyano group-benzyl | Oil | 72.3，6.9，16.1 | 72.5，7.2，15.3 |
| ????62 | 4-(brooethyl) benzonitrile | 4-cyano group-benzyl | Oil | 72.3，6.9，16.1 | 70.6，6.9，15.5 |
| ????63 | 3-bromo-third is fine | 2-cyano group-ethyl | Oil | 67.09，7.74，19.56 | 66.82，7.55，18.92 |
| ????64 | 3-bromo-2-butanone | 2-fourth-3-acyl group | ?59-61 | 67.3，8.31，13.85 | 67.1，8.21，13.50 |
| ????65 | Morpholine-4-carbonyl chloride | Morpholine-4-carbonyl | ?153-4 | [M+]346.43 | MS(m/z)347 |
| ????66 | The ethyl chloride formate | Ethoxycarbonyl | Oil | [M+]306.38 | MS(m/z)306 |
| ????67 | 2-(2-bromotrifluoromethane)-1, the 3-dioxolane | 2-(1,3-dioxolane-2-yl) ethyl | Oil | [M+]333.43 | MS(m/z)334 |
| ????68 | 2-(chloromethyl) tetrahydropyrans | Tetrahydropyrans-2-base-methyl | Oil | [M+]331.46 | MS(m/z)332 |
Embodiment 69
6-(2-dichloro-thiophene-5-yl) methyl-3-ethyl-1-(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
To be similar to the method for embodiment 19,3-ethyl-1-(4-fluorophenyl)-7-oxo-4,5,6,7-four oxygen-1H-pyrazoles [3,4-c] pyridine and the reaction of 2-chloro-5-(chloromethyl) thiophene generate title compound, MS (m/z) 390.
Embodiment 70
3-ethyl-1-(4-fluorophenyl)-7-oxo-6-(thiophene-2-yl)-4,5,6,7-tetrahydrochysene-1H pyrazoles [3,4-c] pyridine
To be similar to the method for embodiment 19,3-ethyl-1-(4-fluorophenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine and the reaction of 2-chloromethyl thiophene generate title compound, and molten point (mp) is 106-70 ℃; MS (m/z) 356.
Embodiment 71
1-cyclopentyl-3-ethyl-6-(2-hydroxy-5-methyl phenyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
With 1-cyclopentyl-3-ethyl-6-(2-methoxyl group-5-tolyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine (0.32g, 0.91mmoles) be dissolved in solution (10ml) wiring solution-forming of 30% HBr (being dissolved in acetate), and solution is stirred down in 95 ℃ of temperature condition.After 24 hours, enriched mixture under reduced pressure is dissolved in ethyl acetate with it again, and is dry on sal epsom with saturated sodium bicarbonate and salt water washing, concentrates under reduced pressure again.Recrystallize obtains the title compound of 0.15g from isopropyl ether.181-2 ℃ of molten point (MP); MS (m/z) 340; To C
20H
25N
3O
2Carry out analytical calculation: C (70.77), H (7.42), N (12.38) records C (71.03), H (7.49), N (12.60).
Embodiment 72-78
To be similar to the method for embodiment 71, make that essential methoxyphenyl replaces 4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine and be dissolved in the 30%HBr reaction of glacial acetic acid, generate compound with following formula IX.
| Embodiment # | R 1 | R 2 | R 3 | Fusing point ℃ (Mp ℃) | Mass spectrum/analysis (calculating gained) %C, %H, %N | Mass spectrum/analysis (actual recording) %C, %H, %N |
| ????72 | Ethyl | 2-hydroxyl-phenyl | Cyclopentyl | 164-5 | [M+]325.41 | MS(m/z)326 |
| ????73 | Ethyl | The 3-hydroxy phenyl | Cyclohexyl | 178-9 | [M+]339.44 | MS(m/z)340 |
| ????74 | Ethyl | The 4-hydroxy phenyl | Cyclopentyl | 228-9 | 70.13，7.12，12.91 | 69.02，7.05，12.79 |
| ????75 | Ethyl | 5-chloro-2-hydroxyl-phenyl | Cyclopentyl | 124-5 | 63.41，6.16，11.68 | 63.60，6.24，11.56 |
| ????76 | Ethyl | 5-chloro-2-hydroxyl-phenyl | The 4-fluorophenyl | 173-4 | 62.26，4.44，10.89 | 62.41，4.61，10.86 |
| ????77 | Ethyl | The 3-hydroxy phenyl | Cyclopentyl | 161-2 | 70.13，7.12，12.91 | 70.18，7.25，12.86 |
| ????78 | Ethyl | The 3-hydroxybenzyl | Cyclopentyl | 134-9 | [M+]339.44 | MS(m/z)340 |
Embodiment 79
6-acetonyl-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
1-cyclopentyl-3-ethyl-6-methylallyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine (0.12g, 0.41mmoles) be dissolved in the solution that diox (25ml) and water (60ml) is made into and handle with salt of wormwood (0.035g), use 33 milliliters NaIO then
4(2.1g) and KMnO
4(0.026g) solution-treated that in water (100ml), forms.Use ether extracting mixture after one hour.With the ether layer that the salt water washing merges, dry on sodium sulfate, and under reduced pressure, concentrate.Chromatography on silicagel column is made elutriant with 1: 3 ethyl acetate/hexane, obtains the title compound of the water white oil of 0.042g.Ms(m/z)290。
Embodiment 80
1-cyclopentyl-3-ethyl-6-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
At 0 ℃, (30mg 0.10mmoles) is dissolved in solution sodium borohydride (38mg) processing that two milliliters of anhydrous methanols are made into 6-acetonyl-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine.After 15 minutes, add saturated aqueous ammonium chloride solution, with ether extracting mixture.With the ether layer that the salt water washing merges, dry on sodium sulfate, and under reduced pressure, concentrate.Chromatography on silicagel column is made elutriant with 1: 2 ethyl acetate/hexane, obtains the title compound of the water white oil of 20g.MS(m/z)292。
Embodiment 81
6-(acetone-1-base oxime)-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine.
At ambient temperature, the solution that in anhydrous pyridine (5ml), forms with oxammonium hydrochloride (0.040g) processing 6-acetonyl-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridines (0.15g).After 20 hours, enriched mixture under reduced pressure, resuspending is in ethyl acetate.Water and salt water washing suspension are in MgSO
4Last dry, and under reduced pressure, concentrate.Recrystallize from isopropyl ether obtains the title compound of 0.1g white solid.147-9 ℃ of fusing point (MP); MS (m/z) 305; To C
16H
24N
4O
2Analytical calculation: C (63.13), H (7.94), N (18.41) records: C (62.80), H (8.20), N (18.55).
Embodiment 82
6-(O-aminocarboxyl oxime acetonyl)-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine
At 0 ℃, be dissolved in tetrahydrofuran (THF) (THF, 5ml) solution of Xing Chenging with chlorosulfonyl isocyanate (70mg) processing 6-(oxime acetonyl)-1-cyclopentyl-3-ethyl-7-oxo-4,5,6,7-tetrahydrochysene-1H pyrazoles [3,4-c] pyridines (0.10g).After 25 ℃ of temperature condition stirred 1 hour down, enriched mixture under reduced pressure was dissolved in ethyl acetate with mixture, and water and salt water washing are dry on MgSO4, and concentrate under reduced pressure again.Chromatography on silicagel column with 1: 3 ethyl acetate/hexane wash-out, obtains the title compound of light yellow oil.MS(m/z)348。
Embodiment 83-86
Be similar to the method for embodiment 19, the sodium hydride reaction among 1-cyclopentyl-3-4,5,6,7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine and the DMF adds essential electrophilic reagent, the compound of production X, wherein R again
1=ethyl and R
3=cyclopentyl.
| Embodiment # | Electrophilic reagent | R 2 | Fusing point ℃ (MP ℃) | Mass spectrum or analysis (calculating gained) %C, %H, %N | Mass spectrum or analysis (actual recording) %C, %H, %N |
| ??83 | Sec.-propyl-sulphonyl ammonia | Sec.-propyl-alkylsulfonyl | 108-113 | 59.05，8.37，112.91 | 58.79，8.38，12.51 |
| ??84 | Thiophene-2-carbonyl-muriate | Thiophene-2-carbonyl | Oil | 65.62，7.04，12.75 | 62.60，6.74，11.84 |
| ??85 | Dimethyl-formamyl | Dimethyl-formamyl | Oil | [M +]290.41 | Mass spectrum (m/z) 291 |
| ??86 | 2-chloro-5-(chloro-methyl)-thiophene | 2-chlorothiophene-5-methyl | Oil | [M +]349.93 | Mass spectrum (m/z) 350 |
Preparation 1
4-isobutyryl-3-methoxyl group-1-phenyl-2-oxo-1,2,5,6-tetrahydropyridine
Stirring new distillatory Diisopropylamine (0.16ml, 2.21mmole) solution that is dissolved in anhydrous tetrahydro furan (4ml) is cooled to 0 ℃, with 2.5M just-(0.85ml 2.11mmole) handles butyllithium.After 15 minutes, mixture is cooled to-78 ℃, (0.52g 2.0mmole) is dissolved in the solution that tetrahydrofuran (THF) (4ml) obtains with managing 4-propionyl-3-methoxyl group-1-phenyl-2-oxo-1,2,5, the 6-tetrahydropyridine that dropwise adds precooling.After about 20 minutes, (0.20ml 3.0mmole), makes mixture reach room temperature more than 2.5 hours to add methyl iodide to this bright orange-red solution.Reaction mixture is poured into saturated aqueous ammonium chloride solution, dry on sodium sulfate with salt water washing organic layer, under reduced pressure, filter and concentrated organic layer.Chromatography on silicagel column as elutriant, obtains the title compound of yellow oil of 0.12g and the starting material that 0.1g reclaims with 1: 4 ethyl acetate/hexane.
1HNMR (250MHz, CDCl
3), 1.15 (d, 6H), 2.72 (t, 2H), 3.47 (septet, 1H), 3.82 (t, 2H), 3.97 (S, 3H), 7.21-7.45 (m, 5H); MS m/z[M+] 274.
Preparation 2-3
Be similar to the method for preparation 1, suitable 3-methoxyl group-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine and N-Lithiodiisopropylamide and methyl iodide react, and generate the compound of following formula VII.
| Preparation # | ?????R 2 | Fusing point ℃ (m.p. ℃) | Molecular weight (M.W) | Mass spectrum ([M +]) |
| ????2 | The 4-methoxyphenyl | Oil | ????303.36 | ????304 |
| ????3 | The 3-methoxyphenyl | Oil | ????303.36 | ????304 |
Preparation 4
3-methoxyl group-1-(4-tolyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine
3-hydroxyl-1-(4-tolyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine (5.9g, 23mmole) and 3-methyl isophthalic acid-right-tolyl triazine (5.1g, the vlil that 34mmole) be dissolved in 1, forms in the 2-ethylene dichloride 45 minutes.Reaction mixture is cooled to room temperature, pours in the water, and use the 6N hcl acidifying.With three extracting water layers of methylene dichloride, and the organic layer that merges with 1N salt acid elution, water and salt water washing again, dry on sal epsom, under reduced pressure, filter and concentrate.With the quantitative brown oil of thin-layer chromatography purification gained, under not refining situation, carry out
1HNMR.
1HNMR(300MHz，CDCl
3)，1.12(t，J＝7.2Hz，3H)，2.34(S，3H)，2.71(t，J＝6.7Hz，2H)，2.93(q，J＝7.2Hz，2H)，3.77(t，J＝6.8Hz，2H)，3.94(S，3H)，7.20(S，4H)；MS[M+]273。
Preparation 5-14
Be similar to the method for preparation 4, suitable 3-hydroxyl-1-aryl-2-oxo-chain triacontanol base-1,2,5,6-tetrahydropyridine and 3-methyl isophthalic acid-right-tolyl triazine is reacted, and generates the compound of following formula VI.
| Preparation # | ?????R 1 | R 2 | Fusing point ℃ (m.p. ℃) | Molecular weight (M.W.) | Mass spectrum ([M +]) |
| ????5 | Ethyl | Phenyl | Oil | ????259.31 | ??260 |
| ????6 | Methyl | The 4-methoxyphenyl | Oil | ????275.30 | ??275 |
| ????7 | Ethyl | The 4-methoxyphenyl | ???81-82 | ????289.33 | ??289 |
| ????8 | N-propyl | The 4-methoxyphenyl | Oil | ????303.36 | ??303 |
| ????9 | Ethyl | The 3-methoxyphenyl | ???59-60 | ????289.33 | 289，290 |
| ????10 | Ethyl | The 2-methoxyphenyl | Oil | ????289.33 | ??289 |
| ????11 | Ethyl | 3, the 4-dimethoxy phenyl | Oil | ????319.26 | ??319 |
| ????12 | Ethyl | 3-cyclopentyloxy-4-methoxyphenyl | Oil | ????373.45 | ??373 |
| ????13 | Ethyl | The 3-aminomethyl phenyl | Oil | ????273.33 | ??273 |
| ????14 | Ethyl | The 3-trifluoromethyl | Oil | ????327.30 | ??327 |
Preparation 15
3-hydroxyl-1-(3-tolyl)-2-oxo-4-propionyl-1,2,5,6-tetrahydropyridine
(5.9ml, (1.9g is 79mmole) in the suspension that forms in the 30ml anhydrous diethyl ether 79mmole) dropwise to join the magnesium chips that stirred monobromethane.After adding about 1ml, beginning slightly refluxes.After magnesium all is consumed, reaction mixture is cooled to 0 ℃, and add immediately N-(3-aminomethyl phenyl)-2-Pyrrolidone (8.7g, 50mmole).After being heated to room temperature and stirring 2 hours, reaction mixture is poured on ice, and use the ethyl acetate extracting.Water and salt water washing blended organism, dry on sal epsom, under reduced pressure, filter and concentrate, obtain the 8.8g white solid.
Above solid dispersed in the mixture of the sodium hydroxide of 40ml benzene and 86ml 1N, and in the violent churned mechanically while, add the ethyl oxalyl chloride (7.2ml, 64mmole).After reflux stirring more than 1.5 hours, layering, and with ethyl acetate extracting water layer.The organism that water and salt water washing merge, dry on sal epsom, under reduced pressure, filter and concentrate, obtain a kind of succinol.Gas chromatography mass spectrometry [M+] 305.
Above intermediate product is dissolved in the 20ml dehydrated alcohol, and handles with sodium methoxide solution [by making] to the careful sodium (1.0g) that adds of 10ml anhydrous methanol.After when refluxing, stirring more than 1.5 hours, enriched mixture under reduced pressure, and add 100ml water.With 6N hydrochloric acid mixture is acidified to pH3, and filters the dark yellow precipitation, wash with water.With 75ml isopropyl ether recrystallize, obtain the 6.8g pale yellow crystals.M.P.115-116℃；
1HNMR(300MHz，CDCl
3)，1.16(t，J＝7.2Hz，3H)，2.37(s，3H)，2.74-2.82(m，4H)，3.85(t，J＝6.8Hz，2H)，7.08-7.14(m，3H)，7.30(t，J＝7.7Hz，1H)；MS?m/z[M+]259。
Preparation 16-29
Be similar to the method described in the preparation 15, ethyl oxalyl chloride and alkaline purification are used in suitable 2-Pyrrolidone and essential alkyl magnesium bromide reaction again, generate the compound of following formula VI.
| Preparation # | ?????R 1 | ????R 2 | Fusing point ℃ (m.p. ℃) | Molecular weight (M.W) | Mass spectrum ([M +]) |
| ????16 | Methyl | Phenyl | Oil | ??231.25 | ????231 |
| ????17 | Ethyl | Phenyl | ??140-142 | ??245.28 | ????245 |
| ????18 | Ethyl | The 4-fluorophenyl | ??133-135 | ??263.27 | ????263 |
| ????19 | Methyl | The 4-methoxyphenyl | Oil | ??261.28 | ????262 |
| ????20 | Ethyl | The 4-methoxyphenyl | ??121-122 | ??275.30 | ????276 |
| ????21 | N-propyl | The 4-methoxyphenyl | ??125-126 | ??289.33 | ????289 |
| ????22 | Ethyl | The 3-methoxyphenyl | ??129-130 | ??275.30 | ????275 |
| ????23 | Ethyl | The 2-methoxyphenyl | ??119-120 | ??275.30 | ????275 |
| ????24 | Ethyl | The 4-methoxyphenyl | ??110-112 | ??259.30 | ????260 |
| ????25 | Ethyl | The 2-methoxyphenyl | Oil | ??259.30 | ????259 |
| ????26 | Ethyl | The 3-trifluoromethyl | ??117-118 | ??313.28 | ????313 |
| ????27 | Ethyl | The 2-trifluoromethyl | Oil | ??313.28 | ????313 |
| ????28 | Ethyl | 3, the 4-dimethoxy phenyl | ??179-180 | ??305.33 | ????306 |
| ????29 | Ethyl | 3-cyclopentyloxy-4-methoxyphenyl | ??133-134 | ??359.42 | ????360 |
Preparation 30
N-(2-methoxyphenyl)-2-Pyrrolidone
When having nitrogen to exist, under 150 ℃ of temperature condition, stir 2-Pyrrolidone (15.0g, 176mmol), 2-phenyl-iodide methyl ether (7.6ml, 59mmoles), copper powder (7.5g, 117mmoles) and salt of wormwood (8.1g, mixture 59mmol).After 18 hours, the silica-gel plate of reaction mixture by a 6 * 15cm filtered, and, obtain light yellow oil with 1: 1 ethyl acetate/hexane wash-out.Remove unreacted reagent by vacuum distilling (0.6mm, 80-100 ℃), stay the title compound of 9.2g honey shape oil.
1HNMR (300MHz, CDCl
3), 2.20 (quintet, 2H), 2.55 (t, 2H), 3.75 (t, 2H), 3.82 (S, 3H), 6.93-7.02 (m, 2H), 7.25-7.30 (m, 2H); MS m/z[M+] 191.
Preparation 31-39
Be similar to the method for preparation 30, suitable iodo or bromobenzene and 2-Pyrrolidone reaction generate the compound with following formula V.
| Preparation # | ?R | Molecular weight (M.W.) | Mass spectrum ([M +]) |
| ????31 | The 4-methoxyphenyl | ????191.22 | ????191 |
| ????32 | The 3-methoxyphenyl | ????191.22 | ????191 |
| ????33 | The 3-tolyl | ????175.23 | ????175 |
| ????34 | The 4-tolyl | ????175.23 | ????175 |
| ????35 | The 2-tolyl | ????175.23 | ????175 |
| ????36 | The 3-trifluoromethyl | ????229.20 | ????229 |
| ????37 | The 2-trifluoromethyl | ????229.20 | ????229 |
| ????38 | 3, the 4-dimethoxy phenyl | ????221.26 | ????221 |
| ????39 | 3-cyclopentyloxy-4-methoxyphenyl | ????275.35 | ????275 |
Claims (6)
1, a kind of compound and pharmaceutically useful salt thereof with following formula:
R wherein
1Be hydrogen, (C
1-C
3) alkyl, (C
2-C
3) alkenyl, (C
3-C
5) cycloalkyl or methylene radical (C
3-C
5) cycloalkyl, wherein each alkyl or alkenyl can be randomly by 2 (C of as many as
1-C
2) alkyl or trifluoromethyl or replaced by maximum three halogens (atom);
X is oxygen or 2 hydrogen atoms;
R
2With R
3Independently be selected from following group respectively: hydrogen; (the C that randomly replaces by halogen or cyano group
1-C
4) alkyl; (C
1-C
14) alkyl sulphonyl; (C
1-C
14) alkoxyl group; Naphthyl; (C
2-C
7) alkenyl; (C
3-C
7) cycloalkyl; (C
1-C
4) alkyl (C
3-C
7) cycloalkyl; (C
3-C
7) cycloalkyl (C
1-C
4) alkyl; (C
4-C
7) heterocyclic radical, wherein contain oxygen, sulphur, SO
2Or NR
5, R wherein
5Be hydrogen or (C
1-C
4) alkyl; (C
4-C
7) Heterocyclylalkyl-(W)
d, (C wherein
4-C
7) Heterocyclylalkyl contains one or more Sauerstoffatom, sulphur atom, SO
2Or NR
5, R wherein
5For hydrogen or randomly by halogen or (C
1-C
4) (the C that replaces of alkyl
1-C
4) alkyl, d be 0 or 1 and W be (C
1-C
4) alkyl, CO or alkylsulfonyl; CONR
10R
11, R wherein
10With R
11All independent is hydrogen or (C
1-C
4) alkyl; (C
1-C
5) alkyl-carbonyl; (C
1-C
5) alkoxy carbonyl; (C
1-C
5) alkyl-carbonyl (C
1-C
5) alkyl, (C
1-C
5) alkoxy carbonyl (C
1-C
5) alkyl; (C
1-C
5) alkoxyl group (C
1-C
5) alkyl; R
12R
13N (C
1-C
5) alkyl, wherein R
12With R
13All independent is hydrogen or (C
1-C
5) alkyl;
Or have a group of following structural formula:
Wherein, a is the integer of 0-5, and b and c are 0 or 1, R
4Independently be selected from hydrogen, hydroxyl, (C
1-C
5) alkyl, (C
2-C
5) alkenyl, (C
1-C
5) alkoxyl group, (C
3-C
6) cycloalkyloxy, halogen, trifluoromethyl, CO
2R
6, CONR
6R
7, NR
6R
7, CONHOH, CN, NO
2Or SO
2NR
6R
7, R wherein
6With R
7All independent is hydrogen or (C
1-C
4) alkyl; Wherein Y is (C
1-C
4) alkyl, (C
2-C
5) alkylidene group or randomly by maximum 2 (C
1-C
7) alkyl or (C
3-C
7) (the C of cycloalkyl substituted
2-C
6) alkenyl; And Z is oxygen, sulphur, CO, SO
2Or NR
8, R wherein
8Be hydrogen or (C
1-C
4) alkyl;
Or be the group of the following structural formula of tool:
Wherein p is the integer of 1-3; W is a hydroxyl; R
9Be (C
1-C
3) alkyl; Wherein each described alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic radical can be selected from (C by 1-14, preferred 1-5 arbitrarily
1-C
2) gene of alkyl, trifluoromethyl or halogen replaces;
Or have a group of following structural formula:
Wherein m, n and p are 1 or 2;
Or group with following structural:
Wherein Q is hydroxyl or the group with following structural formula:
Prerequisite is: at R
1Be ethyl and R
2During for the 4-aminomethyl phenyl, R
3Can not be hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl; At R
2Be 4-aminomethyl phenyl and R
3During for the 4-fluorophenyl, R
1Can not be phenyl, methyl or n-propyl; At R
1Be ethyl and R
2During for phenyl, R
3Can not be 4-chloro-phenyl-, 4-fluorophenyl or 4-tolyl; At R
1Be ethyl and R
2During for the 4-methoxyphenyl, R
3Can not be the 4-fluorophenyl; And when W was CO or alkylsulfonyl, d was 1;
Following situation also is prerequisite: R
2And R
3Can not all independently be selected from hydrogen; (C
1-C
4) alkyl; (C
1-C
14) alkoxyl group; (C
2-C
7) alkenyl; (C
4-C
7) heterocyclic radical, wherein contain aerobic, sulphur, SO
2Or NR
5, R wherein
5Be hydrogen or (C
1-C
4) alkyl; Or group with following structural:
Wherein a is the integer of 1-5; B and c are 0 or 1; R
4Be hydrogen, hydroxyl, (C
1-C
5) alkyl, (C
2-C
5) alkenyl, (C
1-C
5) alkoxyl group, (C
3-C
6) cycloalkyloxy, halogen, trifluoromethyl, CO
2R
6, CONR
6R
7, NR
6R
7, NO
2Or SO
2R
6R
7(R wherein
6With R
7All independent is hydrogen or (C
1-C
4) alkyl); And Y is (C
1-C
5) alkylidene group or at random by maximum 2 (C
1-C
7) alkyl or (C
3-C
7) (the C of cycloalkyl substituted
2-C
6) alkenyl; Or group with following structural:
Wherein, p is the integer of 1-3, and W is oxo or hydroxyl, R
9Be (C
1-C
3) alkyl; Wherein every-described alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic radical can be at random by 1-14, preferred 1-5 (C
1-C
2) alkyl, trifluoromethyl or halogen replace.
2, the compound of claim 1, wherein R
1Be (C
1-C
3) alkyl and R
3Be (C
3-C
7) cycloalkyl, contain SO
2(C
4-C
7) heterocyclic group or have the group of following structural formula:
Wherein, a is integer and the R of 1-5
4Independently be selected from hydrogen, hydroxyl, (C
1-C
5) alkyl, (C
1-C
5) alkoxy or halogen.
3, the compound of claim 1, wherein R
1Be ethyl or sec.-propyl; R
2Be phenyl; the 2-tolyl; the 3-tolyl; the 2-methoxyphenyl; the 3-methoxyphenyl; the 2-hydroxyphenyl; the 3-hydroxyphenyl; the 4-hydroxyphenyl; the cyclopropyl methyl; benzyl; isobutyl-; isobutenyl; 2-ethylbenzene base; naphthalene thiazolinyl (naphthalenyl); the 2-chloro-phenyl-; the 3-methyl butyl; formyl-dimethylamino; the 1-methyl-benzyl; sec.-propyl; the 1-picolyl; the 2-picolyl; the 3-picolyl; 2-methyl-5-chloro phenyl; 2-chlorothiophene-5-base-methyl; 2-hydroxy-5-methyl base phenyl; 3; 5-dimethyl-isoxazole-4-bases-methyl; 3-benzyl chloride base; thiophene-2-base-methyl; 2-hydroxyl-5-chloro-phenyl-; thiophene-2-carbonyl; tetrahydrofurfuryl; 3-cyano group benzyl; morpholine-4-carbonyl; the sec.-propyl alkylsulfonyl; 4-methoxyphenyl alkylsulfonyl or 3-fluoroform phenyl, and R
3Be cyclobutyl, cyclopentyl, cyclohexyl, 3-tetramethylene sulfone base, 4-fluorophenyl or 3,4-dichlorophenyl.
4, a kind of pharmaceutical composition, be used to suppress the generation of phosphodiesterase (PDE) IV type and tumour necrosis factor (TNF) and be used for the treatment of asthma, sacroiliitis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory conditions, acquired immune deficiency syndrome (AIDS), septic shock and other relates to the disease that TNF produces, this pharmaceutical composition contains compound and a kind of pharmaceutically useful carrier of the claim 1 of pharmacy effective dose.
5, the method for a kind of inhibition phosphodiesterase (PDE) IV type and tumour necrosis factor (TNF) generation comprises the formula I compound to the claim 1 of patient's administration effective dose.
6, a kind of treatment and prophylactic method, described disease is selected from asthma, sacroiliitis, bronchitis, chronic obstructive airway disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory conditions, acquired immune deficiency syndrome (AIDS), septic shock and other relates to the disease that TNF produces, and this method comprises the compound to the claim 1 of patient's administration effective dose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US32643494A | 1994-10-20 | 1994-10-20 | |
| US08/326,434 | 1994-10-20 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1161040A true CN1161040A (en) | 1997-10-01 |
| CN1050129C CN1050129C (en) | 2000-03-08 |
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ID=23272184
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|---|---|---|---|
| CN95195743A Expired - Fee Related CN1050129C (en) | 1994-10-20 | 1995-10-06 | Bicyclic tetrahydro pyrazolopyridines and their use as medicaments |
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| Country | Link |
|---|---|
| EP (1) | EP0787132A1 (en) |
| JP (1) | JPH09511758A (en) |
| KR (1) | KR970707124A (en) |
| CN (1) | CN1050129C (en) |
| AU (1) | AU702105B2 (en) |
| BR (1) | BR9504491A (en) |
| CZ (1) | CZ120097A3 (en) |
| FI (1) | FI954991A (en) |
| HU (1) | HUT77517A (en) |
| IL (1) | IL115667A0 (en) |
| MX (1) | MX9504422A (en) |
| NO (1) | NO971811L (en) |
| NZ (1) | NZ292991A (en) |
| PL (1) | PL319758A1 (en) |
| WO (1) | WO1996012720A1 (en) |
| ZA (1) | ZA958839B (en) |
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| CN115043768A (en) * | 2022-06-20 | 2022-09-13 | 新乡市润宇新材料科技有限公司 | Method for synthesizing N-aryl pyrrolidine-2-ketone by acid-promoted ring opening of cyclopropyl |
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| AP1147A (en) * | 1996-05-03 | 2003-02-25 | Pfizer | Substituted indazole derivatives and related compounds. |
| WO1997048697A1 (en) | 1996-06-19 | 1997-12-24 | Rhone-Poulenc Rorer Limited | Substituted azabicylic compounds and their use as inhibitors of the production of tnf and cyclic amp phosphodiesterase |
| CA2258285C (en) * | 1996-06-25 | 2002-11-26 | Anthony Marfat | Substituted indazole derivatives and their use as phosphodiesterase (pde) type iv and tumor necrosis factor (tnf) inhibitors |
| WO1998050367A1 (en) * | 1997-05-08 | 1998-11-12 | Pfizer Products Inc. | Processes and intermediates for preparing substituted indazole derivatives |
| IL126745A (en) * | 1997-11-04 | 2003-09-17 | Pfizer Prod Inc | Methods of preparing 4-cyano-4- (substituted indazole) cyclohexanecarboxylic acids useful as pde4 inhibitors |
| US6858616B2 (en) | 1998-12-23 | 2005-02-22 | Bristol-Myers Squibb Pharma Company | Nitrogen containing heterobicycles as factor Xa inhibitors |
| ES2232202T3 (en) | 1998-12-23 | 2005-05-16 | Bristol-Myers Squibb Pharma Company | HETEROBICICLES CONTAINING NITROGEN AS INHIBITORS OF THE XA FACTOR. |
| US6326495B2 (en) | 1999-04-30 | 2001-12-04 | Pfizer Inc. | Process for preparing 8-cyclopentyl-6-ethyl-3-[substituted]-5,8-dihydro-4H-1,2,3a,7,8-pentaaza-as-indacenes and intermediates useful therein |
| EP2193808A1 (en) | 1999-08-21 | 2010-06-09 | Nycomed GmbH | Synergistic combination |
| BR0113176A (en) * | 2000-08-10 | 2003-06-17 | Pharmacia Italia Spa | Bicyclo-pyrazole compounds, pharmaceutical compositions comprising the compounds, use of the compounds in the manufacture of medicaments, processes for the preparation of the compounds, combinatorial chemical collection and methods for the treatment of mammals including humans using the compounds. |
| US6998408B2 (en) | 2001-03-23 | 2006-02-14 | Bristol-Myers Squibb Pharma Company | 6-5, 6-6, or 6-7 Heterobicycles as factor Xa inhibitors |
| WO2002085356A1 (en) | 2001-04-18 | 2002-10-31 | Bristol-Myers Squibb Company | 1, 4, 5, 6-tetrahydropyrazolo-[3, 4-c]-pyrid in-7-ones as factor xa inhibitors |
| CA2441772A1 (en) | 2001-04-18 | 2002-10-31 | Bristol-Myers Squibb Company | 1,4,5,6-tetrahydropyrazolo-¬3,4-c|-pyridin-7-ones as factor xa inhibitors |
| JP4196678B2 (en) | 2001-04-26 | 2008-12-17 | 味の素株式会社 | Heterocyclic compounds |
| GEP20074098B (en) | 2001-09-21 | 2007-05-10 | Bristol Myers Squibb Co | Lactam-containing compounds and derivatives thereof as factor xa inhibitors |
| TWI331526B (en) | 2001-09-21 | 2010-10-11 | Bristol Myers Squibb Pharma Co | Lactam-containing compounds and derivatives thereof as factor xa inhibitors |
| BR0312924A (en) * | 2002-07-25 | 2005-07-12 | Pharmacia Italia Spa | Active bicyclo-pyrazoles as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| FR2857363B1 (en) * | 2003-07-10 | 2007-09-07 | Aventis Pharma Sa | SUBSTITUTED 4,5,6,7-TETRAHYDRO-1H-PYRAZOLO [3,4-C] PYRIDINES COMPOSITIONS CONTAINING SAME AND USE THEREOF |
| AR045037A1 (en) | 2003-07-10 | 2005-10-12 | Aventis Pharma Sa | TETRAHIDRO-1H-PIRAZOLO [3,4-C] SUBSTITUTED PYRIDINS, COMPOSITIONS THAT CONTAIN THEM AND ITS USE. |
| EA014906B1 (en) * | 2005-12-01 | 2011-02-28 | Элан Фармасьютикалз, Инк. | 5-(arylsulfonyl)-pyrazolopiperidines |
| AU2009243232A1 (en) * | 2008-04-30 | 2009-11-05 | Fredrik Almqvist | New peptidomimetic compounds |
| US7741350B1 (en) | 2009-01-28 | 2010-06-22 | Cara Therapeutics, Inc. | Bicyclic pyrazolo-heterocycles |
| CA2749884C (en) | 2009-01-28 | 2018-01-23 | Cara Therapeutics, Inc. | Bicyclic pyrazolo-heterocycles |
| US10144732B2 (en) | 2014-06-06 | 2018-12-04 | Biogen Ma Inc. | ATX modulating agents |
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| US3340269A (en) * | 1964-09-08 | 1967-09-05 | Ciba Geigy Corp | 1-substituted 4-acyl-2, 3-dioxo-piperidine |
| US3365459A (en) * | 1964-09-08 | 1968-01-23 | Ciba Geigy Corp | Certain tetrahydro pyrazolo-pyridine and pyrazolo-piperidine derivatives |
| FR1463883A (en) * | 1964-09-08 | 1966-07-22 | Ciba Geigy | Process for the preparation of bicyclic triaza-compounds |
| NZ266525A (en) * | 1993-07-06 | 1997-10-24 | Pfizer | 4,5,6,7-tetrahydro-1h-pyrazolo[3,4-c]pyridine derivatives and medicaments |
-
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- 1995-10-06 AU AU35317/95A patent/AU702105B2/en not_active Ceased
- 1995-10-06 KR KR1019970702557A patent/KR970707124A/en active IP Right Grant
- 1995-10-06 HU HU9702289A patent/HUT77517A/en unknown
- 1995-10-06 WO PCT/IB1995/000847 patent/WO1996012720A1/en not_active Application Discontinuation
- 1995-10-06 CZ CZ971200A patent/CZ120097A3/en unknown
- 1995-10-06 JP JP8513751A patent/JPH09511758A/en active Pending
- 1995-10-06 PL PL95319758A patent/PL319758A1/en unknown
- 1995-10-06 NZ NZ292991A patent/NZ292991A/en unknown
- 1995-10-06 CN CN95195743A patent/CN1050129C/en not_active Expired - Fee Related
- 1995-10-06 EP EP95932148A patent/EP0787132A1/en not_active Withdrawn
- 1995-10-18 IL IL11566795A patent/IL115667A0/en unknown
- 1995-10-19 ZA ZA958839A patent/ZA958839B/en unknown
- 1995-10-19 FI FI954991A patent/FI954991A/en unknown
- 1995-10-19 MX MX9504422A patent/MX9504422A/en unknown
- 1995-10-20 BR BR9504491A patent/BR9504491A/en not_active Application Discontinuation
-
1997
- 1997-04-18 NO NO971811A patent/NO971811L/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115043768A (en) * | 2022-06-20 | 2022-09-13 | 新乡市润宇新材料科技有限公司 | Method for synthesizing N-aryl pyrrolidine-2-ketone by acid-promoted ring opening of cyclopropyl |
Also Published As
| Publication number | Publication date |
|---|---|
| FI954991A0 (en) | 1995-10-19 |
| BR9504491A (en) | 1997-05-20 |
| PL319758A1 (en) | 1997-08-18 |
| NO971811D0 (en) | 1997-04-18 |
| MX9504422A (en) | 1997-04-30 |
| NO971811L (en) | 1997-06-18 |
| CN1050129C (en) | 2000-03-08 |
| FI954991A (en) | 1996-04-21 |
| HUT77517A (en) | 1998-05-28 |
| NZ292991A (en) | 1999-02-25 |
| IL115667A0 (en) | 1996-01-19 |
| WO1996012720A1 (en) | 1996-05-02 |
| KR970707124A (en) | 1997-12-01 |
| EP0787132A1 (en) | 1997-08-06 |
| JPH09511758A (en) | 1997-11-25 |
| ZA958839B (en) | 1997-04-21 |
| AU3531795A (en) | 1996-05-15 |
| AU702105B2 (en) | 1999-02-11 |
| CZ120097A3 (en) | 1998-01-14 |
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