CN1129940A - Bicyclic tetrahydro pyrazolopyridines - Google Patents
Bicyclic tetrahydro pyrazolopyridines Download PDFInfo
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- CN1129940A CN1129940A CN94193233A CN94193233A CN1129940A CN 1129940 A CN1129940 A CN 1129940A CN 94193233 A CN94193233 A CN 94193233A CN 94193233 A CN94193233 A CN 94193233A CN 1129940 A CN1129940 A CN 1129940A
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- phenyl
- ethyl
- oxygen
- tetrahydrochysene
- pyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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, this compounds optionally suppresses the generation of IV type phosphodiesterase (PDE) and tumour necrosis factor (to call TNF in the following text), therefore is used for the treatment of asthma, sacroiliitis, bronchitis, chronic tracheae obstacle disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory disease; And AIDS, septic shock and other disease relevant with the generation of TNF.
The invention still further relates to and use this compounds for treating Mammals particularly method of the above-mentioned disease of human body and the use of pharmaceutical composition thereof.
Since recognize the ring AMP be the iuntercellular second messenger since (E.W.Sutherland, and T.W.Rall, Pharmacol.Rev., 1960,12 1265), in a considerable amount of lysises, it is the target that is used to regulate and treat interference that phosphodiesterase suppresses always.Recently, more cognitive unique PDE (J.A.Beavo and D.H.Reifsnyder, TiPS, 1990,11,150), its selective inhibitory makes pharmacological agent improve (C.D.Nicholson, R.A.Challiss and M.Shahid, TiPS, 1991,12.19).Particularly, the inhibition that has realized that IV type PDE can cause inflammatory mediator release (M.W.Verghese et al., J.Mol.Cell Cardiol., 1989,12 (Suppl.II), S 61) and the inhibition (T.J.Torphy that loosens of tracheal smooth muscle, Directions for NewAnti-Asthma Drugs, eds S.R.O ' Donnell and C.G.A.Persson, 1988,37, Birkhauser-Verlag).Therefore, some suppresses the compound of IV type PDE, although very weak to the PDE effect of other type, release that still can the inflammation-inhibiting medium, and tracheal smooth muscle is loosened, and do not cause cardiovascular and antiplatelet effects.
Think that TNF relates to many communicable and autoimmune disease (W.Friers, FEBSletters, 1991,285,199), and then can show that TNF is main medium (C.E.Spooner et al., the Cl-inical Immunology and Immunopathology of being seen Inflammatory response in sepsis and septic shock; 1992,62, S11).
The present invention relates to the compound and the acceptable salt of medicine thereof of following formula:
R wherein
1Be hydrogen, C
1-C
7Alkyl, C
2-C
3Alkenyl, C
3-C
5Cycloalkyl or methylene radical C
3-C
5Cycloalkyl, wherein each alkyl or alkenyl can be randomly by two C at the most
1-C
2Alkyl or trifluoromethyl or three halogens replacements at the most; X is oxygen or two hydrogen atoms, R
2And R
3Be selected from hydrogen, C independently of one another
1-C
14Alkyl, C
1-C
14Alkoxyl group, C
2-C
7Alkenyl, C
4-C
7Contain oxygen, sulphur, SO
2Or NR
5Heterocyclic radical, R wherein
5Be hydrogen or C
1-C
4Alkyl, or the group of following formula
Wherein a is 1 to 5 integer; B and C are 0 or 1; R
4Be hydrogen, hydroxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
1-C
5Alkoxyl group, C
3-C
6Cycloalkyloxy, halogen, trifluoromethyl, CO
2R
6, CONR
6R
7, NR
6R
7, NO
2Or SO
2NR
6R
7, R wherein
6And R
7Be selected from hydrogen or C independently of one another
1-C
4Alkyl; Wherein Z is oxygen, sulphur, SO
2Or NR
8, R wherein
8Be hydrogen or C
1-C
4Alkyl; And Y is can be by two C at the most
1-C
7Alkyl or C
3-C
7The C that alkyl replaces arbitrarily
1-C
5Alkylidene group or C
2-C
6Alkenyl; Or following radicals
Wherein P is 1 to 3 integer, and W is oxygen or hydroxyl, R
9Be C
1-C
3Alkyl, wherein said alkyl, alkenyl, cycloalkyl, alkoxyalkyl or heterocyclic radical can be by following 1 to 14, preferred 1 to 5 C that is selected from
1-C
2Alkyl, the group of trifluoromethyl or halogen replaces arbitrarily, and condition is to work as R
1Be ethyl and R
2When being the 4-aminomethyl phenyl, R
3Not hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl; Work as R
2Be 4-aminomethyl phenyl and R
3When being the 4-fluorophenyl, R
1Not phenyl, methyl or n-propyl; Work as R
1Be ethyl and R
2R when being phenyl
3Not the 4-chloro-phenyl-, 4-fluorophenyl or 4-aminomethyl phenyl and work as R
1Be ethyl and R
2When being the 4-p-methoxy-phenyl, R
3It or not the 4-fluorophenyl.
In a concrete scheme, the present invention relates to the compound of formula I, wherein R
1Be C
1-C
3Alkyl, R
2And R
3Be independently selected from C respectively
3-C
7Cycloalkyl, contain SO
2C
4-C
7Heterocyclic radical or following formula group
Wherein a is 1 to 5 integer, R
4Be hydrogen, hydroxyl, C
1-C
5Alkyl, C
1-C
5Alkoxy or halogen.
In another concrete scheme, the formula I compound that the present invention relates to, wherein R
1Be ethyl or sec.-propyl; R
2Be phenyl, 2-tolyl, 3-tolyl, 2-methoxyphenyl, 3-methoxyphenyl or 3-fluoroform phenyl, R
3Be cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfo group wool base (sulfolanyl), 4-fluorophenyl or 3,4-dichlorophenyl.
The invention still further relates to the pharmaceutical composition that is used to suppress IV type phosphodiesterase (PDE) and tumour necrosis factor (TNF) generation, this pharmaceutical composition comprises formula I compound and the acceptable salt of medicine and the medicine acceptable carrier of medicinal significant quantity.
The invention still further relates to a kind of method that is used to suppress IV type phosphodiesterase (PDE) and tumour necrosis factor (TNF) generation, this method comprises formula I compound and the acceptable salt of medicine thereof of using effective dose to the patient.
The invention still further relates to a kind of method for the treatment of the inflammation in mammals disease, this method comprises to the formula I compound of described administration anti-inflammatory effective amount and medicinal acceptable salt thereof.
The invention still further relates to the pharmaceutical composition that is used for the treatment of asthma, sacroiliitis, bronchitis, chronic tracheae obstacle disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory disease, AIDS, septic shock and other disease relevant with the generation of TNF, this medicinal compositions comprises formula I compound and the acceptable salt of medicine and the medicine acceptable carrier of medicinal significant quantity.
The invention still further relates to treatment or prevention and be selected from the method for the generation relative disease of asthma, sacroiliitis, bronchitis, chronic tracheae obstacle disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory disease, AIDS, septic shock and other and TNF, this method comprises formula I compound and the acceptable salt of medicine thereof of using effective dose to the patient.
The particularly preferred compound of the present invention is:
3-ethyl-1-(4-p-methoxy-phenyl)-6-phenyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3, the 4-dichlorophenyl)-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(4-fluorophenyl)-6-(2-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(3-tolyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(3-fluoroform phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclohexyl-6-(3-methoxyphenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-sec.-propyl-1-cyclopentyl-6-(3-methoxyphenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(3-methoxyphenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(2-tolyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfo group wool base sulfolanyl)-6-(3-tolyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfo group wool base)-6-(3-methoxyphenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(3-tolyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfo group wool base)-6-(3-fluoroform phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(3-fluoroform phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(2-tolyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine.
" halogen " used herein speech except as otherwise noted, is meant chlorine, fluorine and bromine.
Except as otherwise noted, alkyl herein, alkoxyl group and alkenyl can be straight chains, if perhaps to contain three or more carbon atoms can be straight chain, side chain, cyclic or ring-type with side chain or the combining of linear fraction.
" inflammatory disease " that can be treated according to the present invention is not limited to asthma, chronic obstacle pulmonary disorder, bronchitis and sacroiliitis.
R used herein
1, R
2And R
3, except as otherwise noted, all such as among the above-mentioned formula I definition.
Following reaction method is used to illustrate but does not limit the preparation of The compounds of this invention.
Method 1
Method 2
In the 1st step reaction of method 1, the 2-Pyrrolidone compound of formula IV changes into wherein " aryl " by IV and halogenated aryl reaction and is the corresponding N-aryl-2-Pyrrolidone compound of formula II group in the presence of copper powder and salt of wormwood.Suitable halogenated aryl hydrocarbon comprises 1-iodine or 1-bromo-4-anisole, 3-anisole, 2-anisole, 3-toluene, 4-toluene, 2-toluene, 3-phenylfluoroform, 2-phenylfluoroform, 3, and 4-dimethoxy benzene or 3-encircle penta oxygen-4-anisole.This reaction is carried out under the inert reaction condition usually, temperature of reaction usually between about 110 ℃ to about 170 ℃, preferred about 150 ℃, about 14 hours to about 22 hours reaction times, preferred 18 hours.
In the 2nd step reaction of method 1, with R
1Halides join in the suspension of the magnesium in the anhydrous aprotic solvent, this reaction mixture is heated to backflow is consumed until all magnesium.Be cooled to approximately between-15 ℃ to 15 ℃ preferred about 0 ℃ then.N-(the aryl)-2-Pyrrolidone compound that adds formula V then is heated to room temperature with reaction mixture under stirring and reaches between 1.5 hours to 2.5 hours, preferably reaches 2 hours.Suitable haloalkane comprises monobromethane, monobromethane or N-PROPYLE BROMIDE.Preferred anhydrous aprotic solvent is an anhydrous ether.After reaction was finished, required intermediate can separate with following ordinary method, and for example the organic phase that merges of water and salt water washing at first is dry on sodium sulfate then, filter and reduction vaporization with concentrated, obtain the throw out that is easy to reclaim of white solid.
Above-mentioned throw out is scattered in the mixed solution of apolar aprotic solvent and alkali and changes into corresponding formula VI1,2,5, the 6-5,6-tetrahydropyridine compounds.Under vigorous stirring, add the ethyl oxalyl chloride and with this reaction mixture reflux 1.5 hours to about 4.5 hours, preferred 3 hours.Preferred apolar aprotic solvent is a benzene, and preferred alkali is sodium hydroxide.Then solvent is removed the residue of the gained solution-treated of sodium alkyl alcohol in ethanol.Reflux 1 to 3 hour, preferred after about 1.5 hours, arrive PH=3 with the mixture concentrating under reduced pressure and with hcl acidifying.
In the 3rd step reaction of method 1, formula VI compound and 3-methyl isophthalic acid-to tolyl triazene reflux in aprotic solvent, and the corresponding 3-methoxyl group-1 of conversion accepted way of doing sth VII, 2,5, the 6-5,6-tetrahydropyridine compounds, preferred aprotic solvent is 1, the 2-ethylene dichloride, the reaction times is 30 minutes to about 120 minutes, preferred 45 minutes.
Go on foot in the reaction in the 1st of method 2, wherein R
5Be the formula VIII compound 1,2,5 of hydrogen or methyl, 6-tetrahydropyridine, through type VIII-and formula R
3HNNH
2Hydrazine reaction and change into corresponding formula IX compound 4,5,6,7-tetrahydrochysene-7-hydrogen-1H-pyrido [3,4-c] pyridine.Two derivatives of formula VIII compound, 3-hydroxyl and 3-methoxylation compound can be used as initiator to be undertaken by any one of following three groups of differential responses conditions.
Therein under the group reaction condition, 1,2,5 of formula VIII, the 6-5,6-tetrahydropyridine compounds reacts in anhydrous polar aprotic solvent by VIII and hydrazine hydrochloride and sodium alkoxide, and changes into corresponding formula IX compound.Preferred sodium alkoxide is a sodium methylate, and preferred anhydrous polar aprotic solvent is a dehydrated alcohol.Reaction mixture reflux 9 to 15 hours, preferred about 12 hours.
Under the second group reaction condition, formula VIII compound 1,2,5, the 6-tetrahydropyridine reacts in anhydrous polar aprotic solvent preferred alcohol by VIII and hydrazino-benzoic acid, and changes into corresponding formula IX compound.Reaction mixture reflux 16 to 24 hours is preferred 20 hours.The Compound I X that generates further reacted in the polar aprotic solvent particular methanol 15 to 45 minutes by IX and sodium methylate, preferred 30 minutes and obtain corresponding 1-(4-benzamide)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine compounds.Polar aprotic solvent is removed in decompression, and the solid suspension of gained is preferably in the benzene in the non-polarity proton solvent, under reduced pressure removes non-polar solvent then.The gained drying solid is suspended in the cold ether, and with oxalyl chloride and N, and dinethylformamide is handled and stir about 30 to 90 minutes, preferred 60 minutes.Remove and desolvate, crude product is dissolved in the anhydrous tetrahydro furan.With gained solution between-10 ℃ to 10 ℃, in preferred 0 ℃ of solution of ammonium hydroxide that is added drop-wise to stirring.
Under the 3rd group reaction condition, formula VIII compound 1,2,5,6 tetrahydropyridines react in the polar aprotic solvent particular methanol by VIII and hydrazine hydrochloride, and change into corresponding formula IX compound.Reaction mixture is being heated to 70 ℃ to 110 ℃ preferred about 90 ℃ under the nitrogen gas stream slowly, until removing all solvents.With extremely about 120 ℃ to about 180 ℃ of purified mixture heating up, preferred about 150 ℃, reach about 30 to 90 minutes, preferred 60 minutes then.
The aqueous solution of formed formula IX compound by IX and ceric ammonium nitrate (IV) reacts in the preferred acetonitrile, and changes into corresponding 6-R at polar aprotic solvent
2-4,5,6,7-tetrahydrochysene-7-oxygen-1H-pyrazolo [3,4-c] pyridine compounds, wherein R
2Be the group beyond the formula II, the temperature of this reaction between-15 ℃ to about 15 ℃, preferred 0 ℃, about 20 minutes to about 50 minutes reaction times, preferred 35 minutes.After reaction was finished, this mixture of dilute with water was also used ethyl acetate extraction.The organic phase saturated sodium bicarbonate that merges then washs with S-WAT.Formed compound is handled in the preferred tetrahydrofuran (THF) of polar aprotic solvent with sodium hydride, is heated to reflux and stirring, and about 30 to about 60 minutes, preferred 45 minutes.This reaction mixture is cooled to about 20 ℃ to 30 ℃, preferred 25 ℃, adds formula R
2The haloalkane of halides, wherein R
2Suc as formula defined among the I, but not the group of formula II.This reaction mixture is stirred and be heated to backflow reach about 12 to about 20 hours, preferred 16 hours.
In the 2nd step reaction of method 2,2-oxygen-4,5,6, the formula IX compound of 7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine reacts in the preferred ether of apolar aprotic solvent by IX and the preferred lithium aluminium hydride of reductive agent, and changes into corresponding formula X compound.This reactant stir about 12 hours to about 20 hours, preferred 16 hours.Add entry and alkali then, preferred sodium hydroxide continued stirred reaction mixture about 1.5 hours to about 2.5 hours, preferred 2 hours and filtration, and filtrate is concentrated to white solid.
Described compound or the acceptable salt of its medicine are to phosphodiesterase IN (PDE
4) the inhibition ability and the usefulness of corresponding treatment inflammatory disease illustrate by following vitro detection.Bioassay (people's lung PDE
IV)
Human lung tissue with 30 to 40g places PH 7.4 Tris/ benzene methylsulfonyl fluorochemical (PMSF)/sucrose damping fluids of 50ml, uses Tekmar Tissumizer
R(Cincinnati, Ohio 45249 for TekmarCo., 7143 Kemper Road) homogenate 30 seconds at full speed.Homogenate is centrifugal (48.000 * g) 70 minutes at 4 ℃, supernatant liquor filters twice with 0.22 μ m filter, and be added to Mono-QFPLC post (Pharmacia LKB Biotechnology 800 (the entennial Avenue that cross with PH7.4 Tris/PMSF damping fluid pre-equilibration, Piscat-away, New Jersey 08854) on.Flow velocity is per minute 1ml during the sample upper prop, and with flow velocity flushing and the wash-out of per minute 2ml, the ratio of gradient increase NaCl is come wash-out in the Tris/PMSF of PH7.4 damping fluid, collects the 8ml cut for every part subsequently, and each fraction of collection is used to measure specific PDE
IVActive it be by [
3H] cAMP hydrolysis and by known PDE
IVInhibitor (for example rolipram) suppresses hydrolysis and measures.Compiling accordingly, each fraction spent glycol dilutes (zymin of ethylene glycol/5ml of 2ml) and stores for future use in-20 ℃.
Test-compound is dissolved among the DMSO, and concentration is 10mM, in water, be diluted to 1: 25 (400 μ m test-compounds, 4%DMSO).Make serial dilutions to obtain required various concentration with 4%DMSO, being subjected in the test tube final DMSO concentration is 1%, adds following substances (described concentration all refers to be subjected to the ultimate density in the test tube) in repetitive process in the Glass tubing of 12 * 75mm successively
I) 25 μ l compounds or DMSO (1% is used for contrast and blank)
The ii) Tris damping fluid of 25 μ l PH7.5
iii)[
3H]cAMP(1μm)
Iv) 25 μ l PDE
IVEnzyme (be used for blank test, described enzyme is pre-the cultivation 5 minutes in boiling water).
The jolting reaction tube also was placed in the water-bath (37 ℃) 20 minutes, then test tube was placed boiling water bath to make the stopping of reaction in 4 minutes.(0.5ml, the 4-of 0.1M (2-hydroxyethyl)-1-piperazine ethane sulfonic acid (HEPES)/0.1M NaCl PH8.5) join each and place test tube on the ice bath with lavation buffer solution.With whenever-content in the test tube is added to Affi-Gel 601 posts (Biorad Laboratories, P.O.Box 1229,85A MarcusDrive, Melville, New York 11747) (the affine silica gel boronate aff-inity gel of boron), bed volume is 1ml) this post uses the lavation buffer solution balance in advance.[
3H] cAMP washes twice with the 6ml lavation buffer solution, [
3H] the 5 ＇ AMP 0.25M acetic acid wash-out of 4ml.After the vortex, liquid is taken off in the work of 1ml join in the corresponding phial that fills the 3ml scintillation solution, record behind the vortex [
3H] value.
IC
50Be defined as and make [
3H] cAMP be hydrolyzed into [
3H] 5 ' AMP suppresses 50% o'clock this compound concentrations.(TNF)
The inhibition ability that the acceptable salt of described compound and medicine thereof produces TNF with and the treatment of diseases effectiveness relevant with the generation of TNF represented with following external test result:
Gather peripheral blood (100ml) on one's body and place ethylenediamine tetraacetic acid (EDTA) (EDTA) from the volunteer.By Ficoll/Hypaque isolate monocyte and in incomplete HBSS the washing three times.Cell is suspended in again among the RPMI of preheating (containing 5%Fcs, L-glutamic acid, circle/step (pen/step) and nystatin), its final concentration is that every ml contains 1 * 10
6Cell.Monocyte carries out flat board on 24 orifice plates cultivates, and concentration is to have 1 * 10 among every 1.0ml
6Cell.Above-mentioned cell in 37 ℃ of cultivations (5% carbonic acid gas) and allowed to adhere to onboard 2 hours, is washed the cell that does not adhere to as yet to remove subsequently gently.Test-compound (10 μ l) is added to respectively for cultivating 1 hour in the cell of 3-4 concentration.In corresponding hole, add LPS (10 μ l).With this plate in 37 ℃ of overnight incubation (18hrs).When finishing, culturing process uses multilayer ELISA (R﹠amp; D Quantikine Kit) analyzes the value of TNF, determine the IC of each test-compound based on linear regression analysis
50
The acceptable acid salt of the medicine of compound described in the present invention includes but are not limited to: the salt with following acid formation: 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.Formula I compound of the present invention (R wherein
4Be CO
2R
6And R
6Be hydrogen) the acceptable positively charged ion salt of medicine include, but are not limited to following salt: sodium, potassium, calcium, magnesium, ammonium, N, the salt of N '-dibenzyl-ethylenediamin, N-methylglucosamine (Mai Geluming), thanomin and diethanolamine.
Be used for treatment and when prevention of inflammatory disease when being applied to human body, the oral dosage of formula I chemical combination and medicinal acceptable salt class thereof (after this also claiming active compound of the present invention) usually to the adult patients of general body weight 70kg be every day 0.1-100mg scope in.Therefore for specific adult patients, in every or contain 0.1 to 50mg active compound in every capsules, and suitable pharmaceutical excipient and carrier.The dosage of intravenous administration normally is in 0.1 to 10mg the scope in each required single formulation, intranasal or mouthful suck when using, and described dosage is mixed with the solution of 0.1 to 1% (w/v) usually.In fact the doctor will determine the optimum actual dose of individual patient according to patient's situation, and suitably increase and decrease according to concrete patient age, body weight and reaction.Above-mentioned dosage be generally speaking for example, certainly increase or reduce used dosage according to individual cases, whole this dosage all within the scope of the present invention.
When being applied to human body when being used to suppress TNF, can use the route of administration of multiple routine to comprise oral, parenteral introduction and local application.Common described active compound can be used by oral or non-stomach and intestine, its dosage for every day per kilogram to treat weight in patients 0.1 to 25mg, preferred about 0.3 to 5mg/ per kilogram, but have some variation dosage to be inevitable according to treating status of patient, under any circumstance the patient is depended on corresponding dosage to the reaction of medication.
Active compound of the present invention can be applied to human body separately, but normally uses with acceptable diluents or carrier, and described carrier is selected according to the route of administration of intending usefulness and standard drug experiment.For example can be Orally administered by tablet form, contain vehicle such as starch or lactose in the tablet, or combine separately or with vehicle with capsule or pill (ovale) form and to use, or use with the elixir or the suspensoid form that contain flavouring agent or tinting material, also can the parenteral drug administration by injection, for example intravenous injection, intramuscular injection or subcutaneous injection.For the parenteral administration, preferably, wherein may for example also contain other material with the form of aseptic aqueous solution, enough salt or glucose so that solution etc. ooze.
Therefore, another aspect of the present invention provides pharmaceutical composition, and said composition contains formula I compound and the acceptable salt of its medicine and medicine acceptable diluent or carrier.
The present invention further specifies with following embodiment, but is not limited thereto.Embodiment 1
3-ethyl-1-(4-methoxyphenyl)-6-phenyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-hydroxyl-2-oxygen-1-phenyl-4-propionyl-1,2,5; 6-tetrahydro-pyrazole (1.0g; 4.1mmole), 4-methoxyl group hydrazinobenzene hydrochloride salt (0.8g, 4.6mmole) and sodium methylate (0.11g, 2mmol) mixture heating up in 35ml dehydrated alcohol (magnesium distillation) refluxes.After 12 hours, the decompression rotary evaporation falls solvent, and crude product is the chromatograph purifying on the silicagel column of 4 * 20cm, with ether/hexane (1: 1) wash-out, obtains the red buttery title compound of 345mg, and room temperature is placed and separated out crystallization.Desired 1-(4-p-methoxy-phenyl) regional isomer is lower than the polarity of by product 2-(4-methoxyphenyl).M.P.43-45 ℃, IR (chloroform) lactan C=O, 1665cm
-1 1H NMR (300MHz, CDCl
3) d 1.32 (t, J=7.6Hz, 3H), 2.74 (q, J=7.6Hz, 2H), 2.96 (t, J=6.6Hz, 2H), 3.79 (s, 3H); 4.10 (t, J=6.6Hz, 2H), 6.89 (d, J=9.0Hz, 2H), 7.22-7.39 (m, 5H), 7.45 (d, J=9.0Hz, 2H); C
21H
21N
3O
2The analytical calculation value: C, 72.60; H, 6.09; N, 12.09.Measured value: C, 72.48; H, 6.08; N, 11.66; MS m/z (M
+) 347.Embodiment 2-15
According to the method for embodiment 1, with corresponding hydrazonium salt hydrochlorate and the 4-alkyloyl-3-hydroxyl-2-oxygen-1,2,5 that needs, the reaction of 6-tetrahydropyridine obtains following compounds.
| Routine number | ?R 1 | ???R 2 | ????R 3 | ???M.p.℃ | Mass spectrum or ultimate analysis (calculated value) %C, %H, %N | Mass spectrum or ultimate analysis (measured value) %C, %H, %N |
| ?2 | Ethyl | Phenyl | Methyl | 80-83 | 70.56，6.71，16.46 | ?70.61，6.77，15.51 |
| ?3 | Ethyl | Phenyl | The tertiary butyl | 120-121 | 72.70，7.79，14.13 | ?72.50，7.96，14.16 |
| ?4 | Ethyl | The 4-p-methoxy-phenyl | The 4-p-methoxy-phenyl | 42-45 | 70.01，6.14，11.13 | ?70.05，6.07，11.00 |
| ?5 | Ethyl | The 4-fluorophenyl | The tertiary butyl | 92-94 | (M +)315.1747 | ?HRMS(M +) ?315.1741 |
| ?6 | Ethyl | Phenyl | 3, the 4-dichlorophenyl | (oil) | [M +]386.26 | ?MS?m/z[M+]386 |
| ?7 | Ethyl | The 4-fluorophenyl | The 4-p-methoxy-phenyl | 129-130 a | 69.03，5.52，11.50 | ?68.75，5.37，11.43 |
| ?8 | Methyl | Phenyl | The 4-fluorophenyl | 139-140 b | [M +]321.3 | ?MS?m/z[M +]322 |
| ?9 | Ethyl | Phenyl | Cyclopentyl | 73-75 | (M+)309.1841 | ?HRMS(M+) ?309.1823 |
| ?10 | Methyl | Phenyl | The 4-p-methoxy-phenyl | 167-168 | (M+)333.1477 | ?HRMS(M+) ?333.1477 |
| ?11 | Ethyl | Phenyl | The 5-phenylpentyl | (oil) | (M+)388.2389 | ?HRMS(M+) ?388.2395 |
| ?12 | Methyl | The 4-p-methoxy-phenyl | The 4-fluorophenyl | 140-142 b | 68.36，5.16，11.96 | ?67.92，5.03，11.72 |
| ?13 | Methyl | The 4-p-methoxy-phenyl | The 3-fluorophenyl | 133-138 | 68.36，5.16，11.96 | ?68.04，5.04，11.75 |
| ?14 | Ethyl | The 4-p-methoxy-phenyl | 3, the 4-dichlorophenyl | 50-60 | 60.59，4.60，10.09 | ?60.34，4.56，9.86 |
| ?15 | Ethyl | The 3-p-methoxy-phenyl | Methyl | (oil) | [M +]285.35 | ?MS?m/z[M +]286 |
Embodiment 16
3-ethyl-1-(4-phenyl carboxylic acid)-6-phenyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-hydroxyl-2-oxygen-1-phenyl-4-propionyl-1,2,5, the 6-tetrahydro-pyrazole (1.0g, 4.08mmole), 4-hydrazine phenylformic acid (0.68g, 4.49mmole) and the dehydrated alcohol reflux of 30ml.After 20 hours, this mixture under reduced pressure, rotary evaporation concentrates, solid residue is suspended in the mixing solutions of ethyl acetate (500ml) and PH4 damping fluid (200ml), tells organic phase (most by product 2-(4-phenyl carboxylic acid) are removed), use the salt water washing, dried over sodium sulfate, filter and concentrating under reduced pressure, recrystallizing methanol obtains 0.64g orange solid title compound.M.P.261-263℃，
1HNMR(300MH
2，DMSO-d
6?d?1.23(t，J＝7.6Hz，3H)，2.68(q，J＝7.6Hz，2H)，2.94(t，J＝6.5Hz，2H)，4.05(t，J＝6.5Hz，2H)，7.20-7.41(m，5H)，7.65(d，J＝8.6Hz，2H)，7.96(d，J＝8.6Hz，2H)，13.05(s，1H)；MS?m/z(M
+)362。Embodiment 17
1-(4-benzamide)-3-ethyl-6-(4-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
In the solution of methyl alcohol (sodium by 6.6mg makes), add 3-ethyl-6-(4-p-methoxy-phenyl)-1-(4-phenyl carboxylic acid)-7-oxygen-4,5,6 to the sodium methylate that is stirring, and 7-tetrahydrochysene-1H-pyrazoles [3,4-c] pyridine (96mg, 0.25mmole).After 30 minutes, pressure reducing and steaming methyl alcohol is suspended in solid residue in the benzene, pressure reducing and steaming benzene then is suspended in the drying solid thing of gained in the cold diethyl ether (ice bath), with oxalyl chloride (31 μ l, 0.35mmole) and anhydrous N, dinethylformamide (1) is handled.Stir after 1 hour, the pressure reducing and steaming volatile matter is dissolved in crude product in the anhydrous tetrahydro furan, the solution of gained is dissolved in be added drop-wise under 0 ℃ in the ammonium hydroxide that vigorous stirring.Be warmed to room temperature after 2 hours, the reaction mixture concentrating under reduced pressure is precipitated until yellow solid.Be diluted with water to 100ml with this mixture and filter this moment, and the throw out of gained washes with water, obtains the title compound of 81mg.Decomposition point 243-245 ℃;
1H NMR (DMS-d
6) 1.24 (t, J=7.6Hz, 3H), 2.68 (q, J=7.6Hz, 2H), 2.93 (t, J=6.5Hz, 2H), 3.75 (s, 3H), 3.99 (t, J=6.5Hz, 2H), 6.94 (d, J=9.1Hz, 2H), 7.27 (d, J=9.0Hz, 2H), 7.43 (s, 1H), 7.59 (d, J=8.5Hz, 2H), 7.90 (d, J=8.6Hz, 2H), 8.04 (s, 1H); C
22H
22N
4O
3The analytical calculation value: C, 67.68; H, 5.68; N, 14.35.Measured value: C, 67.19; H, 5.31; N, 13.55.C
22H
22N
4O
3[M
+] the HRMS calculated value: 391.1770, measured value: 391.1781.
Initiator 3-ethyl-6-(4-p-methoxy-phenyl)-1-(4-phenyl carboxylic acid)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine is to use reagent corresponding, according to the method preparation of embodiment 16.Embodiment 18
1-(3, the 4-chloro-phenyl-)-3-ethyl-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine
3-methoxyl group-1-(3-p-methoxy-phenyl)-2-oxygen-4-propionyl-1,2,5; 6-tetrahydropyridine (0.49g; 1.7mmole), 3.4-dichlorophenyl hydrazonium salt hydrochlorate (0.40g, 1.87mmol) and sodium methylate (46mg, 0.85mmole) stirring the mixture in dehydrated alcohol is heated to backflow.After 16 hours, with this mixture concentrating under reduced pressure, and on silicagel column chromatography, make elutriant with 1: 4 ethyl acetate/hexane, obtain white solid.The ether recrystallization obtains the 0.46g white, needle-shaped crystals.M.P.97-99℃，
1H?NMR(250MHz，CDCl
3)1.31(t，J＝7.5Hz，3H)，2.73(q，J＝7.6Hz，2H)，2.96(t，J＝6.6Hz，2H)，3.97(s，3H)，4.09(t，J＝6.6Hz，2H)，6.78-6.91(m，3H)，7.29-7.49(m，3H)，7.73(d，J＝1.8Hz，1H)；MS?m/z[M
+]416。Embodiment 19-42
According to the method for embodiment 18, with corresponding hydrazonium salt hydrochlorate and required 4-alkyloyl-3-methoxyl group-2-oxygen-1,2,5, the reaction of 6-tetrahydropyridine obtains following compound.
| Routine number | ???R 1 | ???R 2 | ???R 3 | ??M.p.℃ | Mass spectrum or ultimate analysis (calculated value) %C, %H, %N | Mass spectrum or ultimate analysis (measured value) %C, %H, %N |
| ?19 | Methyl | The 4-p-methoxy-phenyl | The 3-4-dichlorophenyl | 143-144 a | ?59.71，4.26，10.45 | ?56.13，4.02，9.65 |
| ?20 | Ethyl | The 3-p-methoxy-phenyl | Cyclopentyl | 64-65 | ?[M +]340.2025 | ?HRMS[M +] ?340.2046 |
| ?21 | Ethyl | The 4-1 p-methoxy-phenyl | Cyclopentyl | 96-98 | ?70.77，7.42，12.38 | ?70.44，7.68，11.69 |
| ?22 | Methyl | The 4-p-methoxy-phenyl | Cyclopentyl | 121-122 | ?70.13，7.12，12.91 | ?69.48，7.10，12.70 |
| ?23 | Sec.-propyl | Phenyl | 3, the 4-dichlorophenyl | Oil | ?[M +]400.0983 | ?HRMS?[M +] ?400.0966 |
| ?24 | Ethyl | 3, the 4-Dimethoxyphenyl | Cyclopentyl | 107-108 | ?[M +]369.46 | ?MS?m/z[M +]369 |
| ?25 | Ethyl | 3, the 4-Dimethoxyphenyl | 3, the 4-dichlorophenyl | 190-191 b | ?59.20，4.74?9.41 | ?59.41，4.46，9.71 |
| Routine number | ???R 1 | ????R 2 | ???R 3 | ??M.p.℃ | Mass spectrum or ultimate analysis (calculated value) %C, %H, %N | Mass spectrum or ultimate analysis (measured value) %C, %H, %N |
| ?26 | Sec.-propyl | The 4-p-methoxy-phenyl | 3,4 dichlorophenyls | 145-147 c | 61.40，4.92，9.76 | 61.29，4.81，9.53 |
| ?27 | Propyl group | The 4-p-methoxy-phenyl | Cyclopentyl | 102-103 c | 71.36，7.70，11.89 | 70.98，7.66，11.73 |
| ?28 | Sec.-propyl | The 3-methoxyphenyl | 3, the 4-dichlorophenyl | 126-127 d | 61.40，4.92，9.76 | ?61.55，5.10，9.97 |
| ?29 | Ethyl | 4-1 methoxyl group 3-cyclopentyloxy phenyl | 3, the 4-dichlorophenyl | 54-56 | 62.40，5.44，8.40 | 62.15，5.50，7.97 |
| ?30 | Ethyl | 4-methoxyl group 3-cyclopentyloxy phenyl | Cyclopentyl | 88-89 | [M +]423.55 | ?MS?m/z?[M +]423 |
| ?31 | Ethyl | The 3-methoxyphenyl | The 4-fluorophenyl | 139-140 e | 69.03，5.79，11.50 | ?69.05，5.42，11.57 |
| ?32 | Ethyl | The 2-methoxyphenyl | Cyclopentyl | 119-120 | 70.77，7.42，12.38 | ?70.63，7.16，12.01 |
| ?33 | Ethyl | The 2-methoxyphenyl | The 4-fluorophenyl | 103-104′ | [M +]365.41 | ?MS?m/z[M +]366 |
| ?34 | Ethyl | The 3-tolyl | Cyclopentyl | Oil | 74.27，7.79，12.99 | ?74.54，7.89，12.63 |
| ?35 | Ethyl | The 3-tolyl | The 4-fluorophenyl | Oil | 72.19，5.77.12.02 | ?72.06，5.55，11.52 |
| ?36 | Ethyl | 3-fluoroform phenyl | Cyclopentyl | Oil | 63.65，5.87，11.13 | ?63.95，5.73，10.97 |
| ?37 | Ethyl | 3-fluoroform phenyl | The 4-fluorophenyl | 139-140′ | 62.53，4.25，10.42 | ?62.60，4.08，10.41 |
| ?38 | Ethyl | The 4-tolyl | Cyclopentyl | 93-94 | 74.27，7.79，12.99 | ?74.10，7.52，12.59 |
| ?39 | Ethyl | The 2-tolyl | The 4-fluorophenyl | 141-142 b | 72.19，5.77，12.03 | ?72.36，5.52，12.09 |
| ?40 | Ethyl | The 2-tolyl | Cyclopentyl | 130-131 | ?MW?323.44 | ?MS?m/z323 |
| Routine number | ?R 1 | ??R 2 | ??R 3 | ?M.p.℃ | Mass spectrum or ultimate analysis (calculated value) %C, %H, %N | Mass spectrum or ultimate analysis (measured value) %C, %H, %N |
| ?41 | Ethyl | 2-fluoroform phenyl | The 4-fluorophenyl | 48-50 | ?MW?403.38 | ??MS?m/z404 |
| ?42 | Ethyl | The 3-tolyl | The 3-alkylsulfonyl | Oil | ?MW?373.47 | ??MS?m/z374 |
Annotate: recrystallization solvent: a is 5% ethyl acetate/petroleum ether, and b is an isopropyl ether, and c is an ethyl acetate/hexane, and d is an ether, and e is 5% ethyl acetate/pentane, and f is a pentane.Embodiment 43
1-cyclohexyl-3-ethyl-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrido [3,4-c] pyridine
3-methoxyl group-1-(3-p-methoxy-phenyl)-2-oxygen-4-propionyl-1,2,5; (0.80g is 2.8mmole) with hexamethylene hydrazonium salt hydrochlorate (0.54g, 3.6mmole) solution in methyl alcohol (15ml) for the 6-tetrahydropyridine; being heated to 90 ℃ under the nitrogen gas stream slowly, until all solvents are removed.Then, should purified mixture under nitrogen atmosphere, be heated to about 150 ℃ and reach 1 hour.Be cooled to room temperature then, this mixture is dissolved in ether, use the salt water washing again with 1N hydrochloric acid earlier, dried over sodium sulfate is filtered and concentrating under reduced pressure, carries out silica gel column chromatography, makes elutriant with 1: 1 ethyl acetate/hexane, obtains 0.47g yellow oily target compound.
1H NMR (250MHz, CDCl
3) 1, (m, 6H comprise t 1.23, J=7.6Hz to 20-1.52,3H), and 1.64-1.74 (m, 1H), 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); To C
21H
22N
3O
2[M
+] the HRMS calculated value: 353.2103.Measured value: 353.2094.
Embodiment 44-57
According to the method for embodiment 43, with corresponding hydrazonium salt hydrochlorate and required 4-alkyloyl-3-methoxyl group-2-oxygen-1,2,5, the reaction of 6-tetrahydropyridine obtains following compounds.
| Routine number | ?R 1 | ????R 2 | ??R 3 | ?M.p.℃ | Mass spectrum or ultimate analysis (calculated value) %C, %H, %N | Mass spectrum or ultimate analysis (measured value) %C, %H, %N |
| ?44 | Sec.-propyl | The 4-p-methoxy-phenyl | Cyclopentyl | 102-103 a | [M +]?354 | ?MS[M +]354 |
| ?45 | Sec.-propyl | The 3-methoxyphenyl | Cyclopentyl | 99-100 b | 71.36，7.70，11.89 | ?71.10，7.56，11.73 |
| ?46 | Ethyl | The 3-methoxyphenyl | Cyclobutyl | 73-74 b | 70.13，7.12，12.91 | ?70.10，7.22，12.93 |
| ?47 | Ethyl | Phenyl | The methylene cyclopropyl | 60-62 c | 73.19，7.17，14.23 | ?73.34，7.08，13.95 |
| ?48 | Ethyl | The 3-methoxyphenyl | The methylene cyclopropyl | Oil | [M +]326 | ?MS[M +]326 |
| ?49 | Ethyl | The 4-methoxyphenyl | Phenyl | 156-157 b | 72.60，6.09，12.10 | ?72.35，5.91，12.02 |
| ?50 | Ethyl | The 3-methoxyphenyl | The 3-alkylsulfonyl | Oil | 58.59，5.95，10.79 | ?58.46，6.03，9.82 |
| ?51 | Ethyl | The 3-methoxyphenyl | 4-fluoroform phenyl | 124-125 d | 63.61，4.85，10.12 | ?63.40，4.51，10.09 |
| ?52 | Ethyl | The 3-tolyl | Cyclobutyl | Oil | 73.75，7.49，13.58 | ?73.22，7.56，13.03 |
| ?53 | Ethyl | 3-fluoroform phenyl | The 3-alkylsulfonyl | Oil | MW?427.44 | ?MS?m/z428 |
| ?54 | Ethyl | 3-fluoroform phenyl | Cyclobutyl | Oil | 62.80，5.55，11.56 | ?63.01，5.54，11.19 |
| ?55 | Ethyl | Phenyl | The 2-dihydro | 155-156 e | 77.28，6.49，11.76 | ?77.35，6.48，11.08 |
| ?56 | Ethyl | The 2-tolyl | The indenyl rings butyl | 100-102 | MW?309.41 | ?MS?m/z310 |
| ?57 | Ethyl | The 3-methoxyphenyl | The 2-indanyl | 60-62 f | MW?387.48 | ?MS?m/z388，389， ?390 |
Annotate: recrystallization solvent: a is an ethyl acetate/hexane, and b is ether/pentane, and c is isopropyl ether/pentane, and d is an ethyl acetate/petroleum ether, and e is an ethyl acetate, and f is an ethyl acetate/hexane.Embodiment 58
3-ethyl-6-(4-fluorophenyl)-1-(4-p-methoxy-phenyl)-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
To the 3-ethyl-6-that is stirring (4-fluorophenyl)-1-(4-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine (0.3g, 0.82mmole) in the solution of 50ml ether, (33mg 0.86mmole), stirs after 16 hours to add lithium aluminium hydride, add water 0.5ml, then add 3N sodium hydroxide 1ml.Stirred 2 hours, white precipitate is by diatomite filtration, and filtrate decompression concentrates, and carries out silica gel column chromatography then, makes eluent with 1: 3 ethyl acetate/hexane, obtains the faint yellow paste title compound of 0.12g.
1H?NMR(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 59-63
According to embodiment 58 methods, with corresponding 7-oxygen-2,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine and lithium aluminium hydride reaction obtain following compound.
| Routine number | ?R 1 | ???R 2 | ???R 3 | ??M.p.℃ | Molecular weight | Mass spectrum [M +] (measurement) |
| 59 | Ethyl | 4-methoxyl group-3-cyclopentyloxy phenyl | Cyclopentyl | Oil | 409.57 | ?409 |
| 60 | Ethyl | Phenyl | 3, the 4-dichlorophenyl | Oil | 372.30 | ?371.373 |
| 61 | Ethyl | Phenyl | Cyclopentyl | Oil | 295.43 | ?296 |
| 62 | Ethyl | The 3-methoxyphenyl | Cyclobutyl | Oil | 311.43 | ?312 |
| 63 | Ethyl | The 3-methoxyphenyl | Cyclohexyl | Oil | 339.48 | ?340 |
1-cyclopentyl-3-ethyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrido [3,4-c] pyridine
1-cyclopentyl-3-ethyl-6-(4-the p-methoxy-phenyl)-7-oxygen-4 that is stirring, 5,6,7-tetrahydrochysene-1H-pyrido [3,4-c] and pyridine (2,58g, 7.60mmole) solution in acetonitrile (90ml), (12.5g, 22.8mmole) solution in water (110ml) is handled with ceric ammonium nitrate at 0 ℃.Stirred 35 minutes, mixture water (550ml) dilution, with ethyl acetate (100ml * 4) extraction, the organic phase of merging is washed with 50% saturated sodium bicarbonate (250ml) earlier, with the S-WAT washing of l0%, becomes faint yellow until the water washing lotion then.Then, organic phase is again with the washing of saturated sodium bicarbonate and salt, and with the activated carbon treatment of decolouring.Stir after 30 minutes, the mixture dried over sodium sulfate, by diatomite filtration, and concentrating under reduced pressure.Brown residue obtains the brown solid of 8.14g with the ether recrystallization.M.P.143-145 ℃; MS (M/Z) 234;
1H NMR (250MHz, CDCl
3) 1.21 (3H), (m, 8H), 2.62 (2H), 2.73 (2H), 3.51 (2H), 5.47 (s, 1H), 5.61 (1H) embodiment 65 for quintet, J=7.7Hz for dt, J=2.7 and 6.8Hz for t, J=6.8Hz for q, J=7.6Hz for 162-2.13 for t, J=7.6Hz
1-cyclopentyl-3-ethyl-6-cyclopropyl methyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrido [3,4-c] pyridine
1-cyclopentyl-3-ethyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrido [3,4-c] pyridine ((40mg, 1.01mmole) handle in mineral oil with 60% sodium hydride for 0.21g, the 0.92mmole) solution in THF (5ml) by the solution in.Reflux and stir after 45 minutes, reaction mixture is cooled to 25 ℃, and adding (brooethyl)-cyclopropane (0.31g, 2.29mmole).With this mixture stirring and refluxing 16 hours, before concentrating under reduced pressure, be cooled to 25 ℃ then, use purification by silica gel column chromatography, make eluent with 1: 1 ethyl acetate/hexane, obtain the colorless oil title compound of 0.19g.MSm/z[M
+] 288;
1H NMR (300MHz, CDCl
3) 0.26-0.31 (m, 2H), 0.50-0.56 (m, 2H), 0.85-1.06 (m, 1H), 1.20 (t, J=7.6Hz, 3H), 1.62-2.08 (m, 8H), 2.61 (q, J=7.6Hz, 2H), 2.74 (t, J=6.8Hz, 2H), 3,39 (d, J=6.9Hz, 2H), 3.63 (t, J=6.8Hz, 2H), 5.67 (quintet, J=7.8Hz, 1H).Preparation 1
4-isobutyryl-3-methoxyl group-1-phenyl-2-oxygen-1,2,5, the 6-tetrahydropyridine
(0.16ml, 2.21mmole) solution in anhydrous tetrahydro furan (4ml) is cooled to 0 ℃ with the new distilled Diisopropylamine that stirring.Use n-Butyl Lithium (0.85ml, 2.11mmole) processing of 2.5M then.After 15 minutes, this mixture is cooled to-78 ℃, drips 4-propionyl-3-methoxyl group-1-phenyl-2-oxygen-1,2,5 after pre-cooled, 6-tetrahydropyridine (0.52g, 2.0mmole) solution in tetrahydrofuran (THF) (4ml) by sleeve pipe.After about 20 minutes, (0.20ml 3.0mmole) is added in this bright orange-red solution, and mixture was returned to room temperature 2.5 hours with methyl iodide.This reaction mixture is poured in the saturated aqueous ammonium chloride solution, organic phase salt water washing, dry on the sodium sulfate, filter and concentrating under reduced pressure.Chromatography purification on silicagel column is made eluent with 1: 4 ethyl acetate/hexane, obtains the initiator of the recovery of the yellow oily title compound of 0.12g and 0.19g.
1H NMR (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
According to preparation 1 method, with corresponding 3-methoxyl group-2-oxygen-4-propionyl-1,2,5,6-tetrahydropyridine and N-Lithiodiisopropylamide and iodomethane reaction obtain the compound of following formula VII.
Preparation 4
| The preparation number | ????R 2 | ????m.p.℃ | ????M.W. | Mass spectrum [M +] |
| ????2 | The 4-p-methoxy-phenyl | Oil | ??303.36 | ????304 |
| ????3 | The 3-p-methoxy-phenyl | Oil | ??303.36 | ????304 |
3-methoxyl group-1-(4-aminomethyl phenyl)-2-oxygen-4-propionyl-1,2,5, the 6-tetrahydropyridine
With 3-hydroxyl-1-(4-aminomethyl phenyl)-2-oxygen-4-propionyl-1,2,5, the 6-tetrahydropyridine (5.9g, 23mmole) and 3-methyl isophthalic acid-right-tolyl triazine (5.1g, 34mmole) in 1, the vlil in the 2-ethylene dichloride 45 minutes.This mixture is cooled to room temperature, and pours in the water, use the 6N hcl acidifying.With 1N salt acid elution, wash again earlier by water and salt with methylene dichloride extracting 3 times, the organic phase of merging for water, and dried over mgso is filtered and concentrating under reduced pressure.The quantitative brown oil thin-layer chromatography purifying of gained, not needing further, purifying can use.
1H?NMR(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
According to the method for preparation 4, with corresponding 3-hydroxyl-1-aryl-2-oxygen-4-alkyloyl-1,2,5,6-tetrahydropyridine and 3-methyl isophthalic acid-p-methylphenyl triazine is reacted, and obtains the following compound of formula VI.
| The preparation number | ????R 1 | ????R 2 | ???m.p.℃ | ???M.W. | Mass spectrum [M +] |
| ????5 | Ethyl | Phenyl | Oil | ?259.31 | ????260 |
| ????6 | Methyl | The 4-p-methoxy-phenyl | Oil | ?275.30 | ????275 |
| ????7 | Ethyl | The 4-p-methoxy-phenyl | ??81-82 | ?289.33 | ????289 |
| ????8 | N-propyl | The 4-p-methoxy-phenyl | Oil | ?303.36 | ????303 |
| ????9 | Ethyl | The 3-p-methoxy-phenyl | ??59-60 | ?289.33 | ?289，290 |
| ????10 | Ethyl | The 2-p-methoxy-phenyl | Oil | ?289.33 | ????289 |
| ????11 | Ethyl | 3, the 4-dimethoxy phenyl | Oil | ?319.26 | ????319 |
| ????12 | Ethyl | 3-encircles penta oxygen-4-methoxyphenyl | Oil | ?373.45 | ????373 |
| ????13 | Ethyl | The 3-tolyl | Oil | ?273.33 | ????273 |
| ????14 | Ethyl | 3-fluoroform phenyl | Oil | ?327.30 | ????327 |
3-hydroxyl-1-(3-aminomethyl phenyl)-2-oxygen-4-propionyl-1,2,5, the 6-tetrahydropyridine
To the magnesium smear metal of stirring (1.9g, 79mmole) dripping bromine ethane in the suspension in the 30ml anhydrous ether (5.9ml, 79mmole).Beginning leniently refluxes after adding about 1ml, after whole magnesium consumption fully, reaction mixture is cooled to 0 ℃ also adds N-(3-aminomethyl phenyl)-2-Pyrrolidone (8.7g immediately, 50mmole), after being warmed to room temperature and stirring 2 hours, pour on ice and use this reaction mixture into ethyl acetate extraction.The organic phase water and the salt water washing that merge, dry on the sodium sulfate, filter and concentrating under reduced pressure, obtain the white solid of 8.8g.
With above-mentioned solid dispersed in the mixed solution of 40ml benzene and 86ml 1N sodium hydroxide, under violent mechanical stirring, add the ethyl oxalyl chloride (7.2ml, 64mmole).Stir and refluxed 1.5 hours after layering, water ethyl acetate extracting.The organic phase water and the salt water washing that merge, dried over mgso is filtered and concentrating under reduced pressure, obtains amber oily thing.GCMS(M
+]305。
Above-mentioned intermediate is dissolved in the dehydrated alcohol of 20ml, handles by sodium (1.0g) is added in the 10ml anhydrous methanol carefully with the solution (making) of sodium methylate in methyl alcohol.After the stirring and refluxing 1.5 hours, the concentrating under reduced pressure mixture also adds the water of 100ml.This mixture, leaches the dark yellow precipitation and washes with water to PH3 with the 6N hcl acidifying, obtains the faint yellow crystallization of 6.8g with 75ml isopropyl ether recrystallization.M.P.115-116°；
1H?NMR(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
According to the method for preparation 15, with corresponding 2-Pyrrolidone and required bromo alkyl reactive magnesium, use ethyl oxalyl chloride and alkaline purification subsequently, obtain following formula VI compound.
| The preparation number | ????R 1 | ????R 2 | ??m.p.℃ | ???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-tolyl | 110-112 | ?259.30 | ????260 |
| ????25 | Ethyl | The 2-tolyl | Oil | ?259.30 | ????259 |
| ????26 | Ethyl | 3-fluoroform phenyl | 117-118 | ?313.28 | ????313 |
| ????27 | Ethyl | 2-fluoroform phenyl | Oil | ?313.28 | ????313 |
| ????28 | Ethyl | 3, the 4-Dimethoxyphenyl | 179-180 | ?305.33 | ????306 |
| ????29 | Ethyl | 3-encircles penta oxygen-4-methoxyphenyl | 133-134 | ?359.42 | ????360 |
N-(2-methoxyphenyl)-2-Pyrrolidone
2-Pyrrolidone (15.0g, 176mmole), the 2-iodanisol (7.6ml, 59mmole), copper powder (7.5g, 117mmole) and salt of wormwood (8.1g, mixture 59mmole) stirs under nitrogen atmosphere in 150 ℃.This reaction mixture filters by the silicagel pad of one 6 * 15cm after 18 hours, with 1: 1 ethyl acetate/hexane wash-out, obtains faint yellow oily thing.(0.6mm, 80-100 ℃) removed in unreacted reagent underpressure distillation, stays the sweet sample buttery title compound of 9.2g.
1H NMR (300 MHz, 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
According to preparation 30 method, corresponding iodine or bromobenzene and 2-Pyrrolidone are reacted, obtain following formula V compound.
| The preparation number | ????R | ???M.W. | Mass spectrum [M +] |
| ????31 | The 4-methoxyphenyl | ?191.22 | ?????91 |
| ????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 | 3-fluoroform phenyl | ?229.20 | ????229 |
| ????37 | 2-fluoroform phenyl | ?229.20 | ????229 |
| ????38 | 3, the 4-dimethoxy phenyl | ?221.26 | ????221 |
| ????39 | 3-encircles penta oxygen-4-p-methoxy-phenyl | ?275.35 | ????275 |
Claims (8)
1, the acceptable salt of the compound of formula I and medicine thereof:
R wherein
1Be hydrogen, (C
1-C
3) alkyl, (C
3-C
3) alkenyl, C
3-C
5Cycloalkyl or methylene radical C
3-C
5Cycloalkyl, wherein each alkyl or alkenyl can be randomly by two C at the most
1-C
2Alkyl or trifluoromethyl or three halogens replacements at the most; X is oxygen or two hydrogen atoms, R
2And R
3Be selected from hydrogen, C independently of one another
1-C
14Alkyl, C
1-C
14Alkoxyl group, C
2-C
7Alkenyl, C
4-C
7Contain oxygen, sulphur, SO
2Or NR
5Heterocyclic radical, R wherein
5Be hydrogen or C
1-C
4Alkyl, or the group of formula II
Wherein a is 1 to 5 integer; B and C are 0 or 1; R
4Be hydrogen, hydroxyl, C
1-C
5Alkyl, C
2-C
5Alkenyl, C
1-C
5Alkoxyl group, C
3-C
6Cycloalkyloxy, halogen, trifluoromethyl, CO
2R
6, CONR
6R
7, NR
6R
7, NO
2Or SO
2NR
6R
7, R wherein
6And R
7Be selected from hydrogen or C independently of one another
1-C
4Alkyl; Wherein Z is oxygen, sulphur, SO
2Or NR
8, R wherein
8Hydrogen or C
1-C
4Alkyl; And Y be can be at random by two C at the most
1-C
7Alkyl or C
3-C
7The C of cycloalkyl substituted
1-C
5Alkylidene group or C
2-C
6Alkenyl; Or following radicals
Wherein P is 1 to 3 integer, and W is oxygen or hydroxyl, R
9Be C
1-C
3Alkyl; Wherein said alkyl, alkenyl, cycloalkyl or heterocyclic radical can be by following 1 to 14, preferred 1 to 5 C that is selected from
1-C
2The group of alkyl, trifluoromethyl or halogen replaces arbitrarily, and condition is to work as R
1Be ethyl and R
2When being the 4-aminomethyl phenyl, R
3Not hydrogen, methyl, phenyl, 4-fluorophenyl or 2-pyridyl; Work as R
2Be 4-aminomethyl phenyl and R
3When being the 4-fluorophenyl, R
1Not phenyl, methyl or n-propyl; Work as R
1Be ethyl and R
2When being phenyl, R
3Not 4-chloro-phenyl-, 4-fluorophenyl or 4-aminomethyl phenyl and work as R
1Be ethyl and R
2When being the 4-p-methoxy-phenyl, R
3It or not the 4-fluorophenyl.
2, according to the compound of claim 1, R wherein
1Be C
1-C
3Alkyl, R
2And R
3Be independently selected from C respectively
3-C
7Cycloalkyl contains SO
2C
4-C
7Heterocyclic radical or following formula group
Wherein a is 1 to 5 integer, R
4Be hydrogen, hydroxyl, C
1-C
5Alkyl, C
1-C
5Alkoxy or halogen.
3, according to the compound of claim 1, R wherein
1Be ethyl or sec.-propyl; R
2Be phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 2-p-methoxy-phenyl, 3-p-methoxy-phenyl or 3-fluoroform phenyl, R
3Be cyclobutyl, cyclopentyl, cyclohexyl, 3-sulfo group wool base (3-sulfolanyl), 4-fluorophenyl or 3,4-dichlorophenyl.
4, according to the compound of claim 1, it is selected from following compounds:
3-ethyl-1-(4-p-methoxy-phenyl)-6-phenyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3, the 4-dichlorophenyl)-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(4-fluorophenyl)-6-(2-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(3-aminomethyl phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(3-fluoroform phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclohexyl-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-sec.-propyl-1-cyclopentyl-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-phenyl-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclopentyl-6-(2-aminomethyl phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfo group wool base (sulfolanyl)-6-(3-aminomethyl phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfo group wool base)-6-(3-p-methoxy-phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(3-aminomethyl phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-(3-sulfo group wool base-6-(3-trifluoromethyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(3-fluoroform phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine;
3-ethyl-1-cyclobutyl-6-(2-aminomethyl phenyl)-7-oxygen-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine.
5, a kind ofly be used to suppress IV type phosphodiesterase (PDE) and TNF) pharmaceutical composition that generates, said composition contains the compound and the medicine acceptable carrier of the claim 1 of medicinal significant quantity.
6, a kind of method that is used to suppress IV type phosphodiesterase (PDE) and tumour necrosis factor (TNF) generation, this method comprises the compound of using the claim 1 of significant quantity to the patient.
7, a kind of pharmaceutical composition that is used for the treatment of asthma, sacroiliitis, bronchitis, chronic tracheae obstacle disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory disease, AIDS, septic shock and other disease relevant with the generation of TNF, said composition contains the compound and the medicine acceptable carrier of the claim 1 of significant quantity.
8, a kind of treatment or prevention are selected from the method for following disease such as asthma, sacroiliitis, bronchitis, chronic tracheae obstacle disease, psoriasis, allergic rhinitis, dermatitis and other inflammatory disease, AIDS, septic shock and other disease relevant with the generation of TNF, and this method comprises the compound of using the claim 1 of effective dose to the patient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8829293A | 1993-07-06 | 1993-07-06 | |
| US08/088,292 | 1993-07-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1129940A true CN1129940A (en) | 1996-08-28 |
| CN1048015C CN1048015C (en) | 2000-01-05 |
Family
ID=22210524
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94193233A Expired - Fee Related CN1048015C (en) | 1993-07-06 | 1994-06-16 | Bicyclic tetrahydro pyrazolopyridines |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0707585A1 (en) |
| JP (1) | JP2944048B2 (en) |
| KR (1) | KR100228949B1 (en) |
| CN (1) | CN1048015C (en) |
| AU (1) | AU695301B2 (en) |
| BR (1) | BR9406946A (en) |
| CA (1) | CA2166721C (en) |
| CZ (1) | CZ3696A3 (en) |
| EG (1) | EG20513A (en) |
| FI (1) | FI943208A (en) |
| HU (1) | HUT74170A (en) |
| IL (1) | IL110175A (en) |
| MX (1) | MX9405132A (en) |
| NO (1) | NO305029B1 (en) |
| NZ (1) | NZ266525A (en) |
| PL (1) | PL312426A1 (en) |
| RU (1) | RU2131876C1 (en) |
| TW (1) | TW316904B (en) |
| WO (1) | WO1995001980A1 (en) |
| ZA (1) | ZA944844B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357888A (en) * | 2018-04-09 | 2019-10-22 | 南京药捷安康生物科技有限公司 | Heterocycle phosphodiesterase inhibitors and application thereof |
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| NZ292991A (en) * | 1994-10-20 | 1999-02-25 | Pfizer | Bicyclic tetrahydropyrazolopyridines that are selective inhibitors of phosphodiesterase (pde) type iv or the production of tnf and pharmaceutical compositions containing them |
| CA2223624C (en) * | 1995-06-06 | 2001-02-20 | Pfizer Inc. | Tricyclic 5,6-dihydro-9h-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-.alpha.]pyridines |
| AP932A (en) * | 1996-08-26 | 2001-02-02 | Pfizer | Tricyclic 5,6-dihydro-9H-pyrazolo (3,4c)-1,2,4,-triazolo (4,3-a) pyridines. |
| TR199900481T2 (en) * | 1996-09-04 | 1999-06-21 | Pfizer Inc. | Indazole derivatives; their use as phosphodiesterase type IV inhibitors. |
| US6858616B2 (en) | 1998-12-23 | 2005-02-22 | Bristol-Myers Squibb Pharma Company | Nitrogen containing heterobicycles as factor Xa inhibitors |
| SI1140941T1 (en) | 1998-12-23 | 2005-04-30 | Bristol-Myers Squibb Pharma Company | Nitrogen containing heterobicycles as factor xa inhibitors |
| 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 |
| EA006685B1 (en) | 1999-08-21 | 2006-02-24 | Алтана Фарма Аг | Synergistic combination |
| TWI243055B (en) * | 2000-04-13 | 2005-11-11 | Nippon Zoki Pharmaceutical Co | Pharmaceutical composition for use in treatment of dermatitis |
| AU2001287654B2 (en) * | 2000-08-10 | 2006-12-14 | Pfizer Italia S.R.I. | Bicyclo-pyrazoles active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
| US6960595B2 (en) * | 2001-03-23 | 2005-11-01 | Bristol-Myers Squibb Pharma Company | 5-6 to 5-7 Heterobicycles as factor Xa inhibitors |
| US6706730B2 (en) | 2001-04-18 | 2004-03-16 | Bristol-Myers Squibb Pharma Company | 1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-ones as factor Xa inhibitors |
| CA2444571A1 (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 inhi bitors |
| WO2002088122A1 (en) * | 2001-04-26 | 2002-11-07 | Ajinomoto Co., Inc. | Heterocyclic compounds |
| US7772188B2 (en) | 2003-01-28 | 2010-08-10 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| WO2004076450A1 (en) | 2003-02-27 | 2004-09-10 | J. Uriach Y Compañia S.A. | Pyrazolopyridine derivates |
| US7135469B2 (en) * | 2003-03-18 | 2006-11-14 | Bristol Myers Squibb, Co. | Linear chain substituted monocyclic and bicyclic derivatives as factor Xa inhibitors |
| KR20050115331A (en) | 2003-04-01 | 2005-12-07 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | Inhibitors of phosphodiesterases in infertility |
| US7145012B2 (en) | 2003-04-23 | 2006-12-05 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
| DE102005031580A1 (en) * | 2005-07-06 | 2007-01-11 | Aicuris Gmbh & Co. Kg | Substituted sulfolanylpyrazoles and their use |
| AR065804A1 (en) * | 2007-03-23 | 2009-07-01 | Smithkline Beecham Corp | COMPOSITE OF INDOL CARBOXAMIDE, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS IT AND USE OF THIS COMPOUND TO PREPARE A MEDICINAL PRODUCT |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| US7879802B2 (en) | 2007-06-04 | 2011-02-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| US20100120694A1 (en) | 2008-06-04 | 2010-05-13 | Synergy Pharmaceuticals, Inc. | Agonists of Guanylate Cyclase Useful for the Treatment of Gastrointestinal Disorders, Inflammation, Cancer and Other Disorders |
| EP2321341B1 (en) | 2008-07-16 | 2017-02-22 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| MX357121B (en) | 2011-03-01 | 2018-06-27 | Synergy Pharmaceuticals Inc Star | Process of preparing guanylate cyclase c agonists. |
| CA2902348C (en) | 2013-02-25 | 2021-11-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| EP2970384A1 (en) | 2013-03-15 | 2016-01-20 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
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| US20200368223A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Methods for inhibiting phosphate transport |
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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 |
| US5356897A (en) * | 1991-09-09 | 1994-10-18 | Fujisawa Pharmaceutical Co., Ltd. | 3-(heteroaryl)-pyrazololi[1,5-a]pyrimidines |
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1994
- 1994-06-16 RU RU96103653A patent/RU2131876C1/en active
- 1994-06-16 NZ NZ266525A patent/NZ266525A/en unknown
- 1994-06-16 KR KR1019960700019A patent/KR100228949B1/en not_active IP Right Cessation
- 1994-06-16 HU HU9503934A patent/HUT74170A/en unknown
- 1994-06-16 CA CA002166721A patent/CA2166721C/en not_active Expired - Fee Related
- 1994-06-16 BR BR9406946A patent/BR9406946A/en not_active Application Discontinuation
- 1994-06-16 CN CN94193233A patent/CN1048015C/en not_active Expired - Fee Related
- 1994-06-16 PL PL94312426A patent/PL312426A1/en unknown
- 1994-06-16 WO PCT/IB1994/000156 patent/WO1995001980A1/en not_active Application Discontinuation
- 1994-06-16 EP EP94916370A patent/EP0707585A1/en not_active Withdrawn
- 1994-06-16 AU AU68057/94A patent/AU695301B2/en not_active Ceased
- 1994-06-16 CZ CZ9636A patent/CZ3696A3/en unknown
- 1994-06-16 JP JP7503938A patent/JP2944048B2/en not_active Expired - Lifetime
- 1994-06-17 TW TW083105518A patent/TW316904B/zh active
- 1994-06-30 IL IL11017594A patent/IL110175A/en active IP Right Grant
- 1994-07-05 MX MX9405132A patent/MX9405132A/en unknown
- 1994-07-05 FI FI943208A patent/FI943208A/en unknown
- 1994-07-05 ZA ZA944844A patent/ZA944844B/en unknown
- 1994-07-05 EG EG40294A patent/EG20513A/en active
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110357888A (en) * | 2018-04-09 | 2019-10-22 | 南京药捷安康生物科技有限公司 | Heterocycle phosphodiesterase inhibitors and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| MX9405132A (en) | 1995-01-31 |
| NO305029B1 (en) | 1999-03-22 |
| IL110175A (en) | 2000-01-31 |
| WO1995001980A1 (en) | 1995-01-19 |
| KR960703852A (en) | 1996-08-31 |
| AU695301B2 (en) | 1998-08-13 |
| CA2166721C (en) | 1999-07-27 |
| BR9406946A (en) | 1996-08-06 |
| IL110175A0 (en) | 1994-10-07 |
| HU9503934D0 (en) | 1996-03-28 |
| NO960056D0 (en) | 1996-01-05 |
| PL312426A1 (en) | 1996-04-29 |
| FI943208A0 (en) | 1994-07-05 |
| EG20513A (en) | 1999-06-30 |
| CA2166721A1 (en) | 1995-01-19 |
| JP2944048B2 (en) | 1999-08-30 |
| CN1048015C (en) | 2000-01-05 |
| HUT74170A (en) | 1996-11-28 |
| CZ3696A3 (en) | 1997-06-11 |
| RU2131876C1 (en) | 1999-06-20 |
| ZA944844B (en) | 1996-01-05 |
| JPH08507084A (en) | 1996-07-30 |
| NZ266525A (en) | 1997-10-24 |
| AU6805794A (en) | 1995-02-06 |
| TW316904B (en) | 1997-10-01 |
| FI943208A (en) | 1995-01-07 |
| EP0707585A1 (en) | 1996-04-24 |
| NO960056L (en) | 1996-01-05 |
| KR100228949B1 (en) | 1999-11-01 |
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