CN1335835A - Arylpiperidine and aryl-1,2,5,6-tetrahydropyridine urea derivatives having 5HT1A receptor activity - Google Patents

Arylpiperidine and aryl-1,2,5,6-tetrahydropyridine urea derivatives having 5HT1A receptor activity Download PDF

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CN1335835A
CN1335835A CN99814560A CN99814560A CN1335835A CN 1335835 A CN1335835 A CN 1335835A CN 99814560 A CN99814560 A CN 99814560A CN 99814560 A CN99814560 A CN 99814560A CN 1335835 A CN1335835 A CN 1335835A
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M·G·凯利
张敢
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Wyeth LLC
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American Home Products Corp
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

Compounds of formula (A) are useful for the treatment of disorder of the central nervous system including anxiety, depression, panic, alcohol and drug addiction, sexual dysfunction, sleep disorders, migraine, obesity, cognitive disorders and neurodegenerative diseases.

Description

Arylpiperidine and aryl-1,2,5 with 5HT1A receptor active, the 6-tetrahydropyridine urea derivatives
Background of invention
US4,882,432 disclose adamantyl and non-adamantyl piperazine carbamate and the urea with high 5-HT1A receptor active.These compounds and 4,797, the compound of No. 489 U.S. Patent Publications can be used for the treatment of the CNS disease.
EP661266-A1 has put down in writing piperidino-(1-position only) and piperazinyl 5-HT2 receptor antagonist and anticoagulant.
WO9504042 has put down in writing 4-phenyl-4-phenylpropyl alcohol (alkene) the phenylpiperidines tachykinin antagenists that is used for the treatment of pain or inflammation or vomiting.
Invention is described
The present invention relates to new Arylpiperidine urea and aryl-1,2,5, the 6-tetrahydropyridine urea derivatives.The invention provides new Arylpiperidine urea and aryl-1,2,5, the 6-tetrahydropyridine urea derivatives belongs to the antagonist of 5HT1A receptor subtype.Because The compounds of this invention has high binding affinity to the 5HT1A acceptor, so they can be used in treatment central nervous system (CNS) disease for example depression, anxiety, fear, obsessional neurosis (OCD), somnopathy, sexual disorder, alcohol and drug addiction, cognitive function enhancing, presenile dementia, Parkinson's disease and migraine.
The compounds of this invention is the compound and the pharmacologically acceptable salt thereof of general formula (A) representative:
Figure A9981456000051
Wherein:
R 0And R 1Be hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, alkyl-cycloalkyl, alkyl heterocycle alkyl, aryl or heteroaryl, perhaps R independently 0And R 1The common Heterocyclylalkyl of forming, condition is R 0And R 1Be not hydrogen simultaneously.
R 2Be hydrogen, alkyl or CH 2(R 5);
R 3It is hydrogen or alkyl;
R 4Be aryl or heteroaryl;
R 5Be alkyl, alkenyl or alkynyl;
X is hydrogen, halogen, whole haloalkyl, hydroxyl, alkoxyl group, perhalogeno alkoxyl group; N is the integer of 1-3; Dotted line is optional two keys.
X is preferably at 4 or 5 halogens replacements, more preferably 4-fluorine or 5-fluorine, most preferably 5-fluorine.
Work as R 2When being alkyl, R 2The straight chained alkyl of preferred 1 to 5 carbon atom, R 3The straight chained alkyl of preferred 1 to 4 carbon atom.
In some embodiment preferred of the present invention, R 0And R 1Be hydrogen or cycloalkyl independently, perhaps they form Heterocyclylalkyl together.More particularly, R 0And R 1Form morpholino together for hydrogen or cyclohexyl or they independently.
In the preferred embodiment of the present invention, R 0And R 1Be hydrogen or cyclohexyl independently, perhaps they form morpholino together, and X is that 5-is fluorine-based, R 4Be phenyl.
Term used herein " alkyl " refers to have 1-6 carbon atom, the more preferably branched-chain or straight-chain alkyl of 1-5 carbon atom.Its example comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.
Term used herein " thiazolinyl " refers to have the side chain or the straight-chain alkyl of 2-6 carbon atom.Its example comprises ethene and propylene.In some embodiments of the present invention, thiazolinyl can be substituted.
Term used herein " alkynyl " refers to have 2-6 carbon atom and the side chain or the straight-chain alkyl of another carbon-carbon triple bond at least.Its example comprises ethynyl and proyl.In some embodiments of the present invention, alkynyl can be replaced by one or more group.
Term used herein " alkoxyl group " refers to alkyl-O-group, and wherein alkyl as previously mentioned.Its example comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and tert.-butoxy.
Term used herein " aryl " refers to have the monocycle or the dicyclo aromatic ring of 6-10 carbon atom, and monocycle preferably has the ring structure of 6 carbon atoms, and dicyclo preferably has the ring structure of 8,9 or 10 carbon atoms.The example of aromatic ring comprises phenyl and naphthyl.In preferred embodiments, aryl is phenyl, 1-naphthyl or 2-naphthyl.In a more preferred embodiment, aryl is a phenyl.Described aryl can be replaced by one or more groups.The aryl that replaces preferably has 1-3 substituting group.
Term used herein " cycloalkyl " refers to have the monocycle alkyl of 3-8 carbon atom.In some preferred embodiments, cycloalkyl can be replaced by 1-3 substituting group.
Term used herein " Heterocyclylalkyl " refer to have 3-8 become annular atoms and these become contain in annular atomses one or more, preferably one or two is selected from N and O as heteroatomic monocycle alkyl.Its example comprises piperidino-(1-position only), piperazinyl and morpholino.In some embodiments, Heterocyclylalkyl can be replaced by 1-3 substituting group.
Halogen used herein refers to fluorine, chlorine, iodine and bromine.
" heteroaryl " refers to have 1-3 heteroatomic monocycle or dicyclo aromatic ring that is selected from N, O and S.Preferred five-ring of monocycle or six-membered ring structure, preferred 8,9 or 10 ring structures of dicyclo.The example of heteroaryl comprises pyrryl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidyl, indyl, quinolyl, isoquinolyl and benzodioxan base.Preferred heteroaryl comprises thienyl, pyridyl and furyl.Preferred heteroaryl comprises 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl and 3-furyl.Described heteroaryl can be replaced by one or more substituting groups.
Except as otherwise noted, suitable substituents comprises halogen, alkyl, hydroxyl, alkoxyl group, amino, amido, nitro, alkylamino, alkyl amido, whole haloalkyl, carboxyalkyl, carboxyl, carbonyl diamine, dialkyl amido and aryl.
Carbonatoms refers to the number of carbon atom in the carbon skeleton, and wherein carbon atom does not comprise for example carbon atom in alkyl or the alkoxyl group of substituting group in the carbon skeleton.
When the combined utilization term, except as otherwise noted, the various piece of combined utilization group adapts to above-mentioned definition.For example alkyl-cycloalkyl is alkyl-cycloalkyl, and wherein the definition of alkyl and cycloalkyl is described according to top.
Pharmacologically acceptable salt refers to acid salt, it can be formed by top general formula compound and pharmaceutically acceptable acid, and wherein said pharmaceutically acceptable acid is phosphoric acid, sulfuric acid, hydrochloric acid, Hydrogen bromide, citric acid, toxilic acid, succsinic acid, fumaric acid, acetate, lactic acid, nitric acid, sulfonic acid, tosic acid and methylsulfonic acid etc. for example.
The compounds of this invention contains chiral centre, thereby has various stereoisomer forms for example outer disappear outstanding mixture and each optical isomer.Can directly prepare or by asymmetric or stereoselectivity synthetic or by from outside disappear and prepare each isomer through conventional optical isomer isolation technique the outstanding mixture.
The organic synthesis those skilled in the art can use reagent and the raw material that obtains easily, prepare compound of the present invention by ordinary method.
The organic synthesis those skilled in the art can prepare compd A and intermediate 4-(halo-2-methoxyl group-phenyl)-piperidines F or 4-(halo-2-methoxyl group-phenyl)-1,2,5,6-tetrahydropyridine H by ordinary method.For example, in scheme I, with alkali for example the aryl halide B of butyllithium and suitable replacement carry out metal-halogen atom exchange and obtain carboanion, with N-protected-mixture that 4-pyridone C processing obtains, obtain tertiary alcohol D.The example of N blocking group Rx is a benzyl among the 4-piperidone C, can be by hydrogenation obtains amine G after removing this group to D.With acid for example sulfuric acid G is dewatered can access needed 4-(halo-2-p-methoxy-phenyl)-1,2,5,6-tetrahydropyridine H.Tertiary alcohol D dehydration, remove N blocking group Rx and two key hydrogenation can obtain 4-(halo-2-p-methoxy-phenyl)-piperidines F.
Dehalogenation intermediate 4-(2-p-methoxy-phenyl)-piperidines F (X=H) and 1,2,3,6-tetrahydrochysene-4-(2-p-methoxy-phenyl) pyridine H (X=H) is compound known, it can prepare according to following document disclosed method: Van Wijingaarden Ineke etc., J.Med.Chem., (1988), 31 (10), 1934-1940.Perregaard Jens etc., J.Med.Chem., (1995), 38 (11), 1998-2008.Modica Maria etc., J.Med.Chem., (1997), 40 (4), 574-585.Solyom Sandor etc., Heterocycles, (1995), 41 (6), 1139-1168.
Scheme I
Figure A9981456000091
At activator for example in the presence of 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (DAEC), I-hydroxybenzotriazole hydrate (HOBT) and the 4-methylmorpholine (NMM); 4-(X-2-p-methoxy-phenyl)-piperidines F (X is H or halogen) or 4-(X-2-p-methoxy-phenyl)-1; 2; 5,6-tetrahydropyridine H (X is a hydrogen or halogen) obtains acid amides J (scheme II) with N-alkyl amino acid (I) coupling of N-protected.Protecting group R is the urethanum type, preferably the tertbutyloxycarbonyl that can be removed by the acid effect.Behind the deprotection, can become amine M to reduction of amide, carry out acidylate then and obtain urea A with reductive agent such as lithium aluminum hydride (LAH) or diborane.
Scheme II
Figure A9981456000101
Following non-limiting special embodiment is used for illustrating the synthetic method that is used for preparation formula A compound.In these embodiments, all chemistry and intermediate are commercially availablely to obtain or can prepare through the standard method of document record, be known to the organic synthesis those skilled in the art perhaps.
Intermediate 1
1-benzyl-4-(5-fluoro-2-methoxyl group-phenyl)-4-hydroxy piperidine
Under-78 ℃ of temperature and nitrogen protection, (5.0g, ether 2.4mmole) (5mL) solution slowly join in ether (20mL) solution of 9.8ml (24mmole) butyllithium (hexane solution of 2.5M) with 2-bromo-5-fluoroanisole.Mixture is warming to-50 ℃.Add 1-benzyl-4-piperidone this moment, and (4.62g is in ether 24.4mmole) (3mL) solution.Under-50 ℃, the mixture that stirring obtains 30 minutes, any room temperature that is warmed to.Splash into the saturated ammonium chloride solution termination reaction.Mixture is transferred to separating funnel, and this layer is separated, water layer ethyl acetate extraction three times.Merge organic phase, use dried over sodium sulfate, filter the back and concentrate.Carry out flash chromatography (eluent: 7: 3 ethyl acetate-hexanes) obtain 5.27g (68%) yellow oil 1-benzyl-4-(5-fluoro-2-methoxyl group-phenyl)-4-hydroxy piperidine.
Intermediate 2
1-benzyl-4-(5-fluoro-2-methoxyl group-phenyl)-1,2,5, the 6-tetrahydropyridine
At room temperature, (1.01g is 3.20mmole) in acetate (40mL) solution of (intermediate 1) 2 vitriol oils to be joined 1-benzyl-4-(5-fluoro-2-p-methoxy-phenyl)-4-hydroxy piperidine.With the vlil that obtains also, stirred the mixture 2 days.Cool off this mixture to room temperature, with ethyl acetate (100mL) and water (100mL) dilution.Alkalize this solution to pH=10 with 50% sodium hydroxide.This layer is separated, with salt water washing organic layer.Water layer is merged, extract 3 times with ethyl acetate (50mL).Merge organic layer, use dried over sodium sulfate, concentrate.Carry out flash chromatography (eluent: ethyl acetate-hexane of 1: 1) obtain 0.62g yellow oil (65%) 1-benzyl-4-(5-fluoro-2-methoxyl group-phenyl)-1,2,5,6-tetrahydropyridine.
Intermediate 3
1-formyl radical-4-(5-fluoro-2-p-methoxy-phenyl)-piperidines
10% palladium-carbon (0.62g) is joined 1-benzyl-4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5, and (0.62g is 2.1mmol) in the methanol solution (20mL) of (intermediate 2) for the 6-tetrahydropyridine.With purging with nitrogen gas solution 5 minutes, splash into formic acid (2mL, 88%) then, the resulting mixture of stirring at room 2 days.With this mixture of diatomite filtration, concentrate and obtain 0.44g (90%) colorless oil 1-formyl radical-4-(5-fluoro-2-methoxyl group-phenyl)-piperidines.
Ultimate analysis: C 13H 16FNO 20.09 (C 3H 7NO)
Calculated value: C, 65.81; H, 6.80; N, 5.90
Measured value: C, 65.36; H, 6.87; N, 6.26
Intermediate 4
4-(5-fluoro-2-p-methoxy-phenyl)-piperidines
Crude product 1-formyl radical-4-(5-fluoro-2 p-methoxy-phenyls)-piperidines (0.80g, 3.4mmole) (intermediate 3) be dissolved in hydrochloric acid (16mL, 0.5N) and in the methyl alcohol (5mL), this mixture of reflux 16 hours.This mixture is chilled to room temperature, with sodium hydroxide (2.5N) alkalization, with ethyl acetate (3 * 25mL) extract), obtains 4-(5-fluoro-2-p-methoxy-phenyl) piperidines, it can directly be used and need not to be further purified.
Intermediate 5
(R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-
-1-yl]-2-carbonyl-ethyl } the methyl carbamic acid tert-butyl ester
Under 0 ℃, the said products 4-(5-fluoro-2-p-methoxy-phenyl)-piperidines (intermediate 4) is dissolved in N, in the dinethylformamide (10mL).Then 0.70g (2.5mmole) 2-[N-methyl-N-(tert-butoxycarbonyl)-amino]-solution of 3-phenylpropionic acid in micro-DMF joins in the above-mentioned solution, add 1-(3-dimethylamine propyl)-3-ethyl-carbodiimide hydrochloride (DAEC) (0.48g again, 2.5mmole), I-hydroxybenzotriazole hydrate (HOBT) (0.41g, 2.5mmole) and 4-methylmorpholine (NMM) (0.37mL, 3.4mmole), mixture is stirred spend the night (temperature of reaction slowly is warmed to room temperature).Water (50mL) and ethyl acetate (50mL) diluted reaction mixture separate each layer.Water layer washs with hydrochloric acid (1N), saturated sodium bicarbonate.Combining water layer is used ethyl acetate extraction three times.Merge organic layer, use dried over sodium sulfate, concentrate.Carry out flash chromatography, with 1: 4 ethyl acetate-hexane to 3: 7 ethyl acetate-hexane carried out gradient elution, obtained yellow oil (R)-{ 1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-2-carbonyl-ethyl } methyl carbamic acid tert-butyl ester.
Intermediate 6
(2R)-1-[4-(5-fluoro-2-methoxyl group-phenyl)-piperidines-1-yl]-
2-methylamino-3-phenyl-propane-1-keto hydrochloride
The said products (R)-{ 1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-2-carbonyl-ethyl } methyl carbamic acid tert-butyl ester (intermediate 5) is dissolved in the 4M HCl/ dioxane (10mL), and heating gained solution is to refluxing.Stirring is spent the night, and then mixture is chilled to room temperature, and evaporating solvent obtains 0.38g (three step overall yields 22%) title product.
Intermediate 7
(1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }
Methylamine
Under 0 ℃ and nitrogen protection, triethylamine (0.14mL 1.0mmol) joins (2R)-1-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-2-methylamino-3-phenyl-third-1-keto hydrochloride (0.38g, 0.93mmole)
In tetrahydrofuran (THF) (20mL) mixture of (intermediate 6).Splash into lithium aluminum hydride (1.9mL, the 1M THF solution of 1.9mmole) then.After the adding, remove cooling bath, stirring at room mixture 2.5 hours.Slowly add the saturated ammonium chloride solution termination reaction, with Celite pad (celite pad) filtering mixt.Concentrated solution obtains the title compound of yellow oil, uses this compound and need not to be further purified.
Intermediate 8
4-(5-fluoro-2-methoxyl group-phenyl)-4-hydroxy piperidine
The following 1.95g of room temperature (6.18mmole) 1-benzyl-4-(5-fluoro-2-p-methoxy-phenyl)-4-hydroxy piperidine (intermediate 7), dried methyl alcohol (40mL) placed the low flask of circle, with this system of purging with nitrogen gas 5 minutes. then 1.95g10% palladium-carbon is joined in this solution.With this system of purging with nitrogen gas 5 minutes, add 2mL formic acid (88%) then once more.Under room temperature and nitrogen protection, the mixture that obtains was stirred 1 day.At this moment, add 2ml formic acid (88%) once more.Sustained reaction 2.5 days.With the diatomite filtration mixture, concentrate and obtain yellow oil 4-(5-fluoro-2-p-methoxy-phenyl)-4-hydroxy piperidine (0.95g, 69% productive rate).
Intermediate 9
4-(5-fluoro-2-methoxyl group-phenyl)-1,2,5, the 6-tetrahydropyridine
At room temperature, (0.56g is 2.5mmole) in acetate (20mL) solution of (intermediate 8), the vlil that obtains 2 days 2 vitriol oils to be joined 4-(5-fluoro-2-p-methoxy-phenyl)-4-tetrahydropyridine.Reaction mixture is chilled to room temperature, with ethyl acetate (50mL) and water (50mL) dilution.Alkalize this solution to pH=10 with 50% sodium hydroxide solution, separate each layer, organic layer washs with salt solution (25mL).(3 * 25mL) extract 3 times the water layer that merges, and merge organic layer, use dried over sodium sulfate, concentrate and obtain 0.49g (95% productive rate) yellow oil 4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydropyridine with ethyl acetate.
Intermediate 10
(R)-{ 1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-
Tetrahydropyridine-1--yl]-2-oxo-ethyl }-methyl-t-butyl carbamate
Under 0 ℃, crude product 4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydropyridine (0.49g, 2.4mmole) (intermediate 9) be dissolved in N, in the dinethylformamide (10mL), with 2-[N-methyl-N-(tert-butoxycarbonyl)-amino]-3-phenylpropionic acid (0.73g, 2.6mmole) a small amount of DMF solution, DAEC (0.50g, 2.6mmole), HOBT (0.42g, 3.1mmole) and NMM (0.40mL 3.6mmole) handles the solution obtain.Stirring is spent the night, with 50ml water and 50Et OAc dilution.Separate each layer, with HCl (1N), saturated sodium bicarbonate washing organic layer, combining water layer is with ethyl acetate washing three times (3 * 25mL).Merge organic layer, use dried over sodium sulfate, concentrated yellow oil (R)-{ 1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydropyridine-1-yl]-2-ketone-ethyl }-methyl carbamic acid tert-butyl ester that obtains.
Intermediate 11
(2R)-and 1-[4-(5-fluoro-2-methoxyl group-phenyl)-1,2,5,6-tetrahydropyridine-1-
Base]-2-methylamino-3-phenyl third-1-keto hydrochloride
Crude product (R)-{ 1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydropyridine-1-yl]-2-ketone-ethyl-the methyl carbamic acid tert-butyl ester (intermediate 10) is dissolved in the 10mL 4M HCl/ dioxane solution, the mixture heating up that obtains to refluxing.After stirring is spent the night, mixture is chilled to room temperature, evaporating solvent obtains 0.62g (two step productive rates 65%) title product.
Intermediate 12
(1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)
-1,2,3,6-tetrahydropyridine-1-yl]-ethyl }-methylamine
Under 0 ℃ and nitrogen protection; triethylamine (0.14mL; 1.0mmol) join (2R)-1-[4-(5-fluoro-2-methoxyl group-phenyl)-1; 2; 3; 6-tetrahydropyridine-1-yl]-(0.41g 1.0mmole) in the 20mL tetrahydrofuran solution of (intermediate 11), slowly adds 1.9mL (1.9mmole) lithium aluminum hydride (the THF solution of 1M) to 2-methylamino-3-phenyl third-1-keto hydrochloride then.After the adding, remove cooling bath, stirring at room mixture 2.5 hours.Slowly add the saturated ammonium chloride solution termination reaction, use the Celite pad filtering mixt.Concentrated solution obtain 0.36g (100%) yellow oil (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydropyridine-1-yl]-ethyl-methylamine, use it need not advance-go on foot purifying.
Embodiment 1
1-{ (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)
Piperidines-1-yl]-ethyl }-3-cyclohexyl-1-methyl-urea
Under nitrogen protection; (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl } methylamine (0.12g; 0.33mmole, as described in above-mentioned intermediate 7) and triethylamine (0.10mL, 0.74mmole) solution in methylene dichloride (10mL) is cooled to 0 ℃.(0.050mL 0.35mmole), stirs the gained mixture overnight down in 0 ℃-room temperature (ice dissolves) to splash into NSC 87419.Evaporating solvent is dissolved in ethyl acetate (25mL) and water (25mL) to resistates.Separate each layer, water (25mL) and salt water washing organic layer extract three times with ethyl acetate (25mL) behind the merging organic layer, use dried over sodium sulfate, filter, and concentrate.Carry out flash chromatography (washing composition is 7: 3 ethyl acetate-hexanes) and obtain 0.16g (100% productive rate) 1-{ (1R)-1-benzyl-2-[4-(5-fluoro-2-methoxyl group-phenyl)-piperidines-1-yl]-ethyl }-3-cyclohexyl-1-methyl urea.The ethanolic soln of this product is heated to slight backflow, adds the hot ethanol solution of 1 equivalent fumaric acid, obtain white solid title compound fumarate.
Fusing point: 70-80 ℃
Ultimate analysis: C 29H 40FN 3O 21.0C 4H 4O 41.0H 2O
Calculated value: C, 64.37; H, 7.53; N, 6.82
Measured value: C, 64.28; H, 7.58; N, 6.96
Embodiment 2
Morpholine-4-formic acid (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-
1,2,5,6 tetrahydrochysenes-4H pyridine-1-yl]-ethyl }-methyl-acid amides
Under nitrogen protection; (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1; 2; 5; 6-tetrahydropyridine-1-yl]-ethyl }-methylamine (0.17g; 0.48mmole, as described in top intermediate 12) and triethylamine (0.15mL, 1.0mmole) solution in methylene dichloride (10mL) is cooled to 0 ℃.(0.06mL 0.51mmole), stirs the gained mixture overnight at 0 ℃ to room temperature (ice dissolving) to add 4-morpholine formyl chloride.Evaporating solvent obtains brown resistates.Carry out flash chromatography (with 7: 3 ethyl acetate-hexane wash-outs) obtain 0.17g (productive rate 74%) morpholine-4-formic acid (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydrochysene-4H-pyridine-1-yl]-ethyl-methyl-acid amides.The ethanolic soln that heats this product refluxes to slight, heats the hot ethanol solution of 1 equivalent fumaric acid, obtains white solid title compound fumarate.
Fusing point: 70-75 ℃
Ultimate analysis: C 27H 34FN 3O 31.0C 4H 4O 40.8H 2O0.8C 2H 6O
Calculated value: C, 62.05; H, 6.81; N, 6.88
Measured value: C, 62.12; H, 6.54; N, 6.67
Embodiment 3
1-{ (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5, the 6-tetrahydrochysene-
4H-pyridine-1-yl]-ethyl }-3-cyclohexyl-1-methyl-urea
Under nitrogen protection; (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1; 2; 3,6-tetrahydropyridine-1-yl]-ethyl }-methyl-amine (0.17g, 0.48mmole; as described in top intermediate 12) and triethylamine (0.15mL; 1.0mmole) solution in methylene dichloride (10mL) is cooled to 0 ℃, splashes into cyclic isocyanate polyhexamethylene (0.070mL, 0.51mmole) solution.Stir this mixture overnight down in 0 ℃-room temperature (ice fusing).Evaporating solvent, resistates are dissolved in ethyl acetate (25mL) and water (25mL).Separate each layer, organic layer water (25mL), salt solution (30mL) washing, dried over sodium sulfate, filter and concentrate and obtain crude product, obtain 0.19g (productive rate 83%) 1-{ (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1 through flash chromatography purifying (using eluent ethyl acetate), 2,5,6-tetrahydrochysene-4H-pyridine-1-yl]-ethyl }-3-cyclohexyl-1-methyl urea.The ethanolic soln of this product is heated to slight backflow, heats the hot ethanol solution of 1 equivalent fumaric acid, obtain white solid title compound fumarate.
Fusing point: 75-80 ℃
Ultimate analysis: C 29H 38FN 3O 21.0C 4H 4O 41.0H 2O
Calculated value: C, 64.58; H, 7.23; N, 6.85
Measured value: C, 64.14; H, 6.09; N, 6.65
Embodiment 4
1-{ (1R)-1-(pyridin-3-yl methyl)-2-[4-(2-p-methoxy-phenyl)-
Piperidines-1-yl]-ethyl }-3-cyclohexyl urea
Under 0 ℃, (1.0g 4.39mmol) joins N-Boc-3 '-(3 '-pyridine)-D-L-Ala (1.17g 4-(2-p-methoxy-phenyl) piperidines, 4.39mmol), (0.84g is 4.39mmol) and in the solution of HOBT (0.77g, 1.3 equivalents) in DMF (20mL) for DEAC.Add NMM (0.7mL, 1.5 equivalents) then.Under room temperature and nitrogen protection, stir this mixture overnight, use ethyl acetate (50mL) dilution then, use 0.1N HCl (15mL), saturated sodium bicarbonate, water and salt water washing successively.Use the anhydrous sodium sulfate drying organic layer, filter, vacuum concentration obtains thick product (100%).In 4.0M HCl/ diox (40mL), stir and spend the night, concentrate and obtain amine hydrochlorate, handle discharging free alkali with saturated sodium bicarbonate solution.This acid amides is dissolved in THF (50mL), splashes into BH 3THF (10 equivalent) handles gained solution, and this mixture was refluxed 16 hours.After the cooling, add 2N hydrochloric acid termination reaction, stir after 8 hours vacuum concentrated mixture.This aqueous solution that alkalizes, (3 * 25mL) extract products, merge organism, and organic layer is isolated in water (50mL) and salt water washing, uses anhydrous sodium sulfate drying with ethyl acetate.Filter, vacuum concentration obtains desired product (productive rate 100%).Under nitrogen protection; (1R)-1-(3-pyridyl-methyl)-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl } amine (0.13g; 0.33mmole) and triethylamine (0.10mL, 0.74mmole) solution in methylene dichloride (10mL) is cooled to 0 ℃.(0.050mL 0.35mmole), stirs the gained mixture overnight down in 0 ℃-room temperature (ice fusing) to splash into the cyclic isocyanate polyhexamethylene.Evaporating solvent is dissolved in ethyl acetate (25mL) and water (25mL) to resistates.Separate each layer, organic layer water (25mL) and salt water washing.The organic washes that merges extracts 3 times with ethyl acetate (25mL), uses dried over sodium sulfate then, filters and concentrates.Carry out flash chromatography (with 7: 3 ethyl acetate-hexane wash-outs) and obtain 0.16g (100% productive rate) 1-{ (1R)-1-(pyridin-3-yl-methyl)-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-3-cyclohexyl urea.The ethanolic soln of this product is heated to slight backflow, heats the hot ethanol solution of 1 equivalent fumaric acid, obtain the title product fumarate of white solid.
Ultimate analysis: C 27H 38FN 4O 21.0C 4H 4O 4
Calculated value: C, 65.70; H, 7.47; N, 9.89
Measured value: C, 65.67; H, 7.40; N, 9.80
The compounds of this invention can be combined by height with 5-HT1A affinely, therefore they can be used in treatment central nervous system primary disease for example depression, anxiety and fear, and can be used in the insecondary property the followed problem of treatment for example somnopathy and sexual disorder.The compounds of this invention can also be used for other central nervous system disease and comprise alcohol and drug addiction, obesity and migraine.The cognitive function enhancing can also be reached by using The compounds of this invention, therefore neurodegenerative disease for example presenile dementia and Parkinson's disease can be treated.
The 5-HT1A receptors bind is measured
The Chinese hamster ovary celI of personnel selection 5HT1A acceptor stable transfection is measured compound exhibits [3H] 8-OH-DPAT bonded ability, determines thrombotonin 5-HT 1AThe high-affinity of acceptor.The Chinese hamster ovary celI of stable transfection is cultivated in containing 10% heat inactivation FBS and nonessential amino acid whose DMEM.From culture dish, scrape cell, it be transferred to centrifuge tube, by damping fluid (50mM, TrispH7.5) in centrifugal (2000rpm, 10 minutes, 4 ℃) washed twice.The particulate state that obtains precipitation equal portions separately, be positioned in-80 ℃ the environment.In test that day,, and it is suspended in the damping fluid again cell thawing.Carrying out combination in cumulative volume is the 96 hole microtiter plates of 250 μ L measures.Measure non-specific binding in the presence of 10mM 5-HT, the ultimate density of part is 1.5nM.Cultivate after 30 minutes under the room temperature, add ice-cold damping fluid termination reaction, filter fast by 30 minutes GF/B strainer of preimpregnation in 0.5%PEI.In single point assay, begin test compounds, determine to determine the Ki value of active compound 1,0.1 and the percentage inhibiting value at 0.01mM place.
The test of 5-HT1A acceptor intrinsic activity
Application is by the Chinese hamster ovary celI of people 5-HT1A acceptor stable transfection, determines the intrinsic activity of The compounds of this invention by measuring ability that described compound reverses cyclic amp in this cell (cAMP) and stimulate.
The Chinese hamster ovary celI of stable transfection placed contain 10% heat inactivation PBS and nonessential amino acid whose DMEM cultivates.This cell with every hole? * 10 6The density of cell places 24 hole culture dish, at CO 2Cultivated 2 days in the incubator.Second day, handle damping fluid (DMEM+25mMHEPES, 5mM theophylline, 10 μ M Supirdyl) with 0.5mL and replace original substratum, cultivated 10 minutes down at 37 ℃.Use test compounds (originally screening is 0.1 and 1 μ M) to handle each hole in the culture dish more immediately with hair monkey element (ultimate density is 1 μ M) earlier.Cultivated 10 minutes down at 37 ℃ again.Take out substratum and add the ice-cold assay buffer of 0.5mL (in the RIA test kit, supplying) and make reaction terminating.Culture dish is placed-20 ℃ store down until measure cAMP formation with RIA.Measure the EC of active testing compound 50Value.For the compound that does not demonstrate agonist activity (Emax=0%), continue to analyze the active ability that it reverses agonist induction.In independently testing, before adding agonist and hair monkey element, the agonist of 6 kinds of concentration was cultivated 20 minutes in advance.Collecting cell as mentioned above.The cAPM test kit is supplied by Amersham, and the specification sheets operation RIA according to each test kit carries out IC by GraphPad Prism 50Calculating.Compound 5-HT1A is in conjunction with cAMP
Ki (nM) Emax IC 50(nM) embodiment 1 3.5 0% 46.9 embodiment 2 26.6 0% embodiment 3 3.5 0% 12.6
Therefore, The compounds of this invention shows the high-affinity of 5HT1A subtype acceptor, and has shown intrinsic activity, and this has obtained proof by the ability that it reverses cyclic amp cAMP stimulation.Therefore, The compounds of this invention can be used for the treatment of central nervous system disease, and can be to suffering from patient's administration that one or more suffer from above-mentioned disease.Term used herein " treatment " refers to alleviate or improve the symptom of patient's disease specific.In addition, can also carry out administration to The compounds of this invention as the part of treatment plan, described treatment plan comprises that other acts on the reagent of nervus centralis wash-out.In some preferred embodiments, the The compounds of this invention described combination therapy of a part that belongs to combination therapy contains serotonin reuptake inhibitors.The serotonin reuptake inhibitors that is used for combination therapy of the present invention comprises fluoxetine, fluvoxamine, paroxetine, Sertraline and Wen Lafa star.The administration simultaneously of described reagent, wherein they can merge in the one-pack type, perhaps in the different time administration, still belong to the part of combined treatment for compound of the present invention.
The compounds of this invention can be by the respective pure form administration or with conventional pharmaceutically acceptable carrier administration together.
Suitable solid carrier comprises one or more materials, and they can also be used as correctives, lubricant, solubilizing agent, suspension agent, weighting agent, glidant, compression auxiliary material, tackiness agent or tablet disintegrant or encapsulating material.For pulvis, described carrier is a fine-particle solid, and it mixes mutually with the particulate activeconstituents.For tablet, activeconstituents mixes with the carrier with necessary compression property with certain proportion, carries out compressing tablet according to desired shape and size.Described pulvis and tablet preferably contain the activeconstituents up to 99%.Suitable solid carrier comprises for example calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Can prepare solution, suspension agent, emulsion, syrup and elixir by the using liquid carrier.Can be dissolved in activeconstituents of the present invention or the pharmaceutically acceptable liquid vehicle of suspension in, described pharmaceutically acceptable liquid vehicle is the mixture of water, organic solvent, acceptable oil or ester for example.Described liquid vehicle can contain other suitable pharmaceutically acceptable additive for example solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, seasonings, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or smell conditioning agent.The suitable example of the liquid vehicle of oral or parenterai administration comprises water (particularly including as above additive derivatived cellulose for example, preferably carboxymethyl cellulose sodium), alcohol (comprising for example dibasic alcohol of monohydroxy-alcohol and polyvalent alcohol) and derivative and oils (for example through fractionated Oleum Cocois and peanut oil).For parenterai administration, all right formula oily ester of carrier is ethyl oleate and Isopropyl myristate for example.Use sterile liquid carrier at the sterile liquid composition that is used for parenterai administration.
Can use for example intramuscularly agent of composition of liquid medicine, peritoneal injection agent and the subcutaneous injection agent of sterile solution or suspension.Can also the intravenous administration sterile solution.Oral can be the liquid or solid composition forms.
Preferably, pharmaceutical composition is a unit dosage, for example tablet or capsule.In such formulation, composition is subdivided into the unitary dose that contains the appropriate amount activeconstituents; Described unit dosage can be packaged composition, for example packaged pulvis, bottle, ampoule, the syringe that is pre-charged with or contain the sachet of liquid.This unit dosage can be for example capsule or tablet itself, perhaps any such composition of the packaged form that it can suitable quantity.
Must come subjectivity to be identified for treating concrete psychotic treatment effective dose by the attending doctor.Related changing factor comprises concrete psychosis or anxiety state or size, age and patient's reaction pattern.In the present invention, it is diseases related or comprised by the novel method of the disease of 5-HT1A acceptor influence to be used for the treatment of the 5-HT1A acceptor: at least a formula A compound or its atoxic pharmaceutically acceptable additive salt that warm-blooded animal are comprised people's effective dosage.Described compound can be oral, rectal administration, parenterai administration or to skin and mucous membrane topical.As a rule, oral dosage every day is 0.01-1000mg/Kg, preferred 0.5-500mg/kg; Dosage every day of parenterai administration is 0.1-100mg/kg, preferred 0.5-50mg/Kg.

Claims (21)

1, formula (A) compound or pharmaceutically acceptable salt thereof, Wherein:
R 0And R 1Be hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, alkyl-cycloalkyl, alkyl heterocycle alkyl, aryl or heteroaryl, perhaps R independently 0And R 1The common Heterocyclylalkyl of forming, condition is R 0And R 1Be not hydrogen simultaneously;
R 2Be hydrogen, alkyl or CH 2(R 5);
R 3It is hydrogen or alkyl;
R 4Be aryl or heteroaryl;
R 5Be alkyl, alkenyl or alkynyl;
X is hydrogen, halogen, whole haloalkyl, hydroxyl, alkoxyl group, perhalogeno alkoxyl group; N is the integer of 1-3; Dotted line is optional two keys.
2, the compound of claim 1, wherein R 0And R 1Form Heterocyclylalkyl together.
3, the compound of claim 1, wherein R 0And R 1Be hydrogen or cycloalkyl independently.
4, any described compound of claim 1-3, wherein X is 4-position or 5-position halogen.
5, any described compound, wherein a R of claim 1-4 0And R 1Be hydrogen or cyclohexyl independently, perhaps they form morpholino together; X is the 5-fluorine; R 4Be phenyl.
6, the compound of claim 1, it is 1-{ (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-3-cyclohexyl-1-methyl-urea or its pharmacologically acceptable salt.
7, the compound of claim 1, its be morpholine-4-formic acid (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydrochysene-4H-pyridine-1-yl]-ethyl-methyl nitrosourea or its pharmacologically acceptable salt.
8, the compound of claim 1, it is 1-{ (1R)-1-benzyl-2-[4-(5-fluoro-2-p-methoxy-phenyl)-1,2,5,6-tetrahydrochysene-4H-pyridine-1-yl]-ethyl }-3-cyclohexyl-1-methyl-urea or its pharmacologically acceptable salt.
9, the compound of claim 1, it is 1-{ (1R)-1-(pyrrole fixed-3-ylmethyl)-2-[4-(2-p-methoxy-phenyl)-pyridine-1-yl)-ethyl }-3-cyclohexyl urea or its pharmacologically acceptable salt.
10, contain the deciliter thing of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
11, treatment suffers from the patient's of serotonin-1A receptor subtype dependency central nervous system disease method, comprises formula (A) compound or pharmaceutically acceptable salt thereof of drug treatment significant quantity:
Figure A9981456000031
Wherein: R 0And R 1Be hydrogen, alkyl, cycloalkyl, Heterocyclylalkyl, alkyl-cycloalkyl, alkyl heterocycle alkyl, aryl or heteroaryl, perhaps R independently 0And R 1The common Heterocyclylalkyl of forming, condition is R 0And R 1Be not hydrogen simultaneously.
R 2Be hydrogen, alkyl or CH 2(R 5);
R 3It is hydrogen or alkyl;
R 4Be aryl or heteroaryl;
R 5Be alkyl, alkenyl or alkynyl;
X is hydrogen, halogen, whole haloalkyl, hydroxyl, alkoxyl group, perhalogeno alkoxyl group; N is the integer of 1-3; Dotted line is optional two keys.
12, the method for claim 11, wherein said disease are dysthymia disorders, anxiety or fear.
13, the method for claim 11, wherein said disease are somnopathy or sexual disorder.
14, the method for claim 11, wherein said disease are that drugs or alcohol are habit-forming.
15, the method for claim 11, wherein said disease are cognitive disorder.
16, the method for claim 11, wherein said disease are neurodegenerative disease.
17, the method for claim 16, wherein neurodegenerative disease is Parkinson's disease or presenile dementia.
18, the method for claim 11, wherein said disease are migraine.
19, the method for claim 11, wherein said disease are obesity.
20, the method for claim 11, this method also further comprise the administration seronine uptake inhibitor.
21, the method for claim 20, wherein said seronine uptake inhibitor are selected from fluoxetine, fluvoxamine, paroxetine, Sertraline and Wen Lafa star.
CN99814560A 1998-12-17 1999-12-16 Arylpiperidine and aryl-1,2,5,6-tetrahydropyridine urea derivatives having 5HT1A receptor activity Pending CN1335835A (en)

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