CN1289333A - Oxazole derivatives as serotonin-1A receptor ogonists - Google Patents
Oxazole derivatives as serotonin-1A receptor ogonists Download PDFInfo
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Abstract
This invention provides compounds of Formula (1), wherein R1 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, benzyloxy, trifluoromethyl, chloro, bromo, or fluoro; a dashed line indicates an optional bond; X is NR4, or no atom; R2 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety is 3-8 cabon atoms and the alkyl moiety is 1-6 carbon atoms, aryl of 5-12 carbon atoms, or arylalkyl of 6-12 carbon atoms; R3 is aryl of 5-12 carbon atoms, arylalkyl of 6-12 carbon atoms, or heteroaryl of 5-12 ring atoms; R4 is hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in the treatment of psychosis (e.g. schizophrenia), anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual dysfunction and memory deficits associated with Alzheimer's disease and other dementias.
Description
Invention field
The invention provides a kind of disease De oxazole derivative relevant with serotonin-1A (5-HT1A) acceptor subclass or that influenced by it that is used for the treatment of.This compounds is specially adapted to treat psychosis (as schizophrenia), anxiety disorder, dysthymia disorders and relevant CNS disease and other diseases, as treatment treatment of alcohol and drug withdrawal, sexual dysfunction and the memory deficit relevant with the Alzheimer syndromes.
Invention is described
The invention provides formula (1) compound or pharmaceutically acceptable salt thereof with following structure,
Wherein: R
1Be hydrogen, the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, benzyloxy, trifluoromethyl, chlorine, bromine or fluorine; Dotted line is represented any key; X is NR
4Or there is not an atom; R
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom, contains the aryl of 5-12 carbon atom or contains the aralkyl of 6-12 carbon atom; R
3For the aryl that contains 5-12 carbon atom, contain the aralkyl of 6-12 carbon atom or contain the heteroaryl of 5-12 annular atoms; R
4For hydrogen or contain the alkyl of 1-6 carbon atom.
Described compound or pharmaceutically acceptable salt thereof can be used for treating psychosis (as schizophrenia), anxiety disorder, dysthymia disorders and relevant CNS disease and other diseases, as treatment treatment of alcohol and drug withdrawal, sexual dysfunction with Alzheimer syndromes and the relevant memory deficit of other dementias.
The term alkyl comprises straight chain and branched-chain alkyl part.The aryl moiety of aryl, heteroaryl or aralkyl can at random be substituted.Two substituting groups on the aromatic ring can be joined together to form another ring system.The example of this bicyclic ring system is the following formula group that replaces arbitrarily:
(phenyl that is replaced by ethylenedioxy just).
The substituent aryl moiety of aryl or aralkyl preferably has 6 to 10 carbon atoms, most preferably is phenyl or 1,4-benzodioxan-5-base.Aryl or aryl moiety can at random be selected from following substituting group one-, two-or three-replace: contain the alkyl of 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, trifluoromethyl, chlorine, fluorine, bromine, the alkoxy carbonyl that contains 2-7 carbon atom, the alkylamino that contains 1-6 carbon atom and dialkylamino, wherein each alkyl contains 1-6 carbon atom.Preferred heteroaryl comprises 1-3 identical or different heteroatoms that is selected from oxygen, nitrogen and sulphur, and preferred especially heteroaryl substituting group is pyridyl, furyl, thienyl, quinolyl, isoquinolyl or indyl.Heteroaryl moieties can at random be selected from following substituting group one-, two-or three-replace: contain the alkyl of 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, trifluoromethyl, chlorine, fluorine, bromine, the alkoxy carbonyl that contains 2-7 carbon atom, the alkylamino that contains 1-6 carbon atom and dialkylamino, wherein each alkyl contains 1-6 carbon atom.
Pharmacologically acceptable salt is by organic or inorganic acid deutero-salt, and described organic or inorganic acid is including, but not limited to acetate, lactic acid, citric acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, Phenylsulfonic acid and similarly known acceptable acid.
In compound of the present invention, preferred compound comprises wherein R
2Be those compounds of alkyl, cycloalkyl or cycloalkylalkyl, and comprise wherein R
3Those compounds for aryl (more preferably phenyl).
The present invention also provides the method for preparation formula (1) compound, and this method comprises:
A) with formula (8) compound and dewatering agent reaction,
Wherein X, R
1, R
2, R
3Define as mentioned with dotted line, or b) with formula (2) compound
Wherein X and dotted line define as mentioned, react with formula (4) compound
R wherein
2And R
3Definition as mentioned.
The compounds of this invention can utilize conventional method preparation easily, for example utilizes the route A and the B that separate shown in following flow process 1.
Flow process 1
Arylpiperidine (2; X=does not have atom) and aryl-tetrahydropyridine (2, X=does not have atom) both commercially available, also can obtain by technician in the organic synthesis field is easily synthetic; for example in flow process 2, the 4-piperidone by suitable N-protected is in lithium aryl or the reaction of aryl magnesium compound.
Flow process 2
In route A, formula (3) amidoalkyl chlorine can utilize the known standard acylations of organic synthesis those skilled in the art condition, is made by corresponding amine (5).
Alkyl chloride (5) can easily obtain, and can be made by corresponding protected amino acid (6) by using the reaction as Arndt-Eistert.For example, with the acyl chlorides and the diazomethane reaction of (6) and utilize HCl to handle the α-diazo-ketones (7) of gained, can obtain required product.
With (2) and alkyl chloride (3) reaction, can obtain keto-amide (8).By dewatering agent (as chlorizating agent POCl
3) effect, this product can be cyclized into Suo Xu De oxazole (1).
In route B, Lv Wan Ji oxazole (4) can pass through dewatering agent (as chlorizating agent POCl
3) effect, make by keto-amide (3).The alkylated reaction of (2) then and muriate (4) can carry out in appropriate solvent (as acetone), can at random use alkali (as salt of wormwood or triethylamine) as acid scavenger.
The compounds of this invention is the 5-HT1A agonist.Thrombotonin 5-HT
1AThe affinity of acceptor can determine in the standard drug test method, this method can measure the compound displacement be combined in stable transfection have in the Chinese hamster ovary celI of people's 5 HT1A acceptors [
3H] ability of 8-OH-DPAT.The Chinese hamster ovary celI of stable transfection is grown up in the DMEM that comprises 10% hot deactivation FBS and non-essential amino acid.Cell is scraped from flat board, gone to centrifuge tube, centrifugal in damping fluid (50mM Tris pH7.5) (under 4 ℃, with 2000rpm speed centrifugal 10 minutes) washed twice.Five equilibrium gained pill also places under-80 ℃.In that day of measuring, melt cell on ice, it is suspended in the damping fluid.Carrying out combination in cumulative volume is the 96 hole titer plates of 250 μ L measures.Measure non-limiting combination under the condition that has 10 mM 5HT, final ligand concentration is 1.5nM.After at room temperature hatching 30 minutes, make reaction terminating by adding ice-cold buffer, rapidly by 30 minutes GF/B filter paper filtering of preliminary wetting in 0.5%PEI.Compound carries out initial testing in single point assay, be determined at 1,0.1 and the inhibition percentage ratio at 0.01mM place, and measures the K of active compound
iValue.
The assessment representational compound of the present invention (compound of embodiment 9) in above-mentioned standard drug test method, its K
iValue is 4.4nM, and this has shown that the 5-HT1A acceptor is had very high affinity.Based on the result who in standard drug Chinese Academy of Social Sciences method, obtains, The compounds of this invention can be used for treating central nervous system disease, latent and treat harshly as dysthymia disorders, anxiety disorder, insomnia, sexual dysfunction, alcohol because of concealing, be used to strengthen cognitive-ability and associated problem, in addition, also can be used for treating Alzheimer syndromes, Parkinson syndromes, obesity and migraine.
The compounds of this invention can carry out separately or carry out oral administration or parenterai administration with the conventional medicine carrier.Applicable solid carrier comprises that one or more can have the material of flavouring agent, lubricant, solubilizing agent, suspension agent, filler, glidants, compression aid, tackiness agent or tablet disintegrant or capsule material function.In pulvis, carrier can be and the levigate solid of levigated activeconstituents blended.In tablet, activeconstituents mixes with carrier, and described carrier has necessary compression performance and can be pressed into required shape and size in proper proportion.Pulvis and tablet preferably comprise the activeconstituents up to 99%.Suitable solid carrier comprises as calcium phosphate, Magnesium Stearate, talcum, sucrose, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt point paraffin and ion exchange resin.
Liquid vehicle can be used for preparing solution, suspension, emulsion, syrup and elixir.Activeconstituents solubilized of the present invention or be suspended in the pharmaceutically acceptable liquid vehicle, described liquid vehicle comprises water, organic solvent, the two mixture or acceptable oil or fat.Liquid vehicle can contain other suitable medicated premix, as solubilizing agent, emulsifying agent, buffer reagent, preservatives, sweeting agent, flavouring agent, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or osmotic pressure regulator.The suitable example that is used for the liquid vehicle of oral or parenterai administration comprises that water (particularly comprises above-mentioned conditioning agent, as derivatived cellulose, preferably carboxymethyl cellulose sodium), alcohol (comprising monohydroxy-alcohol and polyvalent alcohol) and derivative thereof as glycerine, and oil (as fractionated coconut oil and peanut oil).For parenterai administration, carrier also can be the oily ester, as ethyl oleate and Isopropyl myristate.Sterile liquid carrier can be used for being suitable in the preparation of sterile liquid form of parenterai administration.
The pharmaceutically acceptable liquid composition of aseptic emulsion and emulsion can be used by following manner: as intramuscular, intraperitoneal or subcutaneous injection.Aseptic emulsion also can be by administration in quiet.Oral administration can be the liquid or solid dosage form.
Preferably, pharmaceutical preparation is a single dose form, as tablet or capsule.In this case, composition can be subdivided into the unitary dose that comprises an amount of activeconstituents; Unit dosage form can be a packaging compositions, as packing pulvis, bottle, ampoule, prefilled syringe or comprise the folliculus of liquid.Unitary dose can be as capsule or tablet itself, or an amount of composition that exists with packaged form.
The treatment effective dose that is used for the treatment of the special inspirit disease must be determined by the doctor in charge.Related variable can comprise special psychosis or anxious state and patient's stature, age and response mode.In treatment, for oral administration, the design per daily dose of The compounds of this invention is 0.1-2000mg/kg, preferred 0.5-500mg/kg; For parenterai administration, this dosage is 0.1-100mg/kg, preferred 0.5-50mg/kg.
Following indefiniteness embodiment has illustrated the preparation of the representative compound of the present invention.
Embodiment 1
N-hexamethylene acyl group-L-phenyl alanyl chloride methyl ketone
Utilize hexanaphthene carbonyl chlorine (3.2mmol) to handle and be contained in CH
2Cl
2Cooling (10 ℃) mixture of L-phenyl alanyl chloride methyl ketone (3.2mmol) (30ml) and the salt of wormwood (10mmol) in water (10ml).Stir the gained mixture at ambient temperature two hours, and separated organic layer, utilize water (3 * 20ml) washings, drying on anhydrous magnesium sulfate.Filter and vacuum concentration, obtain title compound, be the coloured solid of creamy (2.6mmol, 81%).
Ultimate analysis: C
17H
22ClNO
2
Calculated value: C, 66.33; H, 7.20; N, 4.55
Measured value: C, 66.12; H, 7.12; N, 4.34
Embodiment 2
4-benzyl-5-chloromethyl-2-Huan Ji Ji oxazole
Under nitrogen atmosphere, utilize dimethyl formamide (2ml) and phosphoryl chloride (26mmol) to handle the benzole soln (26ml) of the chloromethyl ketone (2.6mmol) that obtains by embodiment 1.Reflux mixture 15 minutes is collected water simultaneously in Dean-Stark equipment.After being cooled to room temperature, reaction mixture is injected in the ice (25mg), utilize sodium bicarbonate to make the solution becomes alkalize, utilize ethyl acetate (2 * 30ml) extraction products.(organism that 2 * 30ml) washings merge, dry on anhydrous magnesium sulfate, filtration and vacuum concentration obtain crude product to utilize water.This product utilizes the methylene dichloride wash-out by the flash chromatography on silica gel purifying, obtains title compound, is glassy yellow oily matter (1.03mmol, 40%).
Ultimate analysis: C
17H
20ClNO
Calculated value: C, 70.46; H, 6.96; N, 4.83
Measured value: C, 70.35; H, 7.12; N, 5.02
Embodiment 3
N-pivalyl-L-phenyl alanyl chloride methyl ketone
When in the step of pivalyl chloride (5mmol) being used in the foregoing description 1, separablely go out title compound, yield is 80%.
Ultimate analysis: C
15H
20ClNO
2
Calculated value: C, 63.94; H, 7.15; N, 4.97
Measured value: C, 64.23; H, 7.27; N, 5.12
Embodiment 4
4-benzyl-5-chloromethyl-uncle 2-Ding Ji oxazole
According to embodiment 2 described methods, utilize N-pivalyl-L-phenyl alanyl methyl ketone (4mmol), can make title compound.Products therefrom is at SiO
2After " fast " chromatogram purification is glassy yellow oily matter (2.24mmol, yield 56%).
Ultimate analysis: C
15H
18ClNO
Calculated value: C, 68.30; H, 6.88; N, 5.31
Measured value: C, 68.52; H, 7.02; N, 5.42
Embodiment 5
N-benzoyl-L-phenyl alanyl chloride methyl ketone
By Benzoyl chloride (5mmol) is substituted in the foregoing description 1 described step, can make title compound, yield is 88%.Products therefrom (4.4mmole) is a yellow oil, need not during use to be further purified.
Ultimate analysis: C
17H
16ClNO
2
Calculated value: C, 67.66; H, 5.34; N, 4.64
Measured value: C, 67.55; H, 5.30; N, 4.54
Embodiment 6
4-benzyl-5-chloromethyl-2-Ben Ji oxazole
In the step that embodiment 2 is gone back, use N-benzoyl-L-phenyl alanyl chloride methyl ketone (4.4mmol), can make title compound.Products therefrom is at SiO
2After " fast " chromatogram purification is glassy yellow oily matter (1.4mmol, yield 32%).
Ultimate analysis: C
17H
14ClNO
Calculated value: C, 71.96; H, 4.97; N, 4.94
Measured value: C, 72.25; H, 5.15; N, 5.23
Embodiment 7
N-hexanaphthene ethanoyl-L-phenyl alanyl chloride methyl ketone
Use cyclohexyl ethanoyl chlorine (3mmol) in embodiment 1 described step, can make title compound, yield is 83%.The gained compound is glassy yellow oily matter (2.5mmol), and this product need not to be further purified in use.
Ultimate analysis: C
18H
24ClNO
2
Calculated value: C, 67.17; H, 7.52; N, 4.35
Measured value: C, 67.35; H, 7.50; N, 4.51
Embodiment 8
4-benzyl-5-chloromethyl-2-ring hexyl methyl oxazole
In embodiment 2 described methods, use N-hexanaphthene ethanoyl-L-phenyl alanyl methyl ketone (2.5mmol), can make title compound.Products therefrom is at SiO
2After " fast " chromatogram purification is glassy yellow oily matter (1.2mmol, yield 48%).
Ultimate analysis: C
18H
22ClNO
Calculated value: C, 71.16; H, 7.30; N, 4.61
Measured value: C, 71.23; H, 7.45; N, 4.65
Embodiment 9
1-(4-benzyl-2-cyclohexyl-oxazoles-5-ylmethyl)
-4-(2-methoxyl group-phenyl)-piperidines
At ambient temperature, will be in the 4-in the acetone (15ml) (2-p-methoxy-phenyl)-piperidines (0.19g, 1.0mmol), salt of wormwood (0.345g, 2.5mmol), potassiumiodide (0.066g, 0.4mmol) and 4-benzyl-5-chloromethyl-2-Huan Ji Ji oxazole of obtaining by embodiment 2 (0.244g, suspension 0.85mmol) stirred 16 hours.Solvent removed in vacuo adds entry (50ml), and product is extracted to CH2Cl2, and (3 * 50ml) utilize water.(50ml) organism of washing merging, dry on anhydrous sodium sulphate, filter and vacuum concentration, product (0.415g) is carried out silica gel " fast " chromatogram purification (1%MeOH/CHCl
3), obtain colorless oil (0.376g, yield 99%).Utilize the fumaric acid of 1 equivalent in ethanol (2ml) to handle the ethanolic soln of product, obtain title compound, be white crystalline solid.
Mp?170-171℃
Ultimate analysis: C
29H
36N
2O
21.0C
4H
4O
4
Calculated value: C, 70.69; H, 7.19; N, 5.00
Measured value: C, 70.41; H, 7.18; N, 4.96
Embodiment 10
2-(4-benzyl-2-cyclohexyl-oxazoles-5-ylmethyl)
-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
At ambient temperature, will be in acetone (13ml) 1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (0.172g, 1.0mmol), salt of wormwood (0.345g, 2.5mmol), potassiumiodide (0.066g, 0.4mmol) and the 4-benzyl-5-chloromethyl-2-Huan Ji Ji oxazole that obtains by embodiment 2 (0.289g, suspension 1.0mmol) stirred 2 hours.Solvent removed in vacuo adds entry (50ml), and product is extracted to CH
2Cl
2(2 * 20ml).The organism that utilizes water (50ml) washing to merge, dry on anhydrous sodium sulphate, filter and vacuum concentration, product (0.401g) is carried out silica gel " fast " chromatogram purification (2%MeOH/CHCl
3), obtain colorless oil (0.256g, yield 60%).Utilize the fumaric acid of 1 equivalent in ethanol (2ml) to handle the ethanolic soln of product, obtain title compound, be canescence crystalline solid.
Mp?200-201℃
Ultimate analysis: C
28H
31N
3O0.5C
4H
4O
4
Calculated value: C, 74.51; H, 6.88; N, 8.69
Measured value: C, 74.28; H, 6.91; N, 8.59
Embodiment 11
1-(the 4-benzyl-2-tertiary butyl-oxazoles-5-ylmethyl)
-4-(2-methoxyl group-phenyl)-piperidines
At ambient temperature, will be in the 4-in the acetone (15ml) (2-p-methoxy-phenyl)-piperidines (0.19g, 1.0mmol), salt of wormwood (0.345g, 2.5mmol), potassiumiodide (0.066g, 0.4mmol) and 4-benzyl-5-chloromethyl-uncle 2-Ding Ji oxazole of obtaining by embodiment 4 (0.263g, suspension 1.0mmol) stirred 12 hours.Solvent removed in vacuo adds entry (50ml), and product is extracted to CH
2Cl
2(3 * 5ml).The organism that utilizes water (50ml) washing to merge, dry on anhydrous sodium sulphate, filter and vacuum concentration, product (0.4g) is carried out silica gel " fast " chromatogram purification (1%MeOH/CHCl
3), obtain colorless oil (0.32g, yield 76%).Utilize the HCl of 1 equivalent in ether to handle the ethanolic soln of product, obtain title compound, be white crystalline solid.
Ultimate analysis: C
27H
34N
2O
21.0HCl
Calculated value: C, 71.27; H, 7.75; N, 6.16
Measured value: C, 71.45; H, 7.98; N, 6.36
Embodiment 12
2-(4-benzyl-2-cyclohexyl methyl-oxazoles-5-ylmethyl)
-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles
At ambient temperature, will be in acetone (15ml) 1,2,3,4-tetrahydrochysene-9H-pyrido [3,4-b] indoles (0.172g, 1.0mmol), salt of wormwood (0.345g, 2.5mmol), potassiumiodide (0.066g, 0.4mmol) and the 4-benzyl-5-chloromethyl that is obtained by embodiment 8-(0.303g, suspension 1.0mmol) stirred 16 hours 2-ring hexyl methyl oxazole.Solvent removed in vacuo adds entry (50ml), and product is extracted to CH
2Cl
2(2 * 20ml).The organism that utilizes water (50ml) washing to merge, dry on anhydrous sodium sulphate, filter and vacuum concentration, product (0.401g) is carried out silica gel " fast " chromatogram purification (2%MeOH/CHCl
3), obtain colorless oil (0.299g, yield 68%).Be used in the ethanolic soln of the HCl processing product in the ether, obtain title compound, be canescence crystalline solid.
Ultimate analysis: C
29H
33N
3O1.0HCl
Calculated value: C, 73.17; H, 7.20; N, 8.83
Measured value: C, 73.28; H, 7.41; N, 8.89
Claims (19)
1. formula (1) compound or pharmaceutically acceptable salt thereof,
Wherein: R
1Be hydrogen, the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, benzyloxy, trifluoromethyl, chlorine, bromine or fluorine; Dotted line is represented any key; X is NR
4Or there is not an atom; R
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom, contains the aryl of 5-12 carbon atom or contains the aralkyl of 6-12 carbon atom; R
3For the aryl that contains 5-12 carbon atom, contain the aralkyl of 6-12 carbon atom or contain the heteroaryl of 5-12 annular atoms; R
4For hydrogen or contain the alkyl of 1-6 carbon atom.
2. according to the compound of claim 1, R wherein
3For containing the aryl of 5-12 carbon atom.
3. according to the compound of claim 1 or 2, R wherein
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains the cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom.
4. according to the compound of claim 1, this compound is 1-(4-benzyl-2-Huan Ji Ji oxazole-5-ylmethyl)-4-(2-methoxyl group-phenyl)-piperidines or its pharmacologically acceptable salt.
5. according to the compound of claim 1, this compound is 1-(4-benzyl-2-Huan Ji Ji oxazole-5-ylmethyl)-4-(2-methoxyl group-phenyl)-piperidines fumarate.
6. according to the compound of claim 1, this compound is 2-(4-benzyl-2-Huan Ji Ji oxazole-5-ylmethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles or its pharmacologically acceptable salt.
7. according to the compound of claim 1, this compound is 2-(4-benzyl-2-Huan Ji Ji oxazole-5-ylmethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles fumarate.
8. according to the compound of claim 1, this compound is 1-(the 4-benzyl-2-tertiary butyl-oxazoles-5-ylmethyl)-4-(2-methoxyl group-phenyl)-piperidines or its pharmacologically acceptable salt.
9. according to the compound of claim 1, this compound is 1-(the 4-benzyl-2-tertiary butyl-oxazoles-5-ylmethyl)-4-(2-methoxyl group-phenyl)-piperidine hydrochlorate.
10. according to the compound of claim 1, this compound is 2-(4-benzyl-2-cyclohexyl methyl-oxazoles-5-ylmethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indoles or its pharmacologically acceptable salt.
11. according to the compound of claim 1, this compound is 2-(4-benzyl-2-cyclohexyl methyl-oxazoles-5-ylmethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] indole hydrochloride.
12. a method for the treatment of the Mammals anxiety disorder that needs treatment, this method comprises takes formula (1) compound or pharmaceutically acceptable salt thereof to described Mammals,
Wherein: R
1Be hydrogen, the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, benzyloxy, trifluoromethyl, chlorine, bromine or fluorine; Dotted line is represented any key; X is NR
4Or there is not an atom; R
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom, contains the aryl of 5-12 carbon atom or contains the aralkyl of 6-12 carbon atom; R
3For the aryl that contains 5-12 carbon atom, contain the aralkyl of 6-12 carbon atom or contain the heteroaryl of 5-12 annular atoms; R
4For hydrogen or contain the alkyl of 1-6 carbon atom.
13. a method for the treatment of the Mammals dysthymia disorders that needs treatment, this method comprises takes formula (1) compound or pharmaceutically acceptable salt thereof to described Mammals,
Wherein: R
1Be hydrogen, the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, benzyloxy, trifluoromethyl, chlorine, bromine or fluorine; Dotted line is represented any key; X is NR
4Or there is not an atom; R
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom, contains the aryl of 5-12 carbon atom or contains the aralkyl of 6-12 carbon atom; R
3For the aryl that contains 5-12 carbon atom, contain the aralkyl of 6-12 carbon atom or contain the heteroaryl of 5-12 annular atoms; R
4For hydrogen or contain the alkyl of 1-6 carbon atom.
14. one kind is treated, and the Mammals Alzheimer syndromes, understanding disease, dementia, insomnia, the medicine that need treatment are latent, the method for alcohol implied or Phobias, this method comprises takes formula (1) compound or pharmaceutically acceptable salt thereof to described Mammals,
Wherein: R
1Be hydrogen, the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, benzyloxy, trifluoromethyl, chlorine, bromine or fluorine; Dotted line is represented any key; X is NR
4Or there is not an atom; R
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom, contains the aryl of 5-12 carbon atom or contains the aralkyl of 6-12 carbon atom; R
3For the aryl that contains 5-12 carbon atom, contain the aralkyl of 6-12 carbon atom or contain the heteroaryl of 5-12 annular atoms; R
4For hydrogen or contain the alkyl of 1-6 carbon atom.
15. a pharmaceutical composition, this pharmaceutical composition comprise formula (1) compound or pharmaceutically acceptable salt thereof and pharmaceutical carrier,
Wherein: R
1Be hydrogen, the alkyl that contains 1-6 carbon atom, the alkoxyl group that contains 1-6 carbon atom, benzyloxy, trifluoromethyl, chlorine, bromine or fluorine; Dotted line is represented any key; X is NR
4Or there is not an atom; R
2For the alkyl that contains 1-6 carbon atom, contain the cycloalkyl of 3-8 carbon atom, wherein cycloalkyl moiety contains cycloalkylalkyl that 3-8 carbon atom and moieties contain 1-6 carbon atom, contains the aryl of 5-12 carbon atom or contains the aralkyl of 6-12 carbon atom; R
3For the aryl that contains 5-12 carbon atom, contain the aralkyl of 6-12 carbon atom or contain the heteroaryl of 5-12 annular atoms; R
4For hydrogen or contain the alkyl of 1-6 carbon atom.
16. the arbitrary claimed compound of claim 1 to 11 is as medicine.
17. the arbitrary claimed compound of claim 1 to 11 is used for the treatment of relevant with serotonin-1A (5-HT1A) acceptor subclass or is subjected to the purposes of the medicine of its disease that influences in preparation.
Anxiety disorder, dysthymia disorders, A1zheimer syndromes, understanding disease, dementia, insomnia, medicine are latent, the purposes of the medicine of alcohol implied or Phobias 18. the arbitrary claimed compound of claim 1 to 11 is used for the treatment of in preparation.
19. a method for preparing the claimed formula of claim 1 (1) compound, this method one of comprises the steps:
A) with formula (8) compound and dewatering agent reaction,
Wherein X, R
1, R
2, R
3With dotted line such as claim 1 definition, obtain formula (1) compound; Or
B) formula (2) compound
Wherein X and dotted line such as claim 1 definition, with the reaction of formula (4) compound,
R wherein
2And R
3As claim 1 definition, obtain formula (1) compound.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1751798A | 1998-02-03 | 1998-02-03 | |
| US09/017517 | 1998-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1289333A true CN1289333A (en) | 2001-03-28 |
Family
ID=21783033
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99802651A Pending CN1289333A (en) | 1998-02-03 | 1999-02-02 | Oxazole derivatives as serotonin-1A receptor ogonists |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1053235A1 (en) |
| JP (1) | JP2002501920A (en) |
| CN (1) | CN1289333A (en) |
| AU (1) | AU2575399A (en) |
| CA (1) | CA2317515A1 (en) |
| WO (1) | WO1999038864A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829297A (en) * | 2013-12-20 | 2016-08-03 | 埃斯蒂文博士实验室股份有限公司 | Piperidine compounds having multimodal activity against pain |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6242448B1 (en) * | 1998-12-17 | 2001-06-05 | American Home Products Corporation | Trisubstituted-oxazole derivatives as serotonin ligands |
| AR032641A1 (en) * | 2001-01-29 | 2003-11-19 | Otsuka Pharma Co Ltd | RECEIVER SUBTIPE AGONIST 5-HT 1A. |
| US7053092B2 (en) | 2001-01-29 | 2006-05-30 | Otsuka Pharmaceutical Co., Ltd. | 5-HT1a receptor subtype agonist |
| US8106074B2 (en) | 2001-07-13 | 2012-01-31 | Pierre Fabre Medicament | Pyridin-2-yl-methylamine derivatives for treating opiate dependence |
| US8703772B2 (en) | 2001-09-25 | 2014-04-22 | Otsuka Pharmaceutical Co., Ltd. | Low hygroscopic aripiprazole drug substance and processes for the preparation thereof |
| AR033485A1 (en) | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME |
| CN101106994A (en) * | 2005-01-19 | 2008-01-16 | 默克公司 | Aminomethyl beta-secretase inhibitors for the treatment of Alzheimer's disease |
| GB0516313D0 (en) * | 2005-08-08 | 2005-09-14 | Argenta Discovery Ltd | Azole derivatives and their uses |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02167280A (en) * | 1988-08-15 | 1990-06-27 | Glaxo Group Ltd | Lactam derivative |
| US5162322A (en) * | 1991-03-06 | 1992-11-10 | A. H. Robbins Company, Incorporated | Method of treating anxiety with 5-[(4-aryl or heteroaryl-1-piperazinyl]alkyl)-2-oxazolidinones |
-
1999
- 1999-02-02 WO PCT/US1999/002210 patent/WO1999038864A1/en not_active Application Discontinuation
- 1999-02-02 AU AU25753/99A patent/AU2575399A/en not_active Abandoned
- 1999-02-02 CN CN99802651A patent/CN1289333A/en active Pending
- 1999-02-02 CA CA002317515A patent/CA2317515A1/en not_active Abandoned
- 1999-02-02 EP EP99905632A patent/EP1053235A1/en not_active Withdrawn
- 1999-02-02 JP JP2000529332A patent/JP2002501920A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105829297A (en) * | 2013-12-20 | 2016-08-03 | 埃斯蒂文博士实验室股份有限公司 | Piperidine compounds having multimodal activity against pain |
| CN105829297B (en) * | 2013-12-20 | 2019-08-09 | 埃斯蒂文制药股份有限公司 | The active piperidine compounds of multiplex mode with anti-pain |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2575399A (en) | 1999-08-16 |
| JP2002501920A (en) | 2002-01-22 |
| WO1999038864A1 (en) | 1999-08-05 |
| EP1053235A1 (en) | 2000-11-22 |
| CA2317515A1 (en) | 1999-08-05 |
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