CN1312802A - Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents - Google Patents
Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents Download PDFInfo
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- CN1312802A CN1312802A CN99809567A CN99809567A CN1312802A CN 1312802 A CN1312802 A CN 1312802A CN 99809567 A CN99809567 A CN 99809567A CN 99809567 A CN99809567 A CN 99809567A CN 1312802 A CN1312802 A CN 1312802A
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Abstract
This invention relates to compounds which have activity as 5-HT1A agonists and antagonists which may be useful for the treatment of anxiety, depression, cognitive deficits, and prostate cancer. Useful compounds are those of formula(I)where: X is selected from the group consisting of (1), (2), (3); n is selected from the integers 1 through 5; R<1> is optionally substituted C6-C10-aryl or mono or bicyclic heteroaryl, with a proviso that heteroaryl is not thiadiazole; R<2> is selected from the group consisting of H and C1-C6 alkyl; R<3> is selected from the group consisting of H, COR<5>, COOR<5>, and CONR<5>R<6>; R<4>, R<5> and R<6> are as defined hereinabove; or an optical isomer; or a pharmaceutically acceptable salt thereof.
Description
Background of invention
The compound that has the selectivity PAA on the 5-HT1A acceptor is as effective anxiolytic and list marketing (buspirone, Buspar
, United States Patent (USP) 3,717,634).Can find 5-HT
1AAgonist and antagonist are used for the treatment of several diseases, the cognitive disorder that causes as anxiety disorder, dysthymia disorders, schizophrenia, by neurodegenerative disease such as Alzheimer, feel sick and vomiting, and (up-to-date reference is referring to K.Rasmussen and V.P.Rocco, serotonin (5-HT) to be used for treatment of prostate cancer
1AThe latest developments of receptor modulators, the pharmaceutical chemistry annual report, the 30th volume, J.A.Bristol edits, 1-9 page or leaf (1995)).
Invention is described
According to the present invention, one group of new compound is provided, comprise their enantiomorph, it has 5-HT
1AAgonist and antagonist-like activity.Compound of the present invention is illustrated by following general formula:
Wherein: X is selected from following groups:
N is selected from 1 to 5 integer; R
1Be C
6-C
10-aryl or list or bicyclic heteroaryl, by F, Cl, Br, I ,-OH ,-NH
2,
CO
2H ,-CO
2-C
1-C
6Alkyl ,-CN ,-NO
2, C
1-C
6Alkyl, C
2-C
6Alkene
Base, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, OR
4And C
1-C
6The perhalogeno alkoxyl group is optional
Replace, condition is that heteroaryl is not a thiadiazoles; R
2Be to be selected from H and C
1-C
6The group of alkyl; R
3Be to be selected from H, COR
5, COOR
5And CONR
5R
6Group; R
4Be to be selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
6-C
10Aryl,
List or bicyclic heteroaryl, C
7-C
14The group of aralkyl and list or dicyclo heteroaralkyl, its
Described in aryl or heteroaryl groups by 1 to 3 be independently selected from F, Cl, Br, I,
CN ,-NH
2,-NO
2,-OH, alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-
C
6Perhaloalkyl radical, C
1-C
6Alkoxyl group and C
1-C
6The substituting group of perhalogeno alkoxyl group is optional to be got
Generation; R
5And R
6Be independently selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
6
Cycloalkyl, C
2-C
6Cycloalkenyl group, adamantyl and noradamantyl, perhaps R
5And R
6
The nitrogen-atoms that inserts with the centre is joined together to form 5-7 unit nitrogen heterocyclic, optional containing
Be selected from O, S or NR
4Other heteroatoms; Its optically active isomer; With its pharmacy acceptable salt.
Term C
6-C
10Aryl comprises phenyl and naphthyl.Bicyclic heteroaryl represents to have 1-3 heteroatomic 5-6 unit heteroaryl groups that is independently selected from N, O and S, as pyridine, pyrroles, thiophene, furans, imidazoles, oxazole, pyrimidine, pyridazine, pyrazine, thiazole with the Evil thiazole.Bicyclic heteroaryl comprises the phenyl that is fused to monocycle 5-6 unit heteroaryl groups or is fused to the 5-6 unit heteroaryl groups of another 5-6 unit heteroaryl groups, includes but not limited to indoles, quinoline, isoquinoline 99.9, cumarone, benzodioxan, thionaphthene, benzoglyoxaline, naphthyridines and imidazopyridine.Term C
7-C
14Aralkyl represents to have the C as substituent phenyl or naphthyl group
1-C
4Alkyl group, term heteroaralkyl are then represented to have as defined above the C as substituent list or bicyclic heteroaryl group
1-C
4Alkyl group.
The optically active isomer of The compounds of this invention can adopt the optionally synthetic or separation of the ordinary method known to the skilled in the organic synthesis field.
The pharmacy acceptable salt of The compounds of this invention comprises the conventional acid additive salt that is formed by invention compound and the acid of pharmaceutically acceptable organic or inorganic.Described acid salt includes but not limited to acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisul-phate, butyrates, Citrate trianion, camphorate, camsilate, dodecyl sulfate, esilate, fumarate, glycerophosphate, phosphoric acid salt, Hemisulphate, hydrochloride, hydrobromate, hydriodate, lactic acid salt, maleate, mesylate, nicotine salt, oxalate, pamoate, pectate, pivalate, propionic salt, succinate, tartrate and tosylate.Use material also can make alkaline nitrogen-containing group quaternized such as elementary alkyl halide, dialkyl sulfate, long-chain halogenide (as lauryl bromide), aralkyl halide (as benzyl and phenethyl bromide).The present invention describes in detail
Begin synthetic R with four steps (scheme 1) from the cycloalkyl L-Ala
2And R
3At least one is the compound of hydrogen, and this cycloalkyl L-Ala has been used uncle-butoxy carbonyl group (BOC) protection on nitrogen-atoms.With dicyclohexylcarbodiimide (DCC) aryl-heterocyclic that is suitable replacement with this material coupling, wherein X be CH, N or have with adjacent carbons through doubly linked carbon, to obtain compound 1.Under acidic conditions, remove the BOC group, obtain penultimate intermediate 2 with the borane complexes reduction subsequently.Obtain compound 3 with suitable chloride of acid acidylate 2 then, this compound 3 is isolated as acceptable salt.Scheme 1.
Use two usual ways to prepare R
2And R
3Both not all are the compounds of hydrogen.1 step of acid amides with lithium aluminum hydride (LAH) reduction BOC protection obtains methylamine 4 (scheme 2).Obtain N-methyl nitrosourea 5 with suitable chloride of acid acidylate subsequently.Scheme 2.
Perhaps, after intermediate 2 acidylates, obtain alkylamine 6, be translated into final acylate 7 (scheme 3) then with appropriate reductant such as borine-dimethylsulphide reduction again.Scheme 3.
By handle with suitable isocyanate or by with the phosgene equivalent as superpalite or triphosgene with as described in the amine reaction subsequently with suitable alcohol or amine processing, can prepare carbamate and urea by intermediate amine 2,4 and 6.Other synthesis step is cheer and bright to the technician in organic synthesis field.
By the known ordinary method of the technician of chemical field, adopt commercially available chemical substance or prepare compound of the present invention according to the chemical substance that the normative document step is easy to prepare.Following examples only comprise illustration purpose, and are not meant to limit the present invention in any manner.
Embodiment 1 hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl-amine (0.31g, 0.94mmol) and triethylamine (0.26mL, 1.87mmol) methylene dichloride (10mL) solution in drip hexanaphthene formyl chloride (0.15g, methylene dichloride 1.03mmol) (4mL) solution.This reaction mixture was stirred 1 hour under 0 ℃ of nitrogen, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use saturated aqueous NaHCO
3With the salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), be translated into the dihydrochloride of described title compound then with the HCl of dealing with alcohol, obtain 0.41g (85%) beige solid; Mp=121-131 ℃; MS (+) ESI m/z=442 (M+H)
+C
27H
43N
3O
22HCl analytical calculation value: C:63.02; H:8.81; N:8.17 measured value: C:63.56; H:9.27; N:8.07.
Embodiment 21-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl-amine (0.30g, 0.91mmol) and triethylamine (0.25mL, 1.74mmol) methylene dichloride (10mL) solution in drip 1-methyl-cyclohexyl alkane formyl chloride (0.16g, methylene dichloride 1.00mmol) (4mL) solution.This reaction mixture was stirred 1 hour under 0 ℃ of nitrogen, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use saturated aqueous NaHCO
3With the salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), be translated into the hydrochloride hydrate of described title compound then with the HCl of dealing with alcohol, obtain 0.30g (63%) faint yellow solid; Mp=119-121 ℃; MS (+) ESI m/z=456 (M+H)
+C
28H
45N
3O
2HClH
2O analytical calculation value:
C: 65.92; H:9.48; N:8.24 measured value: C:65.85; H:9.26; N:7.67.
Embodiment 3 hexahydrobenzoic acids (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methyl-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl-methyl-amine (0.30g, 0.87mmol) and triethylamine (0.25mL, 1.74mmol) methylene dichloride (10mL) solution in drip hexanaphthene formyl chloride (0.19g, methylene dichloride 1.31mmol) (4mL) solution.This reaction mixture is stirred under room temperature nitrogen spend the night, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use saturated aqueous NaHCO
3With the salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), HCl with dealing with alcohol is translated into dihydrochloride then, obtain 0.41g (89%) white solid with its title compound; Mp=222-224 ℃; MS (+) ESI m/z=456 (M+H)
+C
27H
43N
3O
22HCl analytical calculation value: C:63.62; H:8.96; N:7.95 measured value: C:63.11; H:8.81; N:7.97.
Embodiment 41-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methyl-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl-methyl-amine (0.30g, 0.87mmol) and triethylamine (0.25mL, 1.74mmol) methylene dichloride (10mL) solution in drip 1-methyl-cyclohexyl alkane formyl chloride (0.21g, methylene dichloride 1.31mmol) (4mL) solution.This reaction mixture is stirred under room temperature nitrogen spend the night, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use saturated aqueous NaHCO
3With the salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), be translated into the dihydrochloride of described title compound then with the HCl of dealing with alcohol, obtain 0.41g (86%) white solid; Mp=208-210 ℃; MS (+) ESIm/z=470 (M+H)
+C
29H
47N
3O
22HCl analytical calculation value: C:64.19; H:9.10; N:7.74 measured value: C:63.89; H:9.03; N:7.93.
Embodiment 5 hexahydrobenzoic acids (1R)-1-cyclohexyl methyl-2-[4-(2,3)-dihydrobenzo [1,4]-dioxin-5-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2,3-dihydrobenzo [1,4] dioxin-5-yl)-piperazine-1-yl]-ethyl }-methyl-amine (0.7g, 1.87mmol) and triethylamine (0.5mL, 3.7mmol) methylene dichloride (10mL) solution in drip hexanaphthene formyl chloride (0.27g, dichloromethane solution 1.87mmol).This reaction mixture is stirred under room temperature nitrogen spend the night, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use H
2O and salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (ethyl acetate/hexane), be translated into the hydrochloride semihydrate of described title compound then with ether system HCl, obtain the white solid of 0.82g (91%); Mp=147-148 ℃; MS (+) ESI m/z=484 (M+H)
+C
29H
45N
3O
3HCl0.5H
2O analytical calculation value: C:65.82; H:8.95; N:7.94 measured value: C:65.90; H:9.04; N:7.98.
Embodiment 61-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-piperazine-1-yl]-ethyl }-methyl nitrosourea
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-piperazine-1-yl]-ethyl }-methyl-amine is (o.7g, 1.87mmol) and triethylamine (0.5mL, 3.7mmol) methylene dichloride (10mL) solution in drip 1-methyl-cyclohexyl alkane formyl chloride (0.3g, dichloromethane solution 1.87mmol).This reaction mixture is stirred under room temperature nitrogen spend the night, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use H
2O and salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (ethyl acetate/hexane), be translated into the hydrochloride of described title compound then with ether system HCl, obtain the described title compound of the white solid of 0.85g (91%); Mp=219-220 ℃; MS (+) ESI m/z=498 (M+H)
+C
30H
47N
3O
3HCl analytical calculation value: C:67.45; H:9.06; N:7.87 measured value: C:67.04; H:9.17; N:7.88.
Embodiment 7 cyclohexane carboxylic acids (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl-methyl-amine (0.6g, 1.69mmol) and triethylamine (0.5mL, 3.7mmol) methylene dichloride (10mL) solution in drip hexanaphthene formyl chloride (O.25g, dichloromethane solution 1.69mmol).This reaction mixture is stirred under room temperature nitrogen spend the night, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use H
2O and salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (ethyl acetate/hexane), be translated into hydrochloride 0.3 hydrate of described title compound then with ether system HCl, obtain the white solid of 0.68 g (87%); Mp=＞260 ℃; MS (+) ESI m/z=465 (M+H)
+C
29H
44N
4OHCl0.3H
2O analytical calculation value: C:68.76; H:9.07; N:11.06 measured value: C:68.52; H:9.15; N:11.18.
Embodiment 8l-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(1-indoles-4-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl-methyl-amine (0.6g, 1.69mmol) and triethylamine (0.5mL, 3.7mmol) methylene dichloride (10mL) solution in drip 1-methyl-cyclohexyl alkane formyl chloride (0.27g, dichloromethane solution 1.69mmol).This reaction mixture is stirred under room temperature nitrogen spend the night, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use H
2O and salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (ethyl acetate/hexane), be translated into the hydrochloride of described title compound then with ether system HCl, obtain the white solid of 0.7g (87%); Mp=253-254 ℃; MS (+) ESI m/z=479 (M+H)
+C
30H
46N
4OHCl analytical calculation value: C:69.94; H:9.20; N:10.88 measured value: C:69.68; H:9.21; N:10.89.
Embodiment 9N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methane amide
The Glacial acetic acid of 2.10mL (23.6mmol) and the formic acid of 1.23mL (32.1mmol) are stirred 4 hours formation blended acid anhydrides at 60 ℃.Under nitrogen, gained solution slowly joined ice-cold (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl-(1.18g is in anhydrous tetrahydro furan 3.56mmol) (35mL) solution for amine.This reaction mixture stirs under room temperature nitrogen and spends the night, and slowly pours into the saturated aqueous NaHCO of 60mL then
3In and stirred 10 minutes.Separate each layer and contain water with the outer ethyl acetate extraction of two shares.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into hydrochloride 1.5 hydrates of described title compound with the HCl of dealing with alcohol, obtain the white solid of 1.03g (80%); Mp=157-159 ℃; MS (+) ESI m/z=360 (M+H)
+C
21H
33N
3O
2HCl1.5H
2O analytical calculation value: C:59.62; H:8.81; N:9.93 measured value: C:59.54; H:8.63; N:9.33.
Embodiment 10 hexahydrobenzoic acids (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-acid amides
To salt of wormwood (0.076g, add in water 0.54mmol) (1ml) solution (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-amine (0.18g, methylene dichloride 0.54mmol) (10mL) solution.The gained mixture is cooled to 0 ℃ and add the hexanaphthene formyl chloride (0.54mmol) of 0.076mL.This reaction mixture is spent the night, then with the dilution of 5mL water and 20mL methylene dichloride and separate each phase 0 ℃ of stirring.The dichloromethane extraction outer with three shares contains water.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into the hydrochloride hydrate of described title compound with the HCl of Viraholization, obtain the white solid of 0.177g (68%); Mp=100-103 ℃; MS (+) ESIm/z=441 (M+H)
+C
28H
44N
2O
2HClH
2O analytical calculation value: C:67.91; H:9.56; N:5.66 measured value: C:68.15; H:9.57; N:5.59.
Embodiment 111-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-acid amides
To salt of wormwood (0.076g, add in water 0.54mmol) (1ml) solution (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-amine (0.18g, methylene dichloride 0.54mmol) (10mL) solution.The gained mixture is cooled to 0 ℃ and add the 1-methyl-cyclohexyl alkane carbonyl chloride (0.54mmol) of 0.085g.This reactant is spent the night, then with the dilution of 5mL water and 20mL methylene dichloride and separate each phase 0 ℃ of stirring.The dichloromethane extraction outer with three shares contains water.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into hydrochloride 0.75 hydrate of described title compound with the HCl of Viraholization, obtain the white solid of 0.35g (55%); Mp=208-210 ℃; MS (+) ESI m/z=455 (M+H)
+C
28H
44N
2O
2HCl0.75 H
2O analytical calculation value: C:69.01; H:9.69; N:5.55 measured value: C:69.03; H:9.60; N:5.45.
Embodiment 12 hexahydrobenzoic acids (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-methyl-acid amides
To salt of wormwood (0.080g, add in water 0.58mmol) (1ml) solution (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-methyl-amine (0.20g, methylene dichloride 0.58mmol) (10mL) solution.The gained mixture is cooled to 0 ℃ and add the hexanaphthene formyl chloride (0.58mmol) of 0.090g.This reactant is spent the night, then with the dilution of 5mL water and 20mL methylene dichloride and separate each phase 0 ℃ of stirring.The dichloromethane extraction outer with three shares contains water.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into hydrochloride 0.75 hydrate of described title compound with the HCl of Viraholization, obtain the white solid of 0.195g (69%); Mp=135-137 ℃; MS (+) ESIm/z=455 (M+H)
+C
29H
46N
2O
2HCl0.75 H
2O analytical calculation value: C:69.01; H:9.69; N:5.55 measured value: C:69.07; H:9.52; N:5.19.
Embodiment 131-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-methyl-acid amides is to salt of wormwood (0.08g, 0.58mmol) water (1ml) solution in add (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-methyl-amine (0.18g, methylene dichloride 0.58mmol) (10mL) solution.The gained mixture is cooled to 0 ℃ and add the 1-methyl-cyclohexyl alkane formyl chloride (0.58mmol) of 0.093g.This reaction mixture is spent the night, then with the dilution of 5mL water and 20mL methylene dichloride and separate each phase 0 ℃ of stirring.The dichloromethane extraction outer with three shares contains water.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into hydrochloride 0.75 hydrate of described title compound with the HCl of Viraholization, obtain the white solid of 0.220g (75%); Mp=169-171 ℃; MS (+) ESI m/z=469 (M+H)
+C
30H
48N
2O
2HCl0.75 H
2O analytical calculation value: C:69.52; H:9.82; N:5.40 measured value: C:69.44; H:9.61; N:4.94.
Embodiment 14N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-2,2-dimethyl-propionic acid amide is to salt of wormwood (0.076g, 0.54mmol) water (1ml) solution in add (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-amine (0.18g, methylene dichloride 0.54mmol) (10mL) solution.The gained mixture is cooled to 0 ℃ and add the trimethyl-acetyl chloride (0.54mmol) of 0.066g.This reactant is spent the night, then with the dilution of 5mL water and 20mL methylene dichloride and separate each phase 0 ℃ of stirring.The dichloromethane extraction outer with three shares contains water.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into hydrochloride 0.75 hydrate of described title compound with the HCl of Viraholization, obtain the white solid of 0.137g (56%); Mp=97-99 ℃; MS (+) ESI m/z=415 (M+H)
+C
26H
42N
2O
2HCl0.75 H
2O analytical calculation value: C:67.22; H:9.65; N:6.02 measured value: C:66.91; H:9.68; N:5.90.
Embodiment 15N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-2,2, N-trimethylammonium-propionic acid amide
To salt of wormwood (0.08g, add in water 0.58mmol) (1ml) solution (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl-methyl-amine (0.20g, methylene dichloride 0.58mmol) (10mL) solution.The gained mixture is cooled to 0 ℃ and add the trimethyl-acetyl chloride (0.62mmol) of 0.075g.This reactant is spent the night, then with the dilution of 5mL water and 20mL methylene dichloride and separate each phase 0 ℃ of stirring.The dichloromethane extraction outer with three shares contains water.The organic phase that merges is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), and be translated into hydrochloride 0.25 hydrate of described title compound with the HCl of Viraholization, obtain the white solid of 0.157g (58%); Mp=233-236 ℃; MS (+) ESIm/z=429 (M+H)
+C
27H
44N
2O
2HCl0.25 H
2O analytical calculation value: C:69.05; H:9.77; N:5.97 measured value: C:69.28; H:9.96; N:5.90.
Embodiment 161-methyl-cyclohexyl alkane carboxylic acid (1R)-and 1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-ethyl }-acid amides
0 ℃ to (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-ethyl }-amine (0.25g, 0.76mmol) and triethylamine (0.21mL, 1.52mmol) methylene dichloride (10mL) solution in drip 1-methyl-cyclohexyl alkane formyl chloride (0.13g, methylene dichloride 0.84mmol) (4mL) solution.This reaction mixture was stirred 1 hour under 0 ℃ of nitrogen, on rotary evaporator, concentrate then, with the ethyl acetate dilution and use saturated aqueous NaHCO
3With the salt water washing.Organic phase is dry on anhydrous sodium sulphate, filter and on rotary evaporator, concentrate and obtain crude product, this product is by going up the flash chromatography purifying at silica gel (methylene chloride), be translated into the hydrochloride semihydrate of described title compound then with the HCl of dealing with alcohol, obtain the yellow solid of 0.15g (41%); Mp=93-95 ℃; MS (+) ESIm/z=453 (M+H)
+C
29H
44N
2O
2HCl0.5 H
2O analytical calculation value: C:69.92; H:9.31; N:5.62 measured value: C:69.92; H:9.03; N:5.23.
Pharmacology is according to the described step of J.Dunlop, Y.Zhang, D.Smith and L.Schechter (Eur.J.Pharmacol., submission; Modification by described steps such as J.Zgombick, Naunyn-Schmiedeberg ' s Arch.Pharmacol., 354,226-236 (1996)), determine serotonin 5-HT by detecting test-compound from the ability of its binding site displacement [3H] 8-OHDPAT on the receptor complex of Chinese hamster ovary celI
1AThe avidity of acceptor, this Chinese hamster ovary celI are by people 5-HT
1AThe acceptor stable transfection.As table 1 explanation, described compound of the present invention shows 5-HT
IAThe high-affinity of acceptor.
Table 1
5-HT
1AAvidity agonist activity antagonistic activity embodiment (IC
50) GTP γ S (EC
50) cAMP (IC
50) embodiment 1 0.57nM 0.9nM-embodiment 2 1.23nM-14.6nM embodiment 3 1.46nM-4.0nM embodiment 4 2.82nM-10.2nM embodiment 5 2.37nM-4.6nM embodiment 6 6.92nM-7.3nM embodiment 7 8.84nM-10.5nM embodiment 8 32.68nM--embodiment 9 1.49nM-17.3nM embodiment 10 1.08nM 3.9nM-embodiment 11 5.97nM-46.0nM embodiment 12 1.69nM-91.5nM embodiment 13 5.33nM-97.5nM embodiment 14 2.19nM-40.0nM embodiment 15 5.00nM--embodiment 16 2.75nM-45.5nM
Some compound of the present invention shows 5-HT
1APAA, as according to by Lazareno and the described modify steps of Birdsall [Br.J.Pharmacol., 109,1120 (1993)], stimulate by assessing described test-compound [
35S]-GTP γ S and Chinese hamster ovary celI in 5-HT
1AAcceptor-G albumen composition bonded ability is shown, and this Chinese hamster ovary celI is by people 5-HT
1AThe acceptor stable transfection.Table 1 has provided and proved the alternative cpd of the present invention that agonist activity is arranged in this detection.
Adopt J.Dunlop, Y.Zhang, D.Smith and the described step of L.Schechter [Eur.J.Pharmacol., submission; Modification by described steps such as J.Zgombick, Naunyn-Schmiedeberg ' s Arch.Pharmacol., 354,226-236 (1996)], by measuring the metabolic ability of cAMP that described test-compound suppresses forskolin-stimulation in the Chinese hamster ovary celI, this Chinese hamster ovary celI is by people 5-HT
1AThe acceptor stable transfection, prove that some compound of the present invention has 5-HT
1AAntagonistic activity.Table 1 has provided proves that in this detection 5-HT is arranged
1AThe alternative cpd of the present invention of antagonistic activity.
Medicinal compositions
The solid carrier that is suitable for comprises one or more materials that also can be used as seasonings, lubricant, solubilizing agent, suspension agent, weighting agent, glidant (gidants), compressing tablet assistant agent, tackiness agent or tablet disintegrant or capsule material.In pulvis, described carrier is the solid of fine dispersion, and it mixes mutually with the activeconstituents of fine dispersion.In tablet, described activeconstituents is suppressed with suitable mixed and with required shape and size with the carrier with required compression property.Described pulvis and tablet preferably contain and surpass 99% activeconstituents.Suitable solid carrier comprises as calcium phosphate, Magnesium Stearate, talcum powder, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, Xylo-Mucine, polyvinylpyrrolidone, low melt wax and ion exchange resin.
Liquid vehicle can be used for preparing solution, suspension, emulsion, syrup and elixir.Described activeconstituents among the present invention dissolves in or is suspended in the pharmaceutically acceptable liquid vehicle as in water, organic solvent, both mixture or pharmaceutically acceptable oil or fat.Described liquid vehicle can contain other suitable medicinal additive such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, seasonings, suspension agent, thickening material, tinting material, viscosity modifier, stablizer or Osmolyte regulator.The suitable example that is used for the liquid vehicle of oral and parenteral admin comprises that water (especially contains above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium solution), alcohols (comprising monohydroxy-alcohol and polyvalent alcohol) and derivative thereof and oil (for example fractionated Oleum Cocois and peanut oil) as ethylene glycol.The described carrier that is used for parenteral admin also can be oily ester such as ethyl oleate and Isopropyl myristate.Sterile liquid carrier can be used for the composition of the sterile liquid form of parenteral admin.
The liquid pharmaceutical composition of sterile solution or suspension can be used for for example intramuscular, intraperitoneal or subcutaneous injection.Sterile solution also can intravenous administration.Oral administration can be the liquid or solid composition forms.
Preferred medicinal compositions is a unit dosage form, as tablet or capsule.In this form, described composition separates with the unitary dose of the described activeconstituents that contains appropriate amount again; Described unit dosage form can be packaged composition, for example the powder of parcel, the bottle that contains liquid, ampoule, the syringe that charges in advance or pouch.Described unit dosage form can be, for example, capsule or tablet itself, perhaps it can be any this based composition of the suitable quantity of packaged form.
The dosage that is used for the treatment of specified disease must be by subjectively determining through controlling the doctor.The variable that relates to comprises specific morbid state and patient's body weight, age and reaction pattern.
Claims (10)
1. the compound of following formula or its optically active isomer or its pharmacy acceptable salt
Wherein: X is selected from following groups:
N is selected from 1 to 5 integer;
R
1Be C with 5-10 atom
6-C
10-aryl or list or bicyclic heteroaryl, its 1-3 atom is the heteroatoms that is independently selected from N, S or O, wherein said aryl or heteroaryl groups by F, Cl, Br, I ,-OH ,-NH
2, CO
2H ,-CO
2-C
1-C
6Alkyl ,-CN ,-NO
2, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, OR
4And C
1-C
6The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;
R
2Be selected from H and C
1-C
6Alkyl;
R
3Be selected from H, COR
5, COOR
5And CONR
5R
6
R
4Be selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C as defined above
6-C
10Aryl or list or bicyclic heteroaryl, C
7-C
14Aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or list or bicyclic heteroaryl group as defined above and by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NH
2,-NO
2,-OH, alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, C
1-C
6Alkoxyl group and C
1-C
6The substituting group of perhalogeno alkoxyl group is optional to be replaced;
R
5And R
6Be independently selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
6Cycloalkyl, C
2-C
6Cycloalkenyl group, adamantyl and noradamantyl, perhaps R
5And R
6The nitrogen-atoms that inserts with the centre is joined together to form 5-7 unit nitrogen heterocyclic, and optional containing is selected from O, S or NR
4Other heteroatoms.
2. according to the compound with following formula or its optically active isomer or its pharmacy acceptable salt of claim 1
Wherein: X is selected from following groups:
N is selected from 1 to 5 integer;
R
1Be C
6-C
10-aryl or list or bicyclic heteroaryl are by F, Cl, Br, I, CO
2H ,-CO
2-C
1-C
6Alkyl ,-CN ,-NO
2, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, OR
4And C
1-C
6The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;
R
2Be selected from H and C
1-C
6Alkyl;
R
3Be selected from H, COR
5, COOR
5And CONR
5R
6
R
4Be selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
6-C
10Aryl, list or bicyclic heteroaryl, C
7-C
14Aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or heteroaryl groups by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NO
2, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, C
1-C
6Alkoxyl group and C
1-C
6The substituting group of perhalogeno alkoxyl group is optional to be replaced;
R
5And R
6Be independently selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
6Cycloalkyl, C
2-C
6Cycloalkenyl group, adamantyl and noradamantyl, perhaps R
5And R
6The nitrogen-atoms that inserts with the centre is joined together to form No. 4 positions by being selected from R
4The substituting group piperidines, morpholine or the piperazine that replace.
3. the compound according to claim 1 is:
Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-acid amides,
1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-acid amides,
Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methyl-acid amides,
1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methyl-acid amides,
Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2,3)-dihydrobenzo [1,4]-dioxin (dioxinyl)-5-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides,
1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2,3-dihydro-benzo [1,4] dioxin-5-yl)-piperazine-1-yl]-ethyl }-methyl nitrosourea,
Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides,
1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(1H-indoles-4-yl)-piperazine-1-yl]-ethyl }-methyl-acid amides,
N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperazine-1-yl]-ethyl }-methane amide,
Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-acid amides,
1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-acid amides,
Hexahydrobenzoic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-methyl-acid amides,
1-methyl-cyclohexyl alkane carboxylic acid (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-methyl-acid amides,
N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-2,2-dimethyl-propionic acid amide,
N-{ (1R)-1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-piperidines-1-yl]-ethyl }-2,2, N-trimethylammonium-propionic acid amide, or
1-methyl-cyclohexyl alkane carboxylic acid (1R)-and 1-cyclohexyl methyl-2-[4-(2-p-methoxy-phenyl)-3,6-dihydro-2H-pyridine-1-yl]-ethyl }-acid amides,
Or its optically active isomer,
Or its pharmacy acceptable salt.
4. method for the treatment of mammalian diseases, this disease is by the central nervous system intravital serotonin 5-HT that unifies
1AAcceptor is regulated, and this method comprises following formula: compound or its optically active isomer or its pharmacy acceptable salt of suffering from significant quantity on this sick Mammals therapeutics
Wherein: X is selected from following groups:
N is selected from 1 to 5 integer;
R
1Be C with 5-10 atom
6-C
10-aryl or list or bicyclic heteroaryl, its 1-3 atom is the heteroatoms that is independently selected from N, S or O, wherein said aryl or heteroaryl groups by F, Cl, Br, I ,-OH ,-NH
2, CO
2H ,-CO
2-C
1-C
6Alkyl ,-CN ,-NO
2, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, OR
4And C
1-C
6The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;
R
2Be selected from H and C
1-C
6Alkyl;
R
3Be selected from H, COR
5, COOR
5And CONR
5R
6
R
4Be selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C as defined above
6-C
10Aromatic base or list or bicyclic heteroaryl, C
7-C
14Aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or list or bicyclic heteroaryl group as defined above and by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NH
2,-NO
2,-OH, alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, C
1-C
6Alkoxyl group and C
1-C
6The substituting group of perhalogeno alkoxyl group is optional to be replaced;
R
5And R
6Be independently selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
6Cycloalkyl, C
2-C
6Cycloalkenyl group, adamantyl and noradamantyl, perhaps R
5And R
6The nitrogen-atoms that inserts with the centre links together and can form 5-7 unit nitrogen heterocyclic, and optional containing is selected from O, S or NR
4Other heteroatoms.
5. according to the method for claim 4, wherein Zhi Liao described disease is a dysthymia disorders.
6. according to the method for claim 4, wherein Zhi Liao described disease is an anxiety disorder.
7. according to the method for claim 4, wherein Zhi Liao described disease is memory and/or the learning disorder that is caused by neurodegenerative disease such as Alzheimer.
8. according to the method for claim 4, wherein Zhi Liao described disease is a prostate cancer.
9. according to the method for claim 4, wherein Zhi Liao described disease is to feel sick and vomiting.
10. medicinal compositions, it comprises following formula: compound or its optically active isomer or its pharmacy acceptable salt of significant quantity on pharmaceutically acceptable carrier and the therapeutics
Wherein: X is selected from following groups:
N is selected from 1 to 5 integer;
R
1Be C with 5-10 atom
6-C
10-aryl or list or bicyclic heteroaryl, its 1-3 atom is the heteroatoms that is independently selected from N, S or O, wherein said aryl or heteroaryl groups by F, Cl, Br, I ,-OH ,-NH
2, CO
2H ,-CO
2-C
1-C
6Alkyl ,-CN ,-NO
2, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, OR
4And C
1-C
6The perhalogeno alkoxyl group is optional to be replaced, and condition is that heteroaryl is not a thiadiazoles;
R
2Be selected from H and C
1-C
6Alkyl;
R
3Be selected from H, COR
5, COOR
5And CONR
5R
6
R
4Be selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C as defined above
6-C
10Aryl or list or bicyclic heteroaryl, C
7-C
14The group of aralkyl and list or dicyclo heteroaralkyl, wherein said aryl or list or bicyclic heteroaryl group as defined above and by 1 to 3 be independently selected from F, Cl, Br, I, CN ,-NH
2,-NO
2,-OH, alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Perhaloalkyl radical, C
1-C
6Alkoxyl group and C
1-C
6The substituting group of perhalogeno alkoxyl group is optional to be replaced;
R
5And R
6Be independently selected from H, C
1-C
6Alkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
3-C
6Cycloalkyl, C
2-C
6Cycloalkenyl group, adamantyl and noradamantyl, perhaps R
5And R
6The nitrogen-atoms that inserts with the centre can be joined together to form 5-7 unit nitrogen heterocyclic, and optional containing is selected from O, S or NR
4Other heteroatoms.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US9746398A | 1998-06-15 | 1998-06-15 | |
| US09/097463 | 1998-06-15 |
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| Publication Number | Publication Date |
|---|---|
| CN1312802A true CN1312802A (en) | 2001-09-12 |
Family
ID=22263490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99809567A Pending CN1312802A (en) | 1998-06-15 | 1999-06-14 | Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1087954A1 (en) |
| JP (1) | JP2002518382A (en) |
| CN (1) | CN1312802A (en) |
| AU (1) | AU4566399A (en) |
| BR (1) | BR9911280A (en) |
| CA (1) | CA2334254A1 (en) |
| WO (1) | WO1999065887A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428700A (en) * | 2015-03-30 | 2017-12-01 | 盐野义制药株式会社 | 9 yuan of fused-ring derivatives |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6376494B1 (en) * | 1998-06-15 | 2002-04-23 | American Home Products Corporation | Cycloalkyl-substituted aryl-piperazines, piperidines and tetrahydropyridines as serotonergic agents |
| WO2002085871A2 (en) | 2001-04-04 | 2002-10-31 | Wyeth | Serotonergic agents with long-acting in vivo effects |
| US7067518B2 (en) | 2002-09-05 | 2006-06-27 | Wyeth | Pyridinyl-methyl-ethyl cyclohexanecarboxamides as serotonergic agents |
| EP2338873A1 (en) | 2009-12-22 | 2011-06-29 | Gmeiner, Peter | New aminotetraline derivatives |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2230780B (en) * | 1989-04-22 | 1992-10-21 | American Home Prod | Tertiary alkyl functionalized piperazine derivatives |
| FR2655988B1 (en) * | 1989-12-20 | 1994-05-20 | Adir Cie | NOVEL DERIVATIVES OF NAPHT-1-YL PIPERAZINE, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
| AU645681B2 (en) * | 1991-05-02 | 1994-01-20 | John Wyeth & Brother Limited | Piperazine derivatives |
| IT1251144B (en) * | 1991-07-30 | 1995-05-04 | Boehringer Ingelheim Italia | BENZIMIDAZOLONE DERIVATIVES |
| GB9125900D0 (en) * | 1991-12-05 | 1992-02-05 | Wyeth John & Brother Ltd | Piperazine derivatives |
| GB9306103D0 (en) * | 1993-03-24 | 1993-05-12 | Wyeth John & Brother Ltd | Piperazine derivatives |
| GB9411099D0 (en) * | 1994-06-03 | 1994-07-27 | Wyeth John & Brother Ltd | Piperazine derivatives |
| IL114027A (en) * | 1994-06-08 | 1999-11-30 | Lundbeck & Co As H | 4-Phenyl piperazine (piperidine or tetrahydropyridine) derivatives serotinin 5-HT1A and dopamin D2 receptor ligand pharmaceutical compositions containing them |
| GB9413772D0 (en) * | 1994-07-08 | 1994-08-24 | Wyeth John & Brother Ltd | 5-HT1A ligands |
| FR2727682A1 (en) * | 1994-12-02 | 1996-06-07 | Pf Medicament | NOVEL DERIVATIVES OF 3,5-DIOXO- (2H, 4H) -1,2,4-TRIAZINES, THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT |
| US5486518A (en) * | 1995-04-10 | 1996-01-23 | American Home Products Corporation | 4-indolylpiperazinyl derivatives |
| DE19615232A1 (en) * | 1996-04-18 | 1997-10-23 | Merck Patent Gmbh | New carbamoyl derivatives and their use as 5-HT ¶1¶¶A¶ antagonists |
-
1999
- 1999-06-14 WO PCT/US1999/013397 patent/WO1999065887A1/en not_active Application Discontinuation
- 1999-06-14 BR BR9911280-9A patent/BR9911280A/en not_active IP Right Cessation
- 1999-06-14 CA CA002334254A patent/CA2334254A1/en not_active Abandoned
- 1999-06-14 JP JP2000554713A patent/JP2002518382A/en active Pending
- 1999-06-14 CN CN99809567A patent/CN1312802A/en active Pending
- 1999-06-14 AU AU45663/99A patent/AU4566399A/en not_active Abandoned
- 1999-06-14 EP EP99928648A patent/EP1087954A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428700A (en) * | 2015-03-30 | 2017-12-01 | 盐野义制药株式会社 | 9 yuan of fused-ring derivatives |
| CN107428700B (en) * | 2015-03-30 | 2021-08-03 | 盐野义制药株式会社 | 9-membered fused ring derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002518382A (en) | 2002-06-25 |
| EP1087954A1 (en) | 2001-04-04 |
| AU4566399A (en) | 2000-01-05 |
| BR9911280A (en) | 2001-03-13 |
| WO1999065887A1 (en) | 1999-12-23 |
| CA2334254A1 (en) | 1999-12-23 |
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