CN1036395C - Piperazine derivatives - Google Patents
Piperazine derivatives Download PDFInfo
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- CN1036395C CN1036395C CN92102132A CN92102132A CN1036395C CN 1036395 C CN1036395 C CN 1036395C CN 92102132 A CN92102132 A CN 92102132A CN 92102132 A CN92102132 A CN 92102132A CN 1036395 C CN1036395 C CN 1036395C
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- China
- Prior art keywords
- phenyl
- hydrogen
- acid
- azatropylidene
- piperazinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Hexahydro-1-{4-1-4-(2-methoxyphenyl) piperazine]]-2-phenyl butyryl}-1H-azepin and acid addition salts which can be accepted in the pharmacy are5-HT<IA> bonding agents, and can be used as the anti-anxiolytic agents.
Description
The present invention relates to bridged piperazine derivatives, their preparation method, their purposes and contain their medicinal compositions.New compound of the present invention is by acting on central nervous system (following meeting is explained more fully) with the 5-HT receptor binding, thereby can be used as human and other the mammiferous medicines of treatment.
New compound of the present invention is compound and the pharmacy acceptable salt thereof with following formula:
Compd A is 2,3,4,5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl)-piperazinyl]]-2-phenyl butyryl radicals }-the 1H-azatropylidene).
(described the compound with following general formula in the application number 9008925.1, this general formula comprises new compound of the present invention in our common unsettled Britain's application.The compound of our common pending application is compound and the pharmaceutically-acceptable acid addition thereof with following general formula:
In the formula (I): n is integer 1 or 2; R is hydrogen or low alkyl; R
1Be aryl or nitrogenous heteroaryl; R
2Be hydrogen or low alkyl group; R
3Be aryl, contain the alkyl or an aryl (rudimentary) groups of 4 to 8 carbon atoms; X is
-OCOR
10,-CO
2R
6,-CONR
5R
9,-OCO
2R
6,-NR
4COR
6, OCONHR
11,-NHCO
2R
6,-NR
4CONHR
6,-CONHNHR
6,-CONHOR
6,
R
4And R
5Each is hydrogen or low alkyl group naturally; R
6Be-CHR
7R
8The cycloalkyl or aryl (rudimentary) alkyl that contain 3 to 12 carbon atoms, (R wherein
7And R
8Each is hydrogen or low alkyl group naturally); R
9Be hydrogen, contain the alkyl of 1 to 8 carbon atom, except the tertiary alkyl, contain the cycloalkyl of 3 to 12 carbon atoms, cycloalkyl (rudimentary) alkyl, aryl, aryl (rudimentary) alkyl or 8-azaspiro [4.5] ten-7,9-diketone-8-base-[condition is to work as R to (rudimentary) alkyl
3When being aryl or aralkyl, R
9It or not the phenyl that the ortho position is replaced by chimney element, nitro, trifluoroalkyl, cyano group, sulfonic group, sulfonamido, carboxyl, carbalkoxy, carboxyl phenylamino or 4-carboxyamino-phenylsulfonamido; With work as R
9When being hydrogen, alkyl, aryl or aryl (rudimentary) alkyl, R
5Be hydrogen or-CHR
7R
8]; Perhaps R
5And R
9Represent azetidinyl with the nitrogen-atoms that they connected, pyrrolidyl, piperidino-(1-position only), hexahydroazepine, morpholino, or piperazinyl, above-mentioned group can be replaced by low alkyl group, aryl or aryl (rudimentary) alkyl; R
10Be the cycloalkyl that contains 3 to 12 carbon atoms, or can be by 2 of the plain replacement of low alkyl group, lower alkoxy or chimney, 3-dihydro [1,4] benzo two oxine bases are perhaps worked as R
3Be when containing the alkyl of 4 to 8 carbon atoms, R
10It also can be aryl; R
11Be the cycloalkyl that contains 3 to 12 carbon atoms, aryl or aryl (rudimentary) alkyl; R
12And R
13Each is low alkyl group naturally, perhaps represents C with their institute's banded carbon atoms
4-6Cycloalkyl; R
14Represent hydrogen, halogen, low alkyl group or low alkyl group; With Y be CO or SO
2
The compound of our common pending application can be made by many methods by known initial substance or the initial substance for preparing with usual method.Some method of having delivered is as follows: at a kind of preparation X representative-CONR
5R
9The method of formula (I) acid amides in, with the acid of formula (III) or the amine of its acylated derivatives acidylate formula (II), formula (II) and formula (III) are:
NHR
5R
9(II)
Wherein R, R
1, R
2, R
3, R
5And R
9Definition the same.The example of acylated derivatives comprises carboxylic acid halides (as acyl chlorides); trinitride; acid anhydrides, imidazoles thing (for example obtaining), Acibenzolar or the O-acylurea that obtains by carbodiimide (for example dialkyl group carbodiimide especially dicyclohexyl carbodiimide) by carbonyl dimidazoles.Be more preferably coupling agent (as 1,1 '-carbonyl dimidazoles, chloroformic acid isobutyl or diphenylphosphine muriate) existence down with the above-mentioned amine of acylating acid.
The other method of preparation formula (I) compound comprises: with group-(CH can be provided
2)
nCR
2R
3X (V) (wherein n, R
2, R
3The same with the definition of X) the piperazine of alkylating agent alkanisation formula (IV):
Alkylating agent can be: the compound of following formula for example
Z-CH
2CR
2R
3R in X (VI) formula
2, R
3The same with the definition of X, and Z is a leavings group, for example halogen, alkyl or aryl-sulfonyloxy.Alkylating agent can also be the unsaturated compound of following formula
CH
2=CR
3X (VII) (R wherein
3With X as defined above).Formula (VII) compound is by Michael reaction and the reaction of formula (IV) piperazine.This reaction can be in the presence of alcohol, and intensification is carried out.As X representative-CONR
5R
9The time, can adopt a spot of acid catalyst in the reaction.
Formula A compound of the present invention can prepare by similar method with suitable raw material.The preferred method of preparation compd A comprises the compound with following formula
(wherein X is leavings group such as halogen), react with the amide anion of following formula:
This negatively charged ion can be by making acid amides and highly basic (as LDA) reaction.
Implement the The compounds of this invention that aforesaid method can make free alkali or acid salt form.If the The compounds of this invention that obtains is an acid salt, then free alkali can obtain by the solution of this acid salt that alkalizes.Otherwise, if reaction product is a free alkali, then can be according to the ordinary method for preparing acid salt by alkali cpd, be dissolved in free alkali in the appropriate organic solvent and obtain acid salt, especially pharmaceutically-acceptable acid addition with this solution of acid treatment.
The example of acid salt is those salt that formed by mineral acid and organic acid (as sulfuric acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, tartrate, fumaric acid, toxilic acid, citric acid, acetic acid, formic acid, methylsulphonic acid, tosic acid, oxalic acid and succsinic acid).
Compound of the present invention contains a unsymmetrical carbon, so The compounds of this invention can exist with different stereoisomer forms.These compounds can be racemoid or optically active thing form.Optically active thing form can obtain by the resolution of racemic thing or by asymmetric synthesis.For example, fractionation can be undertaken by laxative remedy: the acid (as dibenzoyl-L-tartaric acid) with an optically active earlier forms diastereomeric salt, separates this diastereo-isomerism salt then and they are converted into alkali or other salt of optically active.
The compounds of this invention has pharmacologically active.Particularly, they are by being used for central nervous system with the cooperation of 5-HT receptor chain.In pharmacological testing, show the special and 5-HT of The compounds of this invention
1AThe receptor binding of type.The compounds of this invention selectively with 5-HT
1AProgram ratio and other acceptors such as the α of receptor bonding
1The degree of receptor binding is many greatly.They show as 5-HT in pharmacological testing
1AThe activity of antagonist.The pharmacological testing of The compounds of this invention is pointed out: they can be in order to treatment CNS disorder, as Mammals, and Ren Lei anxiety particularly.They also can be used as antidepressive, hypotension agent or conduct and regulate the medicine of sleep/wake cycle, epimeletic behaviour and/or sexual function.
By the method for BS Alexander and MD Wood measured The compounds of this invention in the homogenate of rat hippocampus film to 5-HT
1AThe bonding activity of acceptor is referring to J.Pharm Phamacol, 1988,40,888-891.
The result shows: The compounds of this invention is more effective than other compounds of formula I; described other compounds are included in the allied compound described in the embodiment 34 of our common pending application: 2; 3; 4; 5; 6,7-six hydrogen-1-{3-{1-[4-(2-p-methoxy-phenyl-piperazinyl] }-the 2-hydrocinnamoyl }-1H-azatropylidene (compd B).Compd B is one of disclosed compounds effective in this common pending application.The result is as follows, and wherein Compound C is the isomer of describing among the embodiment 2 (a):
IC
50(nM)
Compd A 3
Compd B 9
Compound C 1
These compounds have also been measured it to 5-HT in following test
1AThe antagonistic action of acceptor, described test are the antagonistic effects of 8-hydroxyl-2-(two n-propylamine bases) tetralin (8-OH DPAT) syndromes of rat.The result is as follows:
MED(mg/kg;S.C.)
Compd A 0.03
Compd B 0.3
Bright one two Room/as to have tested The compounds of this invention potential anxiety activity with the active test method of seeking and visiting of measuring mouse in the camera bellows, this method is based on B Costall etc., Nenropharmacology, 1987,26,195-200 and J.N.Crawley etc., Pharme Biochem.Behav, 1980,13, the method for 167-170.The result is as follows:
MED(mg/kg;S.C.)
Compd A 0.03
Compd B 1
The present invention also provides medicinal compositions, and it comprises formula A compound or its pharmaceutically-acceptable acid addition and pharmaceutically acceptable carrier.Any suitable carriers known in the art all can be used for preparing medicinal compositions of the present invention.In such composition, carrier generally is solid or liquid or solid or mixtures of liquids.
The composition of solid form comprises pulvis, granule, tablet, capsule (for example hard and soft gelatine capsule), suppository and vaginal suppository.Solid carrier can be one or more materials, and they also can be used as perfume compound, lubricant, solvating agent, suspensoid, filler, antiseize paste, pressing aid agent, binding agent or tablet disintegrant; It also can be a kind of packing material.In pulvis, carrier is a kind of very thin solid, and it mixes with the active ingredient of fine powder.In tablet, activeconstituents mixes with the carrier with necessary compression property with suitable proportion and is pressed into needed shape and size.Pulvis and tablet preferably contain as many as 99% (as 0.03-99%), the preferably activeconstituents of 1-80%.Suitable solid carrier comprises: for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, sodium carboxy methyl cellulose, polyvinylpyrrolidine, low melt wax and ion exchange resin.
" composition " speech means the prescription that comprises a kind of activeconstituents, this activeconstituents and form capsule together as the packing material of carrier, wherein activeconstituents (being with or without other carriers) suppressed by vector parcel and combination with it.Similarly, capsule is included.
The liquid form composition comprises: for example, and solution, suspension, emulsion, syrup, elixir and pressurized compositions.Activeconstituents solubilized or be suspended in the pharmaceutically acceptable liquid vehicle (as water, organic solvent, the mixture of the two or pharmaceutically acceptable oil or fat).Liquid vehicle can contain other suitable medicated premix such as solubilizing agent, emulsifying agent, buffer reagent, sanitas, sweeting agent, perfume compound, suspensoid, thickening material, pigment, viscosity modifier, stablizer or osmotic pressure regulators.For the suitable example of the liquid vehicle of oral or parenterai administration comprises water (especially comprise above-mentioned additive, as derivatived cellulose, be more preferably carboxymethylcellulose sodium solution) and oil (as fractionated Oleum Cocois and peanut oil).With regard to parenterai administration, carrier can be a grease such as ethyl oleate and Wickenol 101.Sterile liquid carrier is used for the sterile liquid composition forms of parenterai administration.
The sterile solution that liquid medicine is formed or the liquid pharmaceutical composition of suspension can pass through, for example intramuscular injection, peritoneal injection or subcutaneous injection and use.Sterile solution also can intravenous injection.When compound be Orally active then can liquid or solid form oral administration.
Preferred pharmaceutical composition is with presented in unit dosage form, for example tablet or capsule.In this form, the dosage unit composition that contains an amount of activeconstituents is subdivisible; Presented in unit dosage form can be a packaged composition, for example is the pulvis of packing, and bottled dose, ampoule is loaded on the injection of syringe in advance, contains the capsule of liquid.Presented in unit dosage form can be: for example, capsule or tablet itself perhaps can be the packaged form of the proper number of any such composition.The amount of the activeconstituents in the dosage unit of composition is variable or adjustable.From 0.5mg or still less to 750mg or more, this depends on the activity of concrete needs and activeconstituents.
Following example explanation the present invention:
Embodiment 12,3,4,5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-the 1H-azatropylidene
Argon filling and stirring are down; with butyllithium (1.5M hexane solution: 5ml; 7.5mmol) in 5 minutes, be added dropwise to 2,3,4; 5; 6, and 7-six hydrogen-1-phenylacetyl-1H-azatropylidene (1.48g, 6.8mmol) and Diisopropylamine (2.0ml; 1.4g temperature remains on below 8 ℃ in dry toluene 14mmol) (16ml) solution.Mixture stirred 1 hour at 0 ℃, splashed into 1-(2-chloro ethyl)-4-(2-p-methoxy-phenyl) piperazine (1.73g, dry toluene 6.8mmol) (4ml) solution of fresh stratography then.Mixture stirred 18 hours down at 0 ℃ to 20 ℃, added entry (50ml).With two separate, water ethyl acetate extraction (2 * 50ml).Merge organic phase and concentrating under reduced pressure.Thick product (2.91g) is that eluent separates on the silicon-dioxide chromatographic column with ethyl acetate, provides the free alkali (0.15g) of title compound.Product is dissolved in ethyl acetate (30ml), solution hydrogenchloride ether liquid acidifying.Collect product, obtain the dihydrochloride four/trihydrate (0.36g) of title compound, fusing point is 175 °-178 ℃.(record: C, 62.05; H, 7.8; N, 7.75%; Press C
27H
37N
3O
2.2HCl.0.75H
2The calculated value of O is: C, 62.1; H, 7.8; N, 8.05%).
Embodiment 22,3, and 4; 5; 6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-fractionation (a) of 1H-azatropylidene is 2,3; 4; 5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-1H-azatropylidene (12.1g) is dissolved in ethyl acetate (2.5 volumes; be 30ml) in, and add (ethyl acetate (2.5 volume) solution of dibenzoyl-L-tartrate monohydrate (1mol equivalent).The oil that begins to form makes it to dissolve by the acetonitrile (3.6ml) that adds minimum again.After three days, filter and to obtain crystallization (6.2g), analyze this crystallization with the H.P.L.C. of chirality and have 28% optical purity.From ethyl acetate-acetonitrile (3: 10; 13 volumes) middle recrystallization for the first time; the sample that obtains has 84% optical purity; recrystallization from methyl alcohol (7.5 volume) for the second time; obtain the dibenzoyl-L-tartrate (2.1g) of first enantiomorph (isomer I) of product; molten some 147-150 ℃, [α]
D 22=-26 ° (1% methanol solutions) (record: C, 66.7; H, 6.7; N, 5.1%; Press C
27H
37N
3O
2.C
18H
14O
8.H
2O calculated value: C, 66.6; H, 6.6; N, 5.2%), have 97.4% optical purity.Sample is transformed into the free alkali (1.1g) of isomer (I), [α]
D 26=+53 ° (1%, CHCl
3), be converted into hydrochloride with common method then, colourless powder (0.65g), molten some 181-184 ℃, [α]
D 23=+35 ° (1%, methyl alcohol) (record: C, 63.1; H, 7.8; N, 7.9%.Press C
27H
37N
3O
2.2HCl.0.25H
2O calculates: C, 63.2; H, 7.7; N, 8.2%), have 97.6% optical purity.(b) second enantiomorph (isomer II) is to have made second enantiomorph (isomer II) with similar methods from racemoid and the dibenzoyl-D-tartrate-hydrate of embodiment 1.Isomer II dibenzoyl-D-tartrate, molten some 141-142 ℃, [α]
D 25=+25 ° (methanol solutions of 1%) (record: C, 67.3; H, 6.7; N, 5.2%; Press C
27H
37N
3O
2.C
18H
14O
8.0.25H
2O calculated value: C, 67.3; H, 6.5; N, 5.2%).Isomer II alkali: [α]
D 26=-62 ° of (1%CHCl
3Solution); Isomer II hydrochloride, fusing point 181-184 ℃, [α]
D 26=-36 ° (1% methanol solutions) (record: C, 60.2; H, 7.7; N, 7.75%; Press C
27H
37N
3O
2.2HCl.1.75H
2O calculated value: C, 60.05; H, 7.9; N, 7.8%), have 98.2% optical purity.
Claims (3)
1. prepare 2,3,4,5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-preparation method of 1H-azatropylidene and pharmaceutically-acceptable acid addition thereof, this method comprises:
(a) with following formula: compound (X is a leavings group in the formula)
With the anionic reactive of following formula acid amides,
Perhaps
(b), 7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl with free alkali 2,3,4,5,6]]-2-phenyl butyryl radicals }-the 1H-azatropylidene is converted into its pharmaceutically-acceptable acid addition; Perhaps
(c) 2,3,4,5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-1H-azatropylidene and pharmaceutically-acceptable acid addition thereof be converted into its free alkali;
Perhaps
(d) 2,3,4,5,6 of resolution of racemic, 7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-the 1H-azatropylidene.
2. the process of claim 1 wherein that product is 2,3,4,5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-enantiomorph or its pharmacy acceptable salt of 1H-azatropylidene, wherein [α] of free alkali
D 26Be about+53 ° of (1%CHCl
3Solution).
3. the process of claim 1 wherein that product is 2,3,4,5,6,7-six hydrogen-1-{4-[1-[4-(2-p-methoxy-phenyl) piperazinyl]]-2-phenyl butyryl radicals }-enantiomorph or its pharmacy acceptable salt of 1H-azatropylidene, wherein [α] of free alkali
D 26Be about-62 ° of (1%CHCl
3Solution).
Priority Applications (1)
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CN92102132A CN1036395C (en) | 1992-03-19 | 1992-03-19 | Piperazine derivatives |
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CN92102132A CN1036395C (en) | 1992-03-19 | 1992-03-19 | Piperazine derivatives |
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CN1076446A CN1076446A (en) | 1993-09-22 |
CN1036395C true CN1036395C (en) | 1997-11-12 |
Family
ID=4939487
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CN92102132A Expired - Fee Related CN1036395C (en) | 1992-03-19 | 1992-03-19 | Piperazine derivatives |
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CN (1) | CN1036395C (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100345833C (en) * | 1999-12-22 | 2007-10-31 | A.卡尔松研究股份公司 | Modulators of dopamine neurotransmission |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA66370C2 (en) | 1997-12-16 | 2004-05-17 | Lilly Co Eli | Arylpiperazines having activity to setotonin 1 receptors |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4921958A (en) * | 1989-04-22 | 1990-05-01 | American Home Products Corporation | Piperazinylalkylcarboxylic acid adamantylamides |
GB2230781A (en) * | 1989-04-22 | 1990-10-31 | Wyeth John & Brother Ltd | Piperazine derivatives as 5-ht(1a) antagonists |
-
1992
- 1992-03-19 CN CN92102132A patent/CN1036395C/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4921958A (en) * | 1989-04-22 | 1990-05-01 | American Home Products Corporation | Piperazinylalkylcarboxylic acid adamantylamides |
GB2230781A (en) * | 1989-04-22 | 1990-10-31 | Wyeth John & Brother Ltd | Piperazine derivatives as 5-ht(1a) antagonists |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100345833C (en) * | 1999-12-22 | 2007-10-31 | A.卡尔松研究股份公司 | Modulators of dopamine neurotransmission |
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