CN100467464C - Long-chain aromatic piperazine modified duloxetine-like compound, and its preparation and use - Google Patents
Long-chain aromatic piperazine modified duloxetine-like compound, and its preparation and use Download PDFInfo
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- CN100467464C CN100467464C CNB2006101532754A CN200610153275A CN100467464C CN 100467464 C CN100467464 C CN 100467464C CN B2006101532754 A CNB2006101532754 A CN B2006101532754A CN 200610153275 A CN200610153275 A CN 200610153275A CN 100467464 C CN100467464 C CN 100467464C
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Abstract
The invention discloses long chain aroma piperazine attributive duloxetine likes compound and its preparing method and the application. Its preparing method includes the following steps: adding duloxetine or N-R1 displaced duloxetine and chloracyl chloride into chloroform; reacting at room temperature to generate amide under the action of tied acid; alkylating with aroma piperazine to generate long chain aroma piperazine amide; reducing by lithium aluminum hydride in tetrahydrofuran at back flow to generate long chain aroma piperazine duloxetine likes compound. This compound can be used in antidepressant preparing by itself free alkali or salt form. The invention has the advantages of simple preparing process and easy operation.
Description
Technical field
The present invention relates to a kind of long-Chain aromatic piperazine modified duloxetine-like compound and preparation method and application, this technology belongs to the pharmaceutical chemistry field with antidepressant activity.
Background technology
Dysthymia disorders is a kind of common mental disorder, belongs to affective disorder.Continuous quickening along with rhythm of life, people's stress also increases gradually, dysthymia disorders has become the common disease of modern society, high morbidity, its sickness rate is soaring fast, according to incompletely statistics, whole world patients with depression has accounted for 3～5% of world population at present, almost sees each age level, as end identification in time and treatment, will bring more serious consequence (as commit suiside, disabled, too much medical resource waste etc.).According to the World Health Organization deliver＜World Health Report in 2002, dysthymia disorders has become the fourth-largest illness in the world at present, to the year two thousand twenty, dysthymia disorders may be only second to the cardiopathic the 2nd big disease with becoming.
Since first-generation antidepressant drug is invented before more than 50 years, antidepressant drug has developed into the third generation so far, but the common weakness of most of antidepressant drugs of current application is a delayed onset, generally after the 2nd～6 week that begins to take medicine antidepressant effect could appear promptly, SSRIs (the fluoxetine of the s-generation, paroxetine, citalopram, fluvoxamine, sertaline) though improve to some extent in this respect, but still have the onset time in 2～4 weeks, even the good kind of the third generation antidepressant drug of new role mechanism (duloxetine for example, Wen Lafaxin) also still have onset time about 2 weeks.The medicine of quick acting can alleviate patient symptom and with family members' misery, reduce the danger of committing suiside, alleviate social economy's burden simultaneously.Therefore it is outstanding to study showing importance day of the antidepressant drug of quick acting.
Reported first such as Artigas were with pindolol (blended 5-HT in 1993
1A/ beta-2 adrenoceptor antagonist) can significantly reduce SSRI with the medication of SSRIS antidepressant medicament combination
SLag-phase, strengthen antidepressant effect, patient symptom is significantly improved.Result of study subsequently shows, 5-HT
1AAntagonist WAY100635 and several SSRI
SConnection and medication also can show this effect.A kind of hypothesis of this phenomenon is thought it may is the 5-HT of preceding nerve synapse
1ATherefore the autonomous acceptor of nerve synapse 5-HT before the antagonistic action of autonomous acceptor can be blocked has increased the 5-HT concentration between the nerve synapse gap, thereby improves curative effect, reduces the lag-phase etc.
On this basis, current antidepressant drug in the world research focus mainly be with various 5-HT
1AReceptor antagonist or agonist primary structure and SSRI
SPrimary structure be combined in the molecule and make it 5-HT conducting band and 5-HT
1AAcceptor all has higher affinity, thereby brings into play dual antidepressant effect, and this kind idea is further extended, and has just formed so-called SSRI ' plus ' method.Under the guidance of this method, the compound that some new role mechanism occurred is in the clinical study stage at present, for example Flibanserin and Vilazodone, and they antidepressant effect can just occur after taking several days.
Summary of the invention
The object of the present invention is to provide a kind of long-Chain aromatic piperazine modified duloxetine-like compound and preparation method and application, this compound can have 5-HT and 5-HT simultaneously
1AActivity can be used for preparing antidepressant drugs.
The present invention is realized that by following technical proposals a kind of long-Chain aromatic piperazine modified duloxetine-like compound is characterized in that structural formula is as follows:
Wherein: Ar is:
R
2For: hydrogen, C
1-C
3Alkyl, five yuan of cycloaliphatic rings, hexa-atomic cycloaliphatic rings, the five-membered ring that contains S, N, O, the hexa-member heterocycle that contains S, N, O, phenyl, substituted-phenyl, hydroxyl, C
1-C
3Alkoxyl group, amino, substituted-amino, halogen, carboxylic acid, ester, acid amides, nitro, itrile group and trihalogenmethyl in a kind of, two or three; R
1For: hydrogen, C
1-C
3Alkyl or C
1-C
3Acyl group; X, Y are: C, S, N or O; Z is: carbonyl or methylene radical; N=1～4.
Above-mentioned R
2For: hydrogen, C
1-C
3Alkyl, hydroxyl, C
1-C
3Alkoxyl group, amino, substituted-amino, halogen, carboxylic acid, nitro, itrile group and trihalogenmethyl in a kind of, two or three; X, Y are: C or N; R
1For: hydrogen or methyl; N=1～3.
Above-mentioned long-Chain aromatic piperazine modified duloxetine-like compound comprises following compound:
The preparation method of above-mentioned long-Chain aromatic piperazine modified duloxetine-like compound, its preparation general formula is:
It is characterized in that comprising following process:
With 1 mole duloxetine or N-R
1Duloxetine that replaces and 1～1.3 mole chloro acyl chlorides react 1～10 hour generation acid amides in 20 ℃-30 ℃ in the presence of acid binding agents such as triethylamine or pyridine in chloroform; Again with the aromatic piperazine of 1 mole acid amides and 1～1.5 mole at acetonitrile, acetone or N, dinethylformamide solvent generation alkylation generates the long-Chain aromatic piperazine acid amides, at last with 1 mole long-Chain aromatic piperazine acid amides and 0.5～5 mole lithium aluminum hydride in tetrahydrofuran (THF) under refluxing reduction generation long-Chain aromatic piperazine duloxetine-like compound.
The application of above-mentioned long-Chain aromatic piperazine modified duloxetine-like compound, be that form with its free alkali or salt is used to prepare antidepressant drugs, the salt of described compound is the inorganic salt of hydrochloride, hydrobromate or vitriol, perhaps is the organic salt of trifluoroacetate, oxalate, mesylate or maleate.
The salt of above-mentioned compound is hydrochloride, hydrobromate, oxalate or maleate.
The invention has the advantages that its preparation process is simple, easy to operate.Prepared product can have 5-HT and 5-HT simultaneously
1AActivity can be used for preparing antidepressant drugs.
Embodiment
The preparation of intermediate
N-2-chloracetyl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (intermediate 1)
(860mg 2.9mmol), is dissolved in the methylene dichloride (40mL) duloxetine, the adding triethylamine (0.6mL, 4.4mmol), 25 ℃ keep down stirring, 20min dropping chloroacetyl chloride under ice-water bath (0.25ml, 3.2mmol), 25 ℃ of reaction 1.5h, decompression steams solvent, adds entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, get light yellow gluey thing (880mg, 81.3%).
N-3-chlorine propionyl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (intermediate 2)
(860mg 2.9mmol), is dissolved in the methylene dichloride (40mL) duloxetine, the adding triethylamine (0.6mL, 4.4mmol), 30 ℃ keep down stirring, 20min dropping 3-chlorpromazine chloride under ice-water bath (0.24ml, 3.2mmol), 25 ℃ of reaction 1.5h, decompression steams solvent, adds entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, get the light yellow gluey thing of light yellow gluey thing (10.5g, 94.6%).
N-4-chlorobutyryl-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (intermediate 3)
(860mg 2.9mmol), is dissolved in the methylene dichloride (40mL) duloxetine, the adding triethylamine (0.6mL, 4.4mmol), 20 ℃ keep down stirring, 20min dropping 4-chloroacetyl chloride under ice-water bath (0.25ml, 3.2mmol), 25 ℃ of reaction 1.5h, decompression steams solvent, adds entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, get the light yellow gluey thing of light yellow gluey thing (438.1mg, 99.3%).
Embodiment 1:N-[4-(2-methoxyphenylpiperazderivatives) ethanoyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 1 (450.0mg, 1.2mmol), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide, adding 1-(2-p-methoxy-phenyl) piperazine hydrochloride under 20 ℃ of stirrings (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (303.6mg, 47.6%).
Embodiment 2:N-[4-(3-trifluoromethyl piperazine) ethanoyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
(450.0mg 1.2mmol), is dissolved in the acetonitrile (40mL), and (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide adds 1-(3-trifluoromethyl) piperazine hydrochloride (275.6mg, 1.2 under 25 ℃ of stirrings to add triethylamine with intermediate 1
Mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, adds entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, get light yellow gluey thing, PTLC separates (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (320.0mg, 52.7%)
1H?NMR(500MHz，DMSO-d6)δ：8.19-8.11(m，1H，-Nap-
H)，7.81(m，1H，-Nap-
H)，7.51-7.41(m，4H，-Ar-H)，7.37-7.27(m，3H，-Ar-H)，7.17(m，1H，-Ar-H)，7.10-7.02(m，2H，-Ar-H)，6.98-6.91(m，2H，-Ar-H)，5.07(m，1H，-O
CH)，4.50-4.25(m，2H，-CO
CH 2)，3.94(m，2H，-PhN
CH 2)，3.59-3.52(m，2H，-PhN
CH 2)，3.43-3.21(m，6H，-CH
3N
CH 2-CH
2N(
CH 2)
2)，2.99-2.89(m，3H，-N
CH 3)，2.43-1.91(m，2H，-OCH
CH 2)。
Embodiment 3:N-[4-(2-pyrimidylpiperazine) ethanoyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 1 (450.0mg, 1.2mmol), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide, adding 1-(2-pyrimidyl) piperazine under 30 ℃ of stirrings (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (340.6mg, 55.3%)
Embodiment 4:N-[4-(2-methoxyphenylpiperazderivatives) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 2 (450.0mg, 1.2mmol), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide, add under the stirring at room 1-(2-p-methoxy-phenyl) piperazine hydrochloride (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (319.2mg, 25.0%).
1H?NMR(500MHz，DMSO-d6)δ：8.18-8.09(m，1H，-Nap-
H)，7.81(m，1H，-Nap-
H)，7.52-7.41(m，3H，-Ar-H)，7.36-7.26(m，2H，-Ar-H)，7.09-6.88(m，7H，-Ar-H)，5.05-4.95(m，1H，-O
CH)，3.89(s，3H，-O
CH 3)，3.55-2.78(m，17H，-
CH 2N
CH 3，-CO
CH 2 CH 2，-Pip-
H)，2.47-2.33(m，2H，-OCH
CH 2)。
MSm/z(FAB)：80.2(63)，154.1(100)，307.1(11)，400.2(22)，544.1(M+1，22)。
Embodiment 5:N-[4-(3-trifluoromethyl piperazine) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
(450.0mg 1.2mmol), is dissolved in the acetonitrile (40mL), adds triethylamine (0.37mL, 2.7 with intermediate 2
Mol), the catalytic amount anhydrous sodium iodide adds 1-(3-trifluoromethyl) piperazine hydrochloride (275.6mg, 1.2 under the stirring at room
Mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, adds entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, get light yellow gluey thing, PTLC separates (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (125mg, 25.0%).
MSm/z(FAB)：76.8(63)，136.0(73)，243.1(100)，424.1(39)，568.1(M+1，39)。
Embodiment 6:N-[4-(2-pyrimidylpiperazine) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 2 (450.0mg, 1.2mmol), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide, adding 1-(2-pyrimidyl) piperazine under 25 ℃ of stirrings (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (180.0mg, 23.0%).
1H?NMR(500MHz，DMSO-d6)δ：8.47(m，2H，-Pm-
H)，8.19-8.09(m，1H，-Nap-
H)，7.80(m，1H，-Nap-
H)，7.50-7.41(m，3H，-Ar-
H)，7.36-7.27(m，2H，-Ar-
H)，7.07-7.02(m，1H，-Ar-
H)，6.96-6.91(m，2H，-Ar-
H)，6.77(m，1H，-Ar-
H)，5.01-4.93(m，1H，-O
CH)，3.56-2.64(m，17H，-
CH 2N
CH 3，-CO
CH 2 CH 2，-Pip-
H)，2.47-2.31(m，2H，-OCH
CH 2)。
MSm/z(FAB)：80.2(50)，154.1(100)，307.1(15)，372.1(9)，516.1(M+1，9)。
Embodiment 7:N-[4-(2-methoxyphenylpiperazderivatives) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 3 (450.0mg, 1.2mmol), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide, adding 1-(2-p-methoxy-phenyl) piperazine hydrochloride under 30 ℃ of stirrings (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (1.20g, 62.6%).
1H?NMR(500MHz，DMSO-d6)δ：8.18-8.09(m，1H，-Nap-
H)，7.80(m，1H，-Nap-
H)，7.52-7.41(m，3H，-Ar-H)，7.36-7.25(m，2H，-Ar-H)，7.07-6.68(m，6H，-Ar-H)，4.99-4.93(m，1H，-O
CH)，3.89(s，3H，-O
CH 3)，3.48(m，4H，-PhN(
CH 2)
2)，3.38-3.05(m，8H，-CH
3N
CH 2-
CH 2N(
CH 2)
2)，2.96-2.83(m，3H，-N
CH 3)，2.45-1.78(m，6H，-CO
CH 2 CH 2，-OCH
CH 2)。
MSm/z(FAB)：58.3(12)，136.0(73)，154.0(100)，288.9(6)，307.0(8)，414.0(10)，558.0(M+1，5)。
Embodiment 8:N-[4-(3-trifluoromethyl piperazine) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 3 (450.0mg, 1.2mmol), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mol), the catalytic amount anhydrous sodium iodide, adding 1-(3-trifluoromethyl) piperazine hydrochloride under 20 ℃ of stirrings (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (445.6mg, 68.1%).
1H?NMR(500MHz，DMSO-d6)δ：8.18-8.09(m，1H，-Nap-
H)，7.81(m，1H，-Nap-
H)，7.45-7.41(m，4H，-Ar-H)，7.36-7.27(m，4H，-Ar-H)，7.17(m，1H，-Ar-H)，6.97-6.90(m，3H，-Ar-H)，3.94(m，2H，-PhN
CH 2)，3.54-3.48(m，2H，-PhN
CH 2)，3.31-3.08(m，8H，-CH
3N
CH 2N-
CH 2N(
CH 2)
2)，2.92-2.78(m，3H，-N
CH 3)，2.35-1.82(m，6H，-CO
CH 2 CH 2，-OCH
CH 2)。
MSm/z(FAB)：76.3(28)，154.1(100)，299.1(16)，366.0(10)，452.1(34)，596.1(M+1，40)。
Embodiment 9:N-[4-(2-pyrimidylpiperazine) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With intermediate 3 (450.0mg, 1.2mmo1), be dissolved in the acetonitrile (40mL), and the adding triethylamine (0.37mL, 2.7mo1), the catalytic amount anhydrous sodium iodide, adding 1-(2-pyrimidylpiperazine) piperazine under 28 ℃ of stirrings (275.6mg, 1.2mmol), 80 ℃ of back flow reaction 4h, decompression steams solvent, add entry (50mL), dichloromethane extraction (30mL * 3), washing (50mL * 3), dry (anhydrous sodium sulphate), decompression steams solvent, gets light yellow gluey thing, and the PTLC separation (ethyl acetate: ethanol=1:0.8), obtain light yellow gluey thing (386.7mg, 51.2%).
1H?NMR(500MHz，DMSO-d6)δ：8.46(m，2H，-Pm-
H)，8.17-8.09(m，1H，-Nap-
H)，7.81(m，1H，-Nap-
H)，7.52-7.43(m，3H，-Ar-
H)，7.36-7.25(m，2H，-Ar-
H)，7.07-7.02(m，1H，-Ar-
H)，6.97-6.91(m，2H，-Ar-
H)，6.78(m，1H，-Ar-
H)，4.98-4.94(m，1H，-O
CH)，3.54-3.44(m，-PhN(
CH 2)
2)，3.83-2.80(m，11H，-CH
3N
CH 2 CH 2N(
CH 2)
2，-N
CH 3)，2.47-1.81(m，6H，-CO
CH 2 CH 2，-OCH
CH 2)。
MSm/z(FAB)：66.3(43)，123.1(100)，233.1(40)，386.0(74)，530.1(M+1，75)。
Embodiment 10:N-[4-(3-trifluoromethyl piperazine) butyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With lithium aluminum hydride (205mg; 5.4mmol) be dissolved in the tetrahydrofuran (THF) (20mL); under stirring and refluxing (64 ℃); in 30min, drip N-[4-(3-trifluoromethyl piperazine) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (1.07g; 1.8mmol) tetrahydrofuran (THF) (30mL) solution.Drip and finish, at 64 ℃ of following back flow reaction 12h.Cooling slowly adds distilled water (2mL) successively, 15% sodium hydroxide (2mL), and distilled water (6mL), mixture high degree of agitation 30min, filtration under diminished pressure uses methylene dichloride filter wash cake to shallow white.Filtrate adds distilled water (50mL), dichloromethane extraction (30mL * 2), dry (anhydrous sodium sulphate), decompression steams solvent, obtains yellow thickness oily matter (740mg, 68.9%).
Embodiment 11:N-[4-(2-pyrimidylpiperazine) butyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With lithium aluminum hydride (205mg; 5.4mmol) be dissolved in the tetrahydrofuran (THF) (20mL); under stirring and refluxing (64 ℃); in 30min, drip N-[4-(2-pyrimidylpiperazine) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (1.07g; 1.8mmol) tetrahydrofuran (THF) (30mL) solution.Drip and finish, at 64 ℃ of following back flow reaction 12h.Cooling slowly adds distilled water (2mL) successively, 15% sodium hydroxide (2mL), and distilled water (6mL), mixture high degree of agitation 30min, filtration under diminished pressure uses methylene dichloride filter wash cake to shallow white.Filtrate adds distilled water (50mL), dichloromethane extraction (30mL * 2), dry (anhydrous sodium sulphate), decompression steams solvent, obtains yellow thickness oily matter (0.3g, 90.22%).
1H?NMR(500MHz，DMSO-d6)δ：8.45(m，2H，-Pm-
H)，8.19-8.11(m，1H，-Nap-
H)，7.81(m，1H，-Nap-
H)，7.53-7.41(m，3H，-Ar-
H)，7.38-7.31(m，2H，-Ar-
H)，7.11-7.07(m，1H，-Ar-
H)，6.97-6.89(m，2H，-Ar-
H)，6.77(m，1H，-Ar-
H)，4.94(m，1H，-O
CH)，3.57-3.43(m，4H，(
CH 2)
2NPh)，3.17-3.04(m，10H，-
CH 2N
CH 2，-
CH 2N(
CH 2)
2)，2.73(m，3H，-N
CH 3)，2.63(m，2H，-0CH
CH 2)，1.81-1.70(m，4H，-NCH
2 CH 2 CH 2CH
2N)
Embodiment 12:N-[4-(2-methoxyphenylpiperazderivatives) butyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine
With lithium aluminum hydride (205mg; 5.4mmol) be dissolved in the tetrahydrofuran (THF) (20mL); under stirring and refluxing (64 ℃); in 30min, drip N-[4-(2-methoxyphenylpiperazderivatives) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (1.07g; 1.8mmol) tetrahydrofuran (THF) (30mL) solution.Drip and finish, at 64 ℃ of following back flow reaction 12h.Cooling slowly adds distilled water (2mL) successively, 15% sodium hydroxide (2mL), and distilled water (6mL), mixture high degree of agitation 30min, filtration under diminished pressure uses methylene dichloride filter wash cake to shallow white.Filtrate adds distilled water (50mL), dichloromethane extraction (30mL * 2), dry (anhydrous sodium sulphate), decompression steams solvent, obtains yellow thickness oily matter (0.18g, 49.82%).
Embodiment 13:N-[4-(3-trifluoromethyl piperazine) propyl group]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (15b)
With lithium aluminum hydride (205mg; 5.4mmol) be dissolved in the tetrahydrofuran (THF) (20mL); under stirring and refluxing (64 ℃); in 30min, drip N-[4-(3-trifluoromethyl piperazine) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (1.07g; 1.8mmol) tetrahydrofuran (THF) (30mL) solution.Drip and finish, at 64 ℃ of following back flow reaction 12h.Cooling slowly adds distilled water (2mL) successively, 15% sodium hydroxide (2mL), and distilled water (6mL), mixture high degree of agitation 30min, filtration under diminished pressure uses methylene dichloride filter wash cake to shallow white.Filtrate adds distilled water (50mL), dichloromethane extraction (30mL * 2), dry (anhydrous sodium sulphate), decompression steams solvent, obtains yellow thickness oily matter (0.18g, 49.82%).
Embodiment 14:N-[4-(2-pyrimidylpiperazine) propyl group]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (15c)
With lithium aluminum hydride (205mg; 5.4mmol) be dissolved in the tetrahydrofuran (THF) (20mL); under stirring and refluxing (64 ℃); in 30min, drip N-[4-(2-pyrimidylpiperazine) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (1.07g; 1.8mmol) tetrahydrofuran (THF) (30mL) solution.Drip and finish, at 64 ℃ of following back flow reaction 12h.Cooling slowly adds distilled water (2mL) successively, 15% sodium hydroxide (2mL), and distilled water (6mL), mixture high degree of agitation 30min, filtration under diminished pressure uses methylene dichloride filter wash cake to shallow white.Filtrate adds distilled water (50mL), dichloromethane extraction (30mL * 2), dry (anhydrous sodium sulphate), decompression steams solvent, obtains yellow thickness oily matter (0.12g, 59.79%).
Embodiment 15:N-[4-(2-methoxyphenylpiperazderivatives) propyl group]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (15a)
With lithium aluminum hydride (205mg; 5.4mmol) be dissolved in the tetrahydrofuran (THF) (20mL); under stirring and refluxing (64 ℃); in 30min, drip N-[4-(2-methoxyphenylpiperazderivatives) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine (1.07g; 1.8mmol) tetrahydrofuran (THF) (30mL) solution.Drip and finish, at 64 ℃ of following back flow reaction 12h.Cooling slowly adds distilled water (2mL) successively, 15% sodium hydroxide (2mL), and distilled water (6mL), mixture high degree of agitation 30min, filtration under diminished pressure uses methylene dichloride filter wash cake to shallow white.Filtrate adds distilled water (50mL), dichloromethane extraction (30mL * 2), dry (anhydrous sodium sulphate), decompression steams solvent, obtains yellow thickness oily matter (0.26g, 37.69%).
1H?NMR(500MHz，DMSO-d6)δ：8.19-8.13(m，1H，-Nap-
H)，7.81(m，1H，-Nap-
H)，7.50-7.42(m，4H，-Ar-
H)，7.38-7.24(m，2H，-Ar-
H)，6.97-6.89(m，6H，-Ar-
H)，5.12-5.06(m，1H，-O
CH)，3.80(s，3H，-O
CH 3)，3.51(m，4H，(
CH 2)
2NPh)，3.25-3.00(m，10H，-
CH 2N
CH 2，-
CH 2N(
CH 2)
2)，2.78-2.74(m，5H，-N
CH 3，-OCH
CH 2)，2.21-2.16(m，2H，-NCH
2 CH 2CH
2N)。
Embodiment 16: the antidepressant activity experiment
By measure test-compound to standard substance (
3H-8-OH-DPAT with
3H-paroxetine) estimate antidepressant activity with the inhibiting rate of two kinds of receptors bind,, illustrate that then test-compound all has affinity to two kinds of acceptors, thereby have antidepressant activity if test-compound all has inhibiting rate to standard substance and receptors bind.
1. the preparation of film
The rat broken end, cortex is got in operation rapidly on ice, weighs.Add the ice-cold sucrose solution 0.32mol/Lploytron5 shelves 10s homogenate of 20 times of volumes, 70g, 4 ℃ of centrifugal 10min, abandon precipitation, supernatant is in 45000g, 4 ℃ of centrifugal 15min, precipitate 0.05mol/L Tris damping fluid suspendible with 10 times of volumes, 37 ℃ of temperature are incubated 15min, then in 45000g, and 4 ℃ of centrifugal again 15min, tissue storage's damping fluid that precipitation adds an amount of volume suspends, making concentration is 50mg wet tissue/mL, packing, and-20 ℃ store for future use.
2. compound and 5-HT
1AThe receptors bind experiment
The first step: each reaction tubes adds radioligand respectively
3H-8-OH-DPAT100 μ L (final concentration 1nmol/L);
Second step: total binding pipe (TB) adds 100 μ L test damping fluid, non-specific binding pipe (NB) adds cold medicine 8-OH-DPAT of 50 μ L (final concentration 10 μ mol/L) and 50 μ L test damping fluid, and each compound specificity connecting pipe (SB) adds 100 μ L test-compounds (final concentration 10-6M);
The 3rd step: each reaction tubes add respectively membrane prepare thing 200 μ L (final concentration 10mg wet tissue/ml), and different concns treat reagent 100 μ L, the non-specific binding pipe adds the 8-OH-DPAT50 μ L (final concentration 10 μ mol/L) of a fixed concentration in addition
The 4th step: the supplementary test damping fluid is to cumulative volume 1mL (each reaction tubes is all established 3 parallel pipes, and each pipe places on ice during application of sample).
The 5th step: 37 ℃ of temperature of each reaction tubes are incubated 15min, 4 ℃ then, the centrifugal 10min of 4000rpm;
The 6th step: each reaction tubes is refitted on ice, absorbs supernatant as far as possible, adds the ice-cold resuspended precipitation of test damping fluid, thorough washing;
The 7th step: 4 ℃ of each reaction tubess, 4000rpm recentrifuge 10min absorbs supernatant as far as possible;
The 8th step: each reaction tubes adds the resuspended precipitation of 1mL dehydrated alcohol, and moves in the scintillation vial that fills 5mL toluene scintillation solution and mixing;
The 9th step: scintillation vial is put into the liquid scintillation counter counting.
Compound combines experiment with the 5-HT transporter
The first step: each reaction tubes adds radioligand respectively
3H-paroxetine 20 μ L (final concentration 0.2nmol/L);
Second step: total binding pipe (TB) adds 100 μ L test damping fluid, non-specific binding pipe (NB) adds the cold medicine fluoxetine of 100 μ L (final concentration 10 μ mol/L), and each compound specificity connecting pipe (SB) adds 100 μ L test-compounds (final concentration 10-6M);
The 3rd step: each reaction tubes adds membrane prepare thing 200 μ L (final concentration 10mg wet tissue/ml) respectively
The 4th step: the supplementary test damping fluid is to cumulative volume 1mL (each reaction tubes is all established 2-3 parallel pipe, and each pipe places on ice during application of sample).
The 5th step: 23 ℃ of temperature of each reaction tubes are incubated 60min, 4 ℃ then, the centrifugal 10min of 4000rpm;
The 6th step: each reaction tubes is refitted on ice, absorbs supernatant as far as possible, adds the ice-cold resuspended precipitation of test damping fluid, thorough washing;
The 7th step: 4 ℃ of each reaction tubess, 4000rpm recentrifuge 10min absorbs supernatant as far as possible;
The 8th step: each reaction tubes adds the resuspended precipitation of 1mL dehydrated alcohol, and moves in the scintillation vial that fills 5mL toluene scintillation solution and mixing;
The 9th step: scintillation vial is put into the liquid scintillation counter counting.
3. inhibiting rate calculation formula
Inhibiting?rate＝1-[(CPMSB-CPMNB)/(CPMTB-CPMNB)]％
4. experimental result
| The embodiment compound | 5-HT 1AReceptors bind inhibiting rate (%) | The 5-HT transporter is in conjunction with inhibiting rate (%) |
| Embodiment 1 | 70 | 71 |
| Embodiment 2 | 73 | 62 |
| Embodiment 3 | 68 | 54 |
| Embodiment 4 | 86 | 45 |
| Embodiment 5 | 79 | 47 |
| Embodiment 6 | 50 | 63 |
| Embodiment 7 | 74 | 38 |
| Embodiment 8 | 53 | 61 |
| Embodiment 9 | 56 | 62 |
| Embodiment 10 | 85 | 52 |
| Embodiment 11 | 80 | 48 |
| Embodiment 12 | 69 | 40 |
| Embodiment 13 | 90 | 45 |
| Embodiment 14 | 46 | 71 |
| Embodiment 15 | 56 | 66 |
By the result as can be seen, test-compound all has to a certain degree inhibiting rate to standard substance and receptors bind, illustrates that test-compound all has certain affinity to two kinds of acceptors, thereby all has antidepressant effect in various degree.
Claims (5)
1. long-Chain aromatic piperazine modified duloxetine-like compound is characterized in that structural formula is as follows:
Wherein: Ar is: 3-trifluoromethyl, 2-pyrimidyl or 2-p-methoxy-phenyl; R
1Be methyl, Z is: carbonyl or methylene radical; N=1～3.
2. by the described long-Chain aromatic piperazine modified duloxetine-like compound of claim 1, it is characterized in that being in the following compound any one:
N-[4-(2-methoxyphenylpiperazderivatives) ethanoyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(3-trifluoromethyl piperazine) ethanoyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-pyrimidylpiperazine) ethanoyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-methoxyphenylpiperazderivatives) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(3-trifluoromethyl piperazine) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-pyrimidylpiperazine) propionyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-methoxyphenylpiperazderivatives) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(3-trifluoromethyl piperazine) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-pyrimidylpiperazine) butyryl radicals]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(3-trifluoromethyl piperazine) butyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-pyrimidylpiperazine) butyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-methoxyphenylpiperazderivatives) butyl]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(3-trifluoromethyl piperazine) propyl group]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-pyrimidylpiperazine) propyl group]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine; N-[4-(2-methoxyphenylpiperazderivatives) propyl group]-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine.
3. preparation method by the described long-Chain aromatic piperazine modified duloxetine-like compound of claim 1 is characterized in that comprising following process:
React in the presence of triethylamine in room temperature in methylene dichloride with the chloro acyl chlorides of 1 mole duloxetine and 1～1.3 mole and to generate acid amides in 1～10 hour; The aromatic piperazine generation alkylation of 1 mole acid amides and 1～1.5 mole generates the long-Chain aromatic piperazine acid amides, and reaction solvent is an acetonitrile; 1 mole long-Chain aromatic piperazine acid amides with 0.5～5 mole lithium aluminum hydride in tetrahydrofuran (THF) under refluxing reduction generate the long-Chain aromatic piperazine duloxetine-like compound.
4. the application of the described long-Chain aromatic piperazine modified duloxetine-like compound of claim 1 is characterized in that; This compound is that the form with its free alkali or salt is used to prepare antidepressant drugs, and salt is the inorganic salt of hydrochloride, hydrobromate or vitriol, perhaps is the organic salt of trifluoroacetate, oxalate, mesylate or maleate.
5. by the application of the described long-Chain aromatic piperazine modified duloxetine-like compound of claim 4, it is characterized in that; Salt is hydrochloride, hydrobromate, oxalate or maleate.
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