CN102993186B - A kind of novel bridged piperazine derivatives - Google Patents
A kind of novel bridged piperazine derivatives Download PDFInfo
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- CN102993186B CN102993186B CN201210557122.1A CN201210557122A CN102993186B CN 102993186 B CN102993186 B CN 102993186B CN 201210557122 A CN201210557122 A CN 201210557122A CN 102993186 B CN102993186 B CN 102993186B
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- butyl
- cumarone
- piperazinyl
- indyl
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- 0 CC*(NC1c2c1ccc(*C)c2**)=C Chemical compound CC*(NC1c2c1ccc(*C)c2**)=C 0.000 description 2
- DFBMHBJUWYOMEJ-FQEVSTJZSA-N C[C@@H]1C(N2CCN(CCCCc(c3c4)c[nH]c3ccc4C#N)CC2)=CC=C2OC(C=O)=CC2=C1 Chemical compound C[C@@H]1C(N2CCN(CCCCc(c3c4)c[nH]c3ccc4C#N)CC2)=CC=C2OC(C=O)=CC2=C1 DFBMHBJUWYOMEJ-FQEVSTJZSA-N 0.000 description 1
Abstract
Have a kind of novel bridged piperazine derivatives of structure shown in formula I, wherein R is the urea groups or thioureido that do not replace or be substituted with a substituent, substituting group is selected from (C
1-C
8) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
6) cycloalkyl, nitro, hydroxyl, methylol, phenyl or substituted-phenyl, also describe the method preparing this kind of bridged piperazine derivatives.The invention still further relates to the activity of this compounds centering pivot nervous system.
Description
Technical field
The present invention relates to the re-uptake for suppressing serotonin, strengthening the compound of serotonin activity in central nervous system and comprising the composition of these compounds.The present invention also relates to the re-uptake for suppressing serotonin, strengthening the application of the synthesis of the compound of serotonin activity in central nervous system and their disorderly aspects of pivot nervous system in the treatment.
Background technology
Serotonin (5-HT) is a kind of indole derivatives, is extensively present in mammalian tissues, especially cerebral cortex and nerve synapse intensive amount very high, it is also a kind of inhibitory neurotransmitter.In peripheral tissues, serotonin is a kind of strong vasoconstrictor and smooth muscle contraction stimulant.The concentration of serotonin in cerebral tissue is higher, is to regulate neururgic a kind of important substance.Some when injected organism tissue, when being subject to some drugs effect, can discharge serotonin.Serotonin, as neurotransmitter, is mainly distributed in pineal gland and hypothalamus, and central nervous system serotonin content and dysfunction may be relevant with the morbidity of the various diseases such as psychosis and migraine.Therefore, selective serotonin reuptake inhibitor, by the re-uptake of blocking 5-hydroxytryptamine, makes to increase for the serotonin of biological utilisation between nerve synapse gap, thus the disease for the treatment of central nervous system disorder aspect.
Piperazine compounds is a kind of 5-HT
1Aacceptor portion agonist, this excitomotor suppresses the re-uptake of hydroxy-tryptamine simultaneously, thus increases brain frontal cortex and veutro hypothalamus hydroxy-tryptamine level (TimoHeinrich etc., J.Med.Chem.47 (2004), 4684-4692).They can suppress the combination of tritiate serotonin ligand and hippocampal receptor, also can improve the DOPA in striatum gathering and in nuclei of median raphe the gathering (Bartoszyk etc. of 5-HTP, EuropeanJournalofPharmacology322 (1997), 147-153; Cossery etc., EuropeanJournalofPharmacology140 (1987), 143-155).They also have the effect of pain relieving and step-down, also can be used for the sequela that prevention and therapy cerebral infarction causes.
U.S. Patent No. 5002948 discloses the sedative effect of the following bridged piperazine derivatives of structural formula and this compounds centering pivot nervous system.
Wherein,
X is CH, CH
2, N (H) or C=O
R
1for hydrogen, halogen, low alkyl group, low-grade alkenyl, trifluoromethyl, (low alkyl group means 1-6 carbon atom, comprises straight chain or contains branched carbon atoms);
R
2for hydrogen, the low alkyl group that one or two oh group replaces or thiazolinyl (1-6 carbon atom, comprise straight chain or containing branched carbon atoms), any oh group be selected from comprise following carboxyl groups contain two fatty acid esters to 20 four carbon atoms.
Wherein, R
3and R
4be hydrogen, (the C atom of 1-20, comprises straight or branched carbon atom to alkyl, cycloalkyl (3-6 carbon atom), diamantane, aralkyl (containing 4-13 C atom);
Wherein Y is O or S;
Y is H, O, S or CH
2, Z is O, S or CH
2;
N is 1,2 or 3;
R
5hydrogen, low alkyl group or thiazolinyl (1-6 carbon atom comprises straight chain or contain branched carbon atoms);
U.S. Patent No. 5532241 discloses the effect, particularly 5-HT of the following piperidines of structural formula and bridged piperazine derivatives and this compounds centering pivot nervous system
1A-excited and 5-HT-re-uptake suppression, works as serotonin stimulant and antagonist.
Wherein,
Ind is not for replace or by OH, OA, CN, Hal, COR
2or CH
2r
2monosubstituted or polysubstituted indol-3-yl,
R
1for unsubstituted or by CN, CH
2oH, CH
2oA or COR
2mono-substituted cumarone-5-base or 2,3-Dihydrobenzofuranes-5-base, chroman-6-base, chromanone-6-base, 3-chromene-6-base or benzopyran-4-one-6-base,
Q is C
mh
2m,
Z is N or CR
3,
A is C
1-6alkyl,
Hal is F, Cl, Br or I,
R
2for OH, OA, NH
2, NHANA
2
R
3for H, OH or OA
M is 2,3 or 4.
Summary of the invention
The object of this invention is to provide a kind of bridged piperazine derivatives for suppressing serotonin reuptake transporter newly.
The present invention refers to have bridged piperazine derivatives and the pharmaceutically acceptable salt thereof of following logical formula I:
Wherein,
R is following formula group
Wherein,
R
1o or S
R
2hydrogen, (C
1-C
8) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
6) cycloalkyl, nitro, hydroxyl, methylol or phenyl, wherein phenyl can contain 1-3 substituting group, substituting group can in following groups unrestricted choice: halogen, trifluoromethyl, cyano group, hydroxyl, nitro, amino, carboxyl, (C
1-C
8) alkyl, (C
2-C
6) thiazolinyl or (C
1-C
8) alkoxyl group.
Again on the one hand, the compounds of this invention, as Pharmaceutical Compositions, comprises above-claimed cpd and other pharmaceutically acceptable carrier.
The compounds of this invention and pharmaceutically acceptable salt can as the activeconstituentss of antidepressant, anxiety, anti-neurosis, antipsychotic, headache, insomnia and cardiovascular, stomach and intestine nervous function imbalance agent, comprise to described patient to and the medication of above-claimed cpd of dose therapeutically effective.
The present invention relates to bridged piperazine derivatives and the pharmaceutically acceptable salt thereof of formula I,
Wherein,
R is following formula group
Wherein,
R
1o or S
R
2hydrogen, (C
1-C
8) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
6) cycloalkyl, nitro, hydroxyl, methylol or phenyl, wherein phenyl can contain 1-3 substituting group, substituting group can in following groups unrestricted choice: halogen, trifluoromethyl, cyano group, hydroxyl, nitro, amino, carboxyl, (C
1-C
8) alkyl, (C
2-C
6) thiazolinyl, (C
1-C
8) alkoxyl group.
R
2particularly hydrogen, (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl or phenyl.
R
2preferred hydrogen, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclohexyl or phenyl.
Reuptake inhibitor specific examples according to serotonin of the present invention includes but not limited to following compound:
(a) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl urea
(b) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-methyl) urea
(c) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-ethyl) urea
(d) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-propyl group) urea
(e) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-butyl) urea
(f) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-isobutyl-) urea
(g) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-the tertiary butyl) urea
(h) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-phenyl) urea
(i) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-cyclohexyl) urea
(j) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl thiocarbamide
(k) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-methyl) thiocarbamide
(l) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-phenyl) thiocarbamide
Compound of the present invention also can the form of pharmacy acceptable salt or hydrate exist.The form of pharmacy acceptable salt comprises pharmaceutically acceptable acidity/anion salt.The adoptable approach of pharmaceutically acceptable acidity/anion salt be allow basic nitrogen wherein by organic acid or mineral acid protonated, with acid, formula I alkali can be become corresponding acid salt.Can mineral acid be adopted, comprise: hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid; Also can adopt organic acid, comprise: formic acid, acetic acid, propionic acid, propanedioic acid, oxyacetic acid, lactic acid, lactobionic acid, oxysuccinic acid, succsinic acid, toxilic acid, tartrate, citric acid, amygdalic acid, nicotinic acid, γ-picolinic acid, methylsulfonic acid, ethyl sulfonic acid, M-nitro benzoic acid, hydroxyethylsulfonic acid, Phenylsulfonic acid, tosic acid, oxalic acid, cyclohexylamino sulfonic acid, Whitfield's ointment, butyric acid, hexanodioic acid, trifluoroacetic acid.
The invention still further relates to the method preparing formula I bridged piperazine derivatives and pharmacy acceptable salt thereof, it is characterized in that: by 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] coumarilic acid, i.e. formula II compound
With the urea do not replaced or be substituted or thiocarbamide, i.e. formula III compound reaction.
Wherein,
R
1o or S
R
2hydrogen, (C
1-C
8) alkyl, (C
2-C
6) thiazolinyl, (C
3-C
6) cycloalkyl, nitro, hydroxyl, methylol or phenyl, wherein phenyl can contain 1-3 substituting group, substituting group can in following groups unrestricted choice: halogen, trifluoromethyl, cyano group, hydroxyl, nitro, amino, carboxyl, (C
1-C
8) alkyl, (C2-C
6) thiazolinyl, (C
1-C
8) alkoxyl group.
React as shown in following scheme one, wherein, R
1, R
2as mentioned above.
Scheme one:
Formula II
Reaction is carried out under the following conditions:
In aprotic polar solvent, add formula II compound.Wherein, aprotic polar solvent can be selected from DMF, N-Methyl pyrrolidone, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO), HMPA, acetonitrile etc., and if necessary, the mixture formed between these solvents also can use.Under carboxylic acid activating agent's existent condition, add formula III reactant, wherein, the mol ratio of formula II compound and formula III reactant is 1:2 ~ 1:12.Carboxylic acid activating agent can be selected from N, N'-carbonyl dimidazoles (CDI) and salt, chloro-formic ester, DMAP (DMAP), SULPHURYL CHLORIDE, dicyclohexylcarbodiimide (DCC), DIC (DIC), 1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride (EDCI) and I-hydroxybenzotriazole (HOBT), temperature of reaction selects 0 ~ 60 DEG C, preferably 10 ~ 50 DEG C further.
The compounds of this invention can the form of salt or hydrate exist.Within the scope of the invention, use technique well known in the art, the compounds of this invention is converted into the form of the pharmacy acceptable salt that the acid of various organic or inorganic derives with alkali.
When the compounds of this invention possesses free alkali form, make the free alkali of compound and pharmaceutically acceptable inorganic or organic acid reaction, pharmaceutically acceptable acid salt can be prepared, example hydrochloric acid salt, hydrobromate, hydriodate, vitriol, nitrate, phosphoric acid salt; Formate, acetate, propionic salt, malonate, hydroxyl acetate, lactic acid salt, Lactobionate, malate, succinate, maleate, tartrate, Citrate trianion, mandelate, nicotinate, γ-picolinic acid salt, mesylate, esilate, benzoate, isethionate, benzene sulfonate, tosilate, oxalate, cyclohexylamino sulfonate, salicylate, butyrates, adipate, trifluoroacetate etc.
Formula II compound can be prepared by known open method, specifically can with reference to J.Med.Chem.2004, prepared by method described in 47,4684-4692 and US5532241.
The invention still further relates to formula I compound and pharmacy acceptable salt thereof to the application of useful in preparing drug formulations.The invention provides pharmaceutical composition, it comprises bridged piperazine derivatives according to the present invention as activeconstituents.
A. oral Preparation
Oral administered dosage form can be solid, gel or liquid preparation.Solid dosage includes but not limited to tablet, capsule and granule.Oral tablet can be surrounded by enteric coating, sugar-coat or film clothing.Capsule comprises hard capsule or soft capsule.Granule and pulvis can be non-effervesce or effervesce form.
Oral administered dosage form preferred tablet or capsule.The compound of one or more following ingredients can be contained alternatively: tackiness agent, thinner, disintegrating agent, lubricant, glidant, sweeting agent and correctives.
B. injection, solution and emulsion
By parenteral admin to giving the pharmaceutical composition of bridged piperazine derivatives of the present invention as activeconstituents.General is feature with injection, comprises intramuscular or intravenous administration.Injection can be made into any conventionally form, such as liquor, suspension or emulsion.
C. lyophilisate
Aseptic lyophilisate can be prepared like this, compound is dissolved in the buffered soln such as phosphoric acid salt, Citrate trianion, wherein containing glucose or other vehicle be applicable to.According to ordinary method well known by persons skilled in the art, solution is filtered, lyophilize.
The compounds of this invention and pharmaceutically acceptable salt may be used for the treatment of human body or animal body and suppress disease.They can be used for the disorder for the treatment of central nervous system, as anxiety, anxiety, depression, psychosis, headache, insomnia.They also can treat the side effect that hypertension causes.
Embodiment
Below the specific embodiment of the present invention is described in further detail.
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl urea (compound a)
5.14g5-[4-[4-(5-cyano-1 H-indol--3-base) butyl]-1-piperazinyl] cumarone-2-carboxylic acid is added (hereinafter referred to as formula II compound in reaction vessel, specifically can with reference to J.Med.Chem.2004,47,4690 and US5532241 described in method preparation) and 100mlN, dinethylformamide (DMF), the 4mlDMF solution containing 0.405gN, N'-carbonyl dimidazoles is added, stirring reaction 30 minutes under 20 ~ 25 DEG C of conditions under agitation condition.Be added drop-wise to by this solution in the 50mlDMF solution containing 6.0g urea, under 20 ~ 25 DEG C of conditions, stirring reaction 2 hours, adds 150ml water in reaction solution, continues stirring 30 minutes, by reacting liquid filtering, draws solid.With flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying crude product acquisition off-white color compound a (1.2g).
Ultimate analysis (%): C
27h
28n
6o
3
Calculated value: C66.93H5.82N17.34
Measured value: C66.68H5.60N17.46
1h-NMR(DMSO) δ 1.55 (m, 2H), 1.68 (m, 2H), 2.37 (m, 2H), 2.50 (s, 2H), 2.72 (m, 2H), 3.09 (s, 1H), 7.01 (m, 1H), 7.14 (m, 2H), 7.47 (m, 2H), 7.64 (m, 4H), 7.84 (m, 1H), 8.01 (m, 1H), 8.14 (m, 1H), 8.41 (d, 1H), 11.36 (br, 1H, heavy water exchanges and disappears), 11.95 (br, 1H, heavy water exchanges and disappears) ES-MSm/z485(MH
+)
In order to free alkali being become the form of hydrochloride, 46ml tetrahydrofuran (THF) is added in 1.2g compound a, reaction solution is heated to 50 DEG C, HCl gas is passed in reaction solution, continue stirring 30 minutes, by reacting liquid filtering, collect solid, solid tetrahydrofuran (THF) washs 2 times, obtains the faint yellow solid hydrochloride of 0.9g compound a.
Embodiment 2:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl urea (compound a)
In reaction vessel, add 20g formula II compound and 300mlN-methyl-2-pyrrolidone, under agitation condition, add the 15mlN-methylpyrrolidone solution containing 2.1g dicyclohexylcarbodiimide, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.Be added drop-wise to by this solution in the 250mlN-methylpyrrolidone solution containing 27g urea, under 25 ~ 30 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 500ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain off-white color compound, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition pale yellow oil (a).ES-MSm/z485（MH
+）
Embodiment 3:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl urea (compound a)
In reaction vessel, add 20g formula II compound and 300ml acetonitrile, under agitation condition, add the 15ml acetonitrile solution containing 2.1g dicyclohexylcarbodiimide, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.Be added drop-wise to by this solution in the 150ml acetonitrile solution containing 23.3g urea, under 25 ~ 30 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 400ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain off-white color compound, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition pale yellow oil (a).ES-MSm/z485（MH
+）
Embodiment 4:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl urea (compound a)
In reaction vessel, add 10g formula II compound and 160mlN, dinethylformamide, under agitation condition, add the 8mlN containing 0.78g DIC, dinethylformamide solution, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.This solution is added drop-wise to the 100mlN containing 11.6g urea, in dinethylformamide solution, stirring reaction 2 ~ 3 hours under 25 ~ 30 DEG C of conditions, in reaction solution, add 250ml water, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain off-white color compound, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition pale yellow oil (a).ES-MSm/z485（MH
+）
Embodiment 5:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-methyl) urea (compound b)
In reaction vessel, add 15g formula II compound and 250mlN-methyl-2-pyrrolidone, under agitation condition, add the 15mlN-methylpyrrolidone solution containing 1.5g dicyclohexylcarbodiimide, stirring reaction 30 minutes under 30 ~ 40 DEG C of conditions.Be added drop-wise to by this solution in the 140mlN-methylpyrrolidone solution containing 21.4g MU, under 30 ~ 40 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 400ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain off-white color compound, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition pale yellow oil (b).
ES-MSm/z499（MH
+）
Embodiment 6:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-ethyl) urea (compound c)
According to the same step described by embodiment 4, obtain compound as white solid c, 1.8g,
Ultimate analysis (%): C
29h
32n
6o
3
Calculated value: C67.95H6.29N16.39
Measured value: C67.72H6.43N16.42
1h-NMR(DMSO) δ 1.49 (m, 2H), 1.52 (m, 2H), 1.65 (m, 3H), 2.37 (m, 2H), 2.50 (s, 2H), 2.72 (m, 2H), 3.09 (s, 1H), 3.34 (m, 2H), 7.15 (m, 1H), 7.17 (m, 2H), 7.34 (m, 2H), 7.45 (m, 4H), 7.50 (m, 1H), 7.61 (m, 1H), 8.03 (m, 1H), 8.08 (d, 1H), 11.22 (br, 1H, heavy water exchanges and disappears), 11.38 (br, 1H, heavy water exchanges and disappears)
ES-MSm/z513（MH
+）
Embodiment 7:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-propyl group) urea (compound d)
In reaction vessel, add 10g formula II compound and 160mlN, N-N,N-DIMETHYLACETAMIDE, under agitation condition, add the 8mlN containing 0.78g DIC, N-dimethylacetamide solution, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.This solution is added drop-wise to the 100mlN containing 19.4g propyl group urea, in N-dimethylacetamide solution, stirring reaction 2 ~ 3 hours under 25 ~ 30 DEG C of conditions, in reaction solution, add 250ml water, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain faint yellow solid, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition off-white color solid 2.1g (d).
Ultimate analysis (%): C
30h
34n
6o
3
Calculated value: C68.42H6.51N15.96
Measured value: C68.16H6.57N15.62
1h-NMR(DMSO) δ 1.46 (m, 2H), 1.51 (m, 2H), 1.61 (m, 3H), 1.68(m, 2H), 2.41 (m, 2H), 2.53 (s, 2H), 2.69 (m, 2H), 2.99 (s, 1H), 3.34 (m, 2H), 7.11 (m, 1H), 7.18 (m, 2H), 7.30 (m, 2H), 7.45 (m, 4H), 7.49 (m, 1H), 7.60 (m, 1H), 8.01 (m, 1H), 8.05 (d, 1H), 11.26 (br, 1H, heavy water exchanges and disappears), 11.41 (br, 1H, heavy water exchanges and disappears)
ES-MSm/z527（MH
+）
Embodiment 8:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-butyl) urea (Verbindung)
According to the same step described by embodiment 7, obtain pale yellow oil e,
ES-MSm/z541（MH
+）
Embodiment 9:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-isobutyl-) urea (compound f)
In reaction vessel, add 10g formula II compound and 160mlN-methyl-2-pyrrolidone, under agitation condition, add the 8mlN-methylpyrrolidone solution containing 0.78g DIC, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.Be added drop-wise to by this solution in the 100mlN-methylpyrrolidone solution containing 36.3g isobutyl-urea, under 25 ~ 30 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 250ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain faint yellow solid, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition pale yellow oil.ES-MSm/z541（MH
+）
Embodiment 10:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-the tertiary butyl) urea (compound g)
According to the same step described by embodiment 5, obtain compound as white solid 2.5g.
Ultimate analysis (%): C
31h
36n
6o
3
Calculated value: C68.87H6.71N15.54
Measured value: C68.66H6.57N15.39
1h-NMR(DMSO) δ 1.43 (m, 9H), 1.52 (m, 2H), 1.61 (m, 2H), 2.25 (m, 2H), 2.43 (s, 2H), 2.62 (m, 2H), 3.00 (s, 1H), 3.29 (m, 2H), 7.11 (m, 1H), 7.13 (m, 2H), 7.32 (m, 2H), 7.41 (m, 4H), 7.44 (m, 1H), 7.57 (m, 1H), 8.02 (m, 1H), 8.06 (d, 1H), 11.15 (br, 1H, heavy water exchanges and disappears), 11.25 (br, 1H, heavy water exchanges and disappears)
ES-MSm/z541（MH
+）
Embodiment 11:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-phenyl) urea (compound h)
In reaction vessel, add 10g formula II compound and 100ml acetonitrile, under agitation condition, add the 10ml acetonitrile solution containing 0.79gN, N'-carbonyl dimidazoles, stirring reaction 30 minutes under 40 ~ 50 DEG C of conditions.Be added drop-wise to by this solution in the 100ml acetonitrile solution containing 26g phenylurea, under 40 ~ 50 DEG C of conditions, stirring reaction 2 hours, adds 200ml water in reaction solution, continues stirring 30 minutes, by reacting liquid filtering, draws solid.With flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying crude product acquisition off-white color compound h (2.0g).
Ultimate analysis (%): C
33h
32n
6o
3
Calculated value: C70.70H5.75N14.99
Measured value: C70.96H5.67N15.23
1h-NMR(DMSO) δ 1.52 (m, 2H), 1.61 (m, 2H), 2.23 (m, 2H), 2.46 (s, 2H), 2.74 (m, 2H), 3.02 (s, 1H), 7.01 (m, 1H), 7.14 (m, 2H), 7.25(m, 4H), 7.34(m, 1H), 7.41 (m, 2H), 7.69 (m, 4H), 7.83 (m, 1H), 8.01 (m, 1H), 8.12 (m, 1H), 8.28 (d, 1H), 11.11 (br, 1H, heavy water exchanges and disappears), 11.24 (br, 1H, heavy water exchanges and disappears)
ES-MSm/z561（MH
+）
Embodiment 12:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-cyclohexyl) urea (compound i)
According to the same step described by embodiment 5, obtain pale yellow oil i.
ES-MSm/z567（MH
+）
Embodiment 13:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl thiocarbamide (compound j)
In reaction vessel, add 5.14g formula II compound and 100ml dimethyl sulfoxide (DMSO), under agitation condition, add the 5ml dimethyl sulphoxide solution containing 0.405gN, N'-carbonyl dimidazoles, stirring reaction 30 minutes under 10 ~ 20 DEG C of conditions.Be added drop-wise to by this solution in the 50ml dimethyl sulphoxide solution containing 7.4g thiocarbamide, under 10 ~ 20 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 150ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain yellow compound, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition faint yellow solid 1.1g.
Ultimate analysis (%): C
27h
28n
6o
2s
Calculated value: C64.78H5.64N16.79
Measured value: C64.44H5.56N16.89
1h-NMR(DMSO) δ 1.51 (m, 2H), 1.63 (m, 2H), 2.41 (m, 2H), 2.52 (s, 2H), 2.68 (m, 2H), 3.01 (s, 1H), 7.00 (m, 1H), 7.12 (m, 2H), 7.42 (m, 2H), 7.60 (m, 4H), 7.83 (m, 1H), 7.99 (m, 1H), 8.09 (m, 1H), 8.36 (d, 1H), 11.11 (br, 1H, heavy water exchanges and disappears), 12.21 (br, 1H, heavy water exchanges and disappears)
ES-MSm/z501（MH
+）
Embodiment 14:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl thiocarbamide (compound j)
In reaction vessel, add 30g formula II compound and 500ml dimethyl sulfoxide (DMSO), under agitation condition, add the 25ml dimethyl sulphoxide solution containing 1.95g SULPHURYL CHLORIDE, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.Be added drop-wise to by this solution in the 270ml dimethyl sulphoxide solution containing 43g thiocarbamide, under 25 ~ 30 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 700ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain clear yellow viscous thing, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition pale yellow oil.
ES-MSm/z501（MH
+）
Embodiment 15:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl thiocarbamide (compound j)
In reaction vessel, add 25g formula II compound and 400ml acetonitrile, under agitation condition, add the 20ml acetonitrile solution containing 2.5g dicyclohexylcarbodiimide, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.Be added drop-wise to by this solution in the 200ml acetonitrile solution containing 34g thiocarbamide, under 25 ~ 30 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 600ml water in reaction solution, continues stirring 30 ~ 40 minutes, by reacting liquid filtering, obtains dope, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition oily matter.
ES-MSm/z501（MH
+）
Embodiment 16:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-methyl) thiocarbamide (compound k)
In reaction vessel, add 5.14g formula II compound and 100ml dimethyl sulfoxide (DMSO), under agitation condition, add the 5ml dimethyl sulphoxide solution containing 0.405gN, N'-carbonyl dimidazoles, stirring reaction 30 minutes under 25 ~ 30 DEG C of conditions.Be added drop-wise to by this solution in the 50ml dimethyl sulphoxide solution containing 8.8g methylthiourea, under 25 ~ 30 DEG C of conditions, stirring reaction 2 ~ 3 hours, adds 150ml water in reaction solution, continue stirring 30 ~ 40 minutes, by reacting liquid filtering, obtain yellow compound, with flash chromatography on silica gel (CH
2cl
2/ MeOH, 20:1) purifying acquisition faint yellow solid 0.7g.
Ultimate analysis (%): C
28h
30n
6o
2s
Calculated value: C65.35H5.88N16.33
Measured value: C65.10H6.12N16.54
1h-NMR(DMSO) δ 1.46 (m, 2H), 1.59 (m, 2H), 2.36 (m, 2H), 2.48 (s, 2H), 2.64 (m, 2H), 2.98(m, 3H), 3.07 (s, 1H), 7.12 (m, 1H), 7.14 (m, 2H), 7.41 (m, 2H), 7.56 (m, 4H), 7.79 (m, 1H), 7.95 (m, 1H), 8.03 (m, 1H), 8.32 (d, 1H), 11.31 (br, 1H, heavy water exchanges and disappears), 11.66 (br, 1H, heavy water exchanges and disappears)
ES-MSm/z515（MH
+）
Embodiment 17:5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N
2-phenyl) thiocarbamide (compound l)
According to the same step described by embodiment 14, obtain pale yellow oil l.
ES-MSm/z577（MH
+）
Embodiment 18 to 24
By the method for embodiment 1, synthesis following compounds, sees the following form
Embodiment 25: tablet
Clearly specific as an oral medicine, by the mixture conventionally tabletted that the compound in 1kg embodiment 1,6kg N.F,USP MANNITOL, 4kg starch, pre-paying of 3kg starch, 0.1kg talcum powder and 0.1kg Magnesium Stearate form, make the tablet of every sheet containing 10mg activeconstituents.
Embodiment 26: capsule
Conventionally, in being incapsulated containing formula I activeconstituents by 1kg, make each capsule containing 20mg activeconstituents.
Experimental example 27: parachlorophenylalamine (PCA) 5-HT exhausts model
Male and female 50 Wistar rats, are divided into 5 groups at random by body weight, often organize male and female half and half, per os gives 8,6,4,2, the compounds of this invention of 1mg/kg, give PCA after 180min, after 30min, rat is put to death, detect the content of 5-HT in hypothalamus by HPLC-ECD method.
Result: the compound of formula I representative of the present invention can suppress the exhaustion of PCA inducing hypothalamic effects 5-HT effectively.Such as, the compound of embodiment 1,5,6,7,9,10,11,12,13,16,17 and 18 demonstrates the effect suppressing 5-HT reuptake.
Experimental example 28: forced swimming test
The ICR male mice of body weight 20 ~ 24g 60, before experiment, 24h carries out the swimming instruction of 15min at experiment pondlet, and the depth of water is 10cm.Animal is divided into 6 groups at random by body weight, often organizes 10.
Test first 2 hours per os give respectively 3 groups of mouse the compounds of this invention 10,30,60mg/kg, 1 group gives vilazodone 10mg/kg, and 1 group of test first 0.5 hour per os gives imipramine 10mg/kg, and 1 group gives physiological saline 0.1ml/10g.Dead time in observed and recorded 5 minutes.
The results are shown in following table:
Each group of medication is on the impact (n=10, mean+SD, second) of forced swim test dead time
Compare with physiological saline group, * P<0.05, * * P<0.01, the method for inspection is studentt inspection
Compared with physiological saline, each dosage of the compounds of this invention significantly shortens the dead time of animal in water (P<0.05 or 0.01).Action effect is suitable with vilazodone.
Experimental example 29: outstanding tail test
The C57BL/6 male mice of body weight 20 ~ 24g 60, is divided into 6 groups at random by body weight, often organizes 10.The compounds of this invention 3 groups, each group dosage is respectively 10,30,60mg/kg, vilazodone 1 group of dosage is 60mg/kg, and imipramine 1 group of dosage is 60mg/kg, and 1 group, physiological saline gives 0.1ml/10g physiological saline.
Respectively at 24h, 5h and 1h administration before test totally three times, observed and recorded hanged the tail dead time in 5 minutes.
The results are shown in following table:
The impact (n=10, mean+SD, second) of tail dead time is hanged in each group of medication on animal
Compare with physiological saline group, * P<0.05, * * P<0.01, the method for inspection is studentt inspection
Compared with physiological saline, each dosage of the compounds of this invention significantly shortens animal and hangs the tail dead time (P<0.05 or 0.01).Action effect is suitable with vilazodone.
Experimental example 30: Xi Zezong is tested
Male Wistar rat (180 ~ 200g) 60, is divided into 6 groups at random by body weight, often organizes 10.The compounds of this invention 2 groups, each group of dosage is respectively 60,100mg/kg, and vilazodone 1 group of dosage is 100mg/kg, and imipramine 1 group of dosage is 100mg/kg, model group 1 group gives 0.1ml/10g physiological saline, and normal group 1 group gives 0.1ml/10g physiological saline.
Rat is shuttled back and forth the rat shuttle box tester that the real-time testing and analysis system of computer picture adopts computer program to control, shuttle box is made up of the experimental box that 2 volumes are consistent, the dividing plate of each experimental box centre band door opening is divided into 2 equal cells, be respectively 20cm × 6.5cm × 20cm, there is 1 wicket (7cm × 7cm) centre.Top is equipped with 1 8W tengsten lamp.Each case is all connected with computer by primary controller, and be stainless (steel) wire grid bottom case, the distance between grid is 1cm, is connected with electric shock device.
Rat has been divided into " helpless " group and control group, and has been separately placed one and has in the shuttle box of two compartments (centre is provided with passage)." helpless " group is subject to a series of foot shock that cannot avoid in shuttle box, and control group is then shocked by electricity.Two days later, these rats have been taken back to again in shuttle box, and receive conditionality escape training for three days on end.
Xi Zezong depression model inductive phase: during experiment in the 1st day, rat is put into electric shock Induction experiments case, 1, every case, give two rooms foot shock of 60 no signal inevitabilities continuously, adopt the voltage of 40V, each electric shock continues 15s, and (time variable control is 45,60 in intermittent phase half randomization, 75s), every rat trains 1 time.Normal group animal puts into the experimental box same time (1h), but does not give foot shock.Experiment in 2nd day roughly the same.
The conditioned avoidance response learning period: (after electric shock induction 48h) carried out conditioned avoidance response training, every day 1 time in the 3rd day.During training, rat is put into shuttle box, 1, every case, after adapting to 5min, carry out 30 cycles of operation continuously.The time of each cycle of operation is 30s, is followed successively by 3s conditioned stimulus (light) phase, 3s condition+unconditioned stimulus (electric shock 35V) phase and 24s intermittent phase (not giving any stimulation).When rat is when the opposite side only having the conditioned stimulus phase of light to shuttle back and forth to case is to exempt from electric shock, be designated as avoiding reaction; When the opposite side shuttled back and forth when rat has light at the same time and electric shock stimulates to case is to hide electric shock, be then designated as fugue reaction.Experimental arrangement, by computer control, is avoided number of times and is escaped number of times by the automatic record of computer.4th, within 5 days, experimental technique is the same with 3d, but need not carry out shuttle box adaptation.Observation index is for escaping the frequency of failure=30-(avoiding number of times+escape number of times).
In 5 days after training terminates, give each group of rat relative medicine every day, record calculates escapes the frequency of failure, and carries out statistical study to the 4th, the 5 day escape frequency of failure.
The results are shown in following table:
Each group of medication is on the impact (n=10, mean+SD, secondary) escaping the frequency of failure
Compare with model group, * P<0.05, * * P<0.01, compares with normal group, and the #P<0.01 method of inspection is studentt inspection
Compared with model group, each dosage of the compounds of this invention significantly reduces escapes the frequency of failure (P<0.05 or 0.01).Action effect is suitable with vilazodone.
Claims (5)
1. the bridged piperazine derivatives represented by logical formula I and pharmacy acceptable salt thereof
Wherein,
R is following formula group
Wherein,
R
1o or S
R
2hydrogen, C
1-C
6alkyl, C
3-C
6cycloalkyl or phenyl.
2. compound according to claim 1, is characterized in that described R
2be selected from following group: hydrogen, C
1-C
6alkyl, cyclohexyl or phenyl.
3. compound according to claim 1, is characterized in that this compound is selected from:
(a) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl urea
(b) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-methyl) urea
(c) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-ethyl) urea
(d) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-propyl group) urea
(e) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-butyl) urea
(f) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-isobutyl-) urea
(g) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(the N-tertiary butyl) urea
(h) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-phenyl) urea
(i) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-cyclohexyl) urea
(j) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl thiocarbamide
(k) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-methyl) thiocarbamide
(l) 5-[4-[4-(5-cyano group-3-indyl)-butyl]-1-piperazinyl] cumarone-2-formyl-(N-phenyl) thiocarbamide.
4. a pharmaceutical composition, is characterized in that comprising the compound of claim 1 and pharmaceutically acceptable carrier.
5. the application in the medicine of the compound in claim 1-4 described in any one and pharmacy acceptable salt class disease in preparation treatment central nervous system disorder thereof.
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| US5002948A (en) * | 1988-12-28 | 1991-03-26 | H. Lundbeck A/S | 3-[4-[4-substituted-1-piperazinyl]-1-butyl]-1H-2,3-dihydroindoles |
| US5532241A (en) * | 1993-09-30 | 1996-07-02 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Piperidines and piperazines |
| CN1805954A (en) * | 2003-06-16 | 2006-07-19 | 默克专利股份有限公司 | Indole derivatives as serotonin reuptake inhibitors |
| CN101990535A (en) * | 2008-04-18 | 2011-03-23 | 默克专利有限公司 | Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators |
| CN102482264A (en) * | 2009-06-30 | 2012-05-30 | 阿斯利康(瑞典)有限公司 | 2-carboxamide-7-piperazinyl-benzofuran derivatives 774 |
-
2012
- 2012-12-20 CN CN201210557122.1A patent/CN102993186B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5002948A (en) * | 1988-12-28 | 1991-03-26 | H. Lundbeck A/S | 3-[4-[4-substituted-1-piperazinyl]-1-butyl]-1H-2,3-dihydroindoles |
| US5532241A (en) * | 1993-09-30 | 1996-07-02 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Piperidines and piperazines |
| CN1805954A (en) * | 2003-06-16 | 2006-07-19 | 默克专利股份有限公司 | Indole derivatives as serotonin reuptake inhibitors |
| CN101990535A (en) * | 2008-04-18 | 2011-03-23 | 默克专利有限公司 | Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators |
| CN102482264A (en) * | 2009-06-30 | 2012-05-30 | 阿斯利康(瑞典)有限公司 | 2-carboxamide-7-piperazinyl-benzofuran derivatives 774 |
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Effective date of registration: 20160322 Address after: 100176, Beijing economic and Technological Development Zone, Hongda North Road, No. 12, block B, zone 1, 410 Patentee after: Beijing Hi Tech Co., Ltd. Address before: 100176, Beijing, Beijing economic and Technological Development Zone, Hongda North Road, No. 12, innovation building, block B, zone 1, 306, Daxing District Patentee before: BEIJING HOPE PHARMACEUTICAL CO., LTD. |