CN1345724A - Indolylpiperidine compound and preparation process and use thereof - Google Patents
Indolylpiperidine compound and preparation process and use thereof Download PDFInfo
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- CN1345724A CN1345724A CN 00125487 CN00125487A CN1345724A CN 1345724 A CN1345724 A CN 1345724A CN 00125487 CN00125487 CN 00125487 CN 00125487 A CN00125487 A CN 00125487A CN 1345724 A CN1345724 A CN 1345724A
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Abstract
The present invention provides a kind of indoxyl piperidine compound. The pharmacological tests show that said kind of compound can be used as inhibitor of acetylcholin esterase, can competitively inhibit the activity of acetylcholin esterase, can delay hydrolysis of acetylcholin so as to raise the action of acetylcholin in synapsis and attain the goal of curing presenile dementia.
Description
The present invention relates to the synthetic and purposes of Indolylpiperidine analog derivative.
Presenile dementia (Alzheimer ' s disease) be that a kind of multi-pathogenesis participates in gradual cerebral functional deterioration disease, its cause of disease does not have conclusive illustrating so far yet.But it is a kind of common geriatric disease, the health that is seriously threatening the elderly, and during aging, this situation is all the more severe, thereby causes people's common concern gradually in especially current society.
At present presenile dementia is carried out drug research and mainly contains the following aspects:
1, acetylcholinesterase depressant (ChEI), it is the activity of acetylcholine esterase inhibition competitively, slows down the hydrolysis of vagusstoff, thereby strengthens the purpose that be used for reach treatment presenile dementia of vagusstoff in cynapse.
2, from the vagusstoff precursor, as considerations such as vagusstoff phosphoric acid ester, purpose is to supply with by the biosynthesizing that improves vagusstoff in the body;
3, consider from the vagusstoff releasing agent,, thereby increase the generation of vagusstoff because the vagusstoff releasing agent is used for the presynaptic.
4, consider M1 receptor stimulant, simulation vagusstoff and act on postsynaptic acceptor from receptor stimulant.
5, M2 and M4 receptor stimulant act on the presynaptic, regulate the release of vagusstoff by reverse feedback.
6, nicotine compound also can increase the release of vagusstoff.
Treatment to presenile dementia mainly is according to acetylcholinesterase depressant (AChEI) at present, with what the clinical drug of this mechanism of action was used tacrine (Tacrine) donepezil etc. arranged, still there are tens kinds of medicines to be in preclinical research or doing clinical study, from present researching and analysing, the structure of these inhibitor has nothing in common with each other, not tangible structure activity relationship, and close compound with the present invention has following patent WO 9312085, WO 9307140, and EP 562832.
Though scientist has made big quantity research and has obtained bigger progress the presenile dementia disease, the appearance of example tacrine and donepezil medicine, but they still have different defectives, tacrine is bigger to hepatotoxicity, and donepezil the biological agent availability is poor in vivo, therefore the presenile dementia disease is required further study and seek out a class novel cpd, the Development of New Generation toxic side effect is low, the medicine that curative effect is high.
The present invention seeks to seek a class and have the inhibiting Indolylpiperidine compounds of acetylcholinesterase highly selective, it can be used for treating in the presenile dementia disease medicament uses.
Indolylpiperidine compound has following general structure:
R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl;
R
2Be H, C
1-C
4Alkyl C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl;
X is C=O, C=N-ORb, S=O, So
2Deng, wherein Rb is H, C
1-C
4Alkyl
Y is N-Ra, O, CH
2Deng, wherein Ra is H, C
1-C
4Alkyl, aryl, benzyl, C
1-C
4Alkyloyl, aroyl etc., m=1-2, n=0-4.
Above-mentioned general structure can make by following steps:
Top reaction formula when Y=NRa or O, prepares the reaction formula of Compound I for to work as X=CO
Top reaction formula is to be used for preparing in the Compound I as X=CO, Y=NRa or O.Wherein X is connected 2 or 3 of indole ring, is connected 2 usually.Wherein initiator II available or according to document (Ulf.Pinder, methods such as J.Heterocyclic Chem 25,1 (1988) make.IV or reference literature method make (Aloke k.D.et al.J.Med.Chem.1996,39 (3), 794; HachiroSugimoto, et.al.J.Med.Chem.1990,33,1880-1887).
Shown in reaction formula, Compound I I and chlorination reagent in inert solvent, react acyl chlorides III.Reaction is usually at tetrahydrofuran (THF) (THF), ether (Et
2O), methylene dichloride (CH
2Cl
2), chloroform (CHCl
3), benzene, toluene, N, carry out in N-diformamide (DMF) equal solvent, used chlorination reagent has thionyl chloride (SOCl
2), oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride etc.Reaction can be carried out between-20～40 ℃, at room temperature reacts usually 2～24 hours.The acyl chlorides of gained obtains target product Ia with the IV reaction in the presence of alkali in inert solvent.The solvent that is suitable for is the same.Used alkali has organic bases such as pyridine, triethylamine, 4-dimethylamino pyridine (DMAP), diisopropylethylamine etc., mineral alkali such as yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide etc.Reaction is carried out between-40～40 ℃ usually.The product of gained can get pure products through purifications such as appropriate means such as column chromatography, recrystallizations.
Top reaction formula during Y=C, prepares the reaction formula of Compound I for to work as X=CO
Be one and be used for preparing the process when X=CO, Y=C in the Compound I.Wherein X is connected 2 or 3 of indole ring.Used raw material V is available or make with reference to following literature method that (Gordon w.g.Tetrahedron 44,3195 (1988); Kuldip s.b.et al.Can.J.Chem.49,2354 (1971); D.M.Ketcha et.al.J.Org.Chem.50,5451 (1985).
Shown in reaction formula, the condensation in the presence of alkali of compound V and compound VI obtains compounds ib.Reaction in inert solvent, is carried out under-78～0 ℃ usually.Used solvent has THF, Et
2O, DMF, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane etc.Used alkali has butyllithium, phenyl lithium, diisopropylamine lithium, potassium tert.-butoxide, sodium tert-butoxide etc.The compound shown in Ib of gained gets Ic by catalytic reduction, and catalyzer carries out under normal pressure with Pd/C, Pt/C, Raney nickel etc. usually.Used solvent has ethanol, methyl alcohol, ethyl acetate, tetrahydrofuran (THF) etc., and temperature of reaction can at room temperature be carried out between 0～60 ℃ usually.Product Ic in protic solvent under the catalysis of acid or in organic bases with NH
2OR
bReaction can get Id.The available protic solvent has the mixed solvent of methyl alcohol, ethanol, acetate, water and ethanol or methyl alcohol and water etc.The available organic bases has pyridine, triethylamine etc., generally carries out in pyridine.Temperature of reaction can be controlled in 20～100 ℃, is preferably between 60～70 ℃ to carry out.Above all available appropriate means of Ib～d such as purifications such as column chromatography, recrystallization can get pure products.
Top reaction formula is worked as X=SO
2During Y=NRa, the reaction formula of preparation Compound I is to be used for preparing working as X=SO in the Compound I
2, the process during Y=NRa, wherein X is connected 2 or 3 of indole ring.And compound VIII is worked as SO
2But reference literature European patent EP 70698 made when Cl was connected in 2.
Shown in reaction formula, work as SO
2When Cl was connected 3 of indole rings, can be obtained by following approach: compound VI I carried out sulfonylation promptly with chlorsulfonic acid.Reaction usually can be solvent-free or carry out under inert solvent, and used inert solvent has methylene dichloride, chloroform, ether, tetrahydrofuran (THF) etc., and temperature of reaction is carried out under-10 ℃ in-78～10 ℃ of scopes usually.SULPHURYL CHLORIDE VIII and compound IV can produce Ie in the presence of alkali.Be reflected in the inert solvent and carry out, the solvent that is suitable for has methylene dichloride, chloroform, tetrahydrofuran (THF), ether, DMF, benzene, toluene, ethyl acetate etc., and used alkali has triethylamine, pyridine, DMAP, salt of wormwood, yellow soda ash etc.Be reflected in-40～40 ℃ of scopes and carry out, carry out at 0 ℃ usually.The product Ie of gained hydrolysis under the effect of alkali gets If.Reaction is carried out in protic solvent usually, and used solvent has ethanol, methyl alcohol, propyl carbinol, water etc., is preferably in the mixed solvents such as second alcohol and water or first alcohol and water to carry out.Used alkali has salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide etc., and reaction is carried out between 0～100 ℃ usually, generally gets final product in room temperature.The product If of gained can get product Ig with effects such as halohydrocarbon, sulphonate, acyl chlorides in inert solvent in the presence of alkali.Here used halohydrocarbon has methyl iodide, monobromethane, benzyl chlorine, benzyl bromine, chloromethylpyridine etc., used sulphonate has methyl-sulfate, ethyl sulfate, p-methyl benzenesulfonic acid ester etc., and used acyl chlorides has p-methyl benzene sulfonic chloride, benzene sulfonyl chloride, Benzoyl chloride etc.Used alkali has sodium hydrogen, amido sodium, potassium hydroxide, sodium hydroxide, potassium tert.-butoxide, sodium tert-butoxide etc.; Used solvent has DMF, THF, Et
2O etc.Reaction is carried out between-30～40 ℃ usually, generally carries out under 0 ℃.All available appropriate means of the compound of above gained such as purifications such as column chromatography, recrystallization can get pure products.
The cholinesterase activity measuring method:
Acetylcholinesterase enzyme source adopts rat layer 5% homogenate (to use 75mmol, pH7.4,4 ℃ of phosphoric acid buffers are made the homogenate medium), by the selective depressant tetra isopropyl pyrophosphoramide (iso-OMPA) that adds the 4mmol butyrylcholine esterase at 10: 1,37 ℃ are incubated 5 minutes before the experiment.Butyrylcholine esterase enzyme source is a rat blood serum.With colorimetric method for determining ChE vigor.The reaction total volume is 4ml, include acetylthiocholine iodide 0.3mmol or sulfur iodide for BuCh 0.4mmol, 0.1MpH7.4 sodium phosphate buffer 1ml, compound 0.1-0.5ml, adding water mends to 4ml (comprising the enzyme-added liquid measure in back), add enzyme liquid 0.1 or 0.2ml after 5 minutes in 37 ℃ of insulations, add 1ml 3% sodium laurylsulfonate (SDS) termination reaction after being incubated 8 minutes again, add the colour developing of 1ml 0.2% 2 (3-carboxyl-4-nitro) phenyl disulphide (being Ellman ' s reagent) solution at last, produce yellow 5-sulphur-2-nitrophenoxy acid negatively charged ion.Measure optical density(OD) with 752 type spectrophotometers in 440nm, all samples is all surveyed two-tube.As 100%, compound determination pipe optical density(OD) compares with it with the mensuration pipe optical density(OD) that do not add compound, and the percentage of reduction is enzyme inhibition rate.Each compound all is made into 10
-5Mol/L concentration is carried out primary dcreening operation, and enzyme inhibition rate reaches 50% above person and carries out IC
50Mensuration.Select seven to nine its enzyme inhibition rates of concentration determination of compound according to the primary dcreening operation result, and carry out linear recurrence, try to achieve the IC that 50% volumetric molar concentration when suppressing is this compound with the negative logarithm and the enzyme inhibition rate of this compound volumetric molar concentration
50Value.The active the results list of the part of compounds of gained is as follows:
Table 1
| ??????IC50(μmol) | |||||
| Comp. | ?R1 | ?R2 | ?X-Y(CH m) n- | ?AchE | ??BuchE |
| ?1 | ?H | ?H | ?2-CONHCH 2 | ?11.5 | |
| ?2 | ?H | ?H | ?2-CONHCH 2CH 2 | ?4.4 | |
| ?3 | ?Me | ?H | ?2-CON(Me)CH 2 | ||
| ?4 | ?Me | ?H | ?2-CON(Me)CH 2CH 2 | ?5.19 | |
| ?5 | ?Me | ?OMe | ?2-COCH＝CH | ?0.014 | ?＞32 |
| ?6 | ?Me | ?OMe | ?2-COCH 2CH 2 | ?0.064 | ?9.2 |
| ?7 | ?Me | ?H | ?2-COCH＝CH | ?0.042 | ?＞210 |
| ?8 | ?Me | ?H | ?2-COCH 2CH 2 | ?0.154 | ?25.6 |
| ?9 | ?Bs | ?H | ?3-COCH＝CH | ?1.7 | |
| ?10 | ?Bs | ?H | ?3-COCH 2CH 2 | ?0.9 | ?592 |
| ?11 | ?Bs | ?OMe | ?2-COCH＝CH | ?0.175 | ?57.6 |
| ?12 | ?Bs | ?OMe | ?2-COCH 2CH 2 | ?0.364 | ?394 |
| ?13 | ?Bs | ?H | ?2-COCH 2CH 2 | ?5.4 | |
| ?14 | ?Bs | ?H | ?3-SO 2NHCH 2 | ?1.3 | |
| ?15 | ?Bs | ?H | ?3-SO 2N(Me)CH 2 | ?0.6 | |
| ?16 | ?Bs | ?H | ?3-SO 2NHCH 2CH 2 | ?63.5 | |
| ?17 | ?Bs | ?H | ?3-SO 2N(Me)CH 2CH 2 | ?1.75 | |
| ?18 | ?H | ?H | ?3-SO 2NHCH 2 | ?3.2 | |
| ?19 | ?Me | ?H | ?3-SO 2N(Me)CH 2 | ?0.78 | |
| Selagine | ?0.114 | ?135 | |||
| Tacrine | ?0.223 | ?92 | |||
As shown in table 1, these compounds all have stronger activity, in addition, a little less than their effects very to BuChE, thereby very high selectivity are arranged.
Embodiment: example 1: indoles-2-formyl (1-benzyl-4-piperidyl) methylamine
0.3g the 2-indolecarboxylic acid is suspended in the 6ml exsiccant chloroform, with the ice-water bath cooling, adds the thionyl chloride that 0.5ml newly handled, and allows it heat up naturally, stirring is spent the night.Pressure reducing and steaming solvent (controlled temperature T＜35 ℃).Add 10ml exsiccant methylene dichloride, evaporate to dryness.So repeat to handle again 2 times, obtain faint yellow solid, be dissolved in the 10ml methylene dichloride, with the ice-water bath cooling, be added dropwise to the 270mgl-benzyl-solution of 4-piperidines methylamine in the 5ml methylene dichloride, add the 0.3ml triethylamine after adding again, 0 ℃ is stirred 30min, reaction solution is washed secondary with 20ml, washes once organic layer Anhydrous potassium carbonate drying again with the saturated sodium carbonate solution of 15ml.Boil off solvent, residuum cross post (with 200～300 purpose silica gel, pure ethyl acetate drip washing) solid, recrystallization from ethyl acetate again, colourless needle 0.35g, MP=199～200 ℃
1H?NMR(CDCl3，AM＝400)：1.30-1.42(2H，m)，1.58-1.78(3H，m)，1.90-
2.00(2H，t-d)，2.90(2H，d)，3.38(2H，t)，3.50(2H，s)，6.26(1H，br)，
6.80 (1H, d), (9H, m), 9.40 (1H, br) example 2: indoles-2-formyl (1-benzyl-4-piperidyl) ethamine for 7.10-7.62
Operating process such as example 1 just replace 1-benzyl-4-piperidines methylamine with 1-benzyl-4-piperidyl ethamine.Obtain the needle-like needle, MP=168～169 ℃
1H?NMR(CDCl3，AM＝400)：1.26～1.42(3H，m)，1.50～1.80(4H，m)，
1.90～2.00(2H，m)，2.96(2H，m)，3.48～3.58(4H，m)，6.12(1H，br)，
6.70～7.66 (10H, m), 9.52 (1H, S) routine 3:1-skatole-2-formyl (1-benzyl-4-piperidyl) methylamines
Operating process such as example 1 just replace indole-2-carboxylic acid with 1-skatole-2-formic acid.Obtain needle, MP=141～2 ℃
1H?NMR(CDCl3，AM＝400)：1.30～1.42(2H，q-d)，1.60(1H，m)，1.68～1.76(2H，
d)，1.90～2.00(2H，t-d)，2.90(2H，d)，3.32(2H，t)，3.50(2H，s)，4.02(3H，s)，
6.22 (1H, br), 6.78 (1H, s), 7.08～7.60 (9H, m) routine 4:1-skatole-2-formyl (1-benzyl-4-piperidyl) ethamine
Operating process such as example 1 just replace indole-2-carboxylic acid with 1-skatole-2-formic acid, replace 1-benzyl-4-piperidines methylamine with 1-benzyl-4-piperidyl ethamine.Obtain needle, MP=134～135 ℃
1H?NMR(CDCl3，AM＝400)：1.24～1.40(3H，m)，1.50～1.60(2H，q)，
1.66～1.76(2H，m)，1.90～2.00(2H，t)，2.82～2.92(2H，d)，3.40～3.50(4H，m)，
4.02 (3H, s), 6.12 (1H, br), 6.78 (1H, s), 7.08～7.62 (9H, m) routine 5:1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles
5-a:1-benzyl-4-methoxy methyne piperidines
50g chlorination methoxyl methyl triphenylphosphine is suspended in the 600ml exsiccant anhydrous diethyl ether, ice-water-bath cooling, keep temperature T=0～5 ℃, the 19g potassium tert.-butoxide adds in three batches, add the back and stir 2.5hr at 0～5 ℃, be cooled to-5 ℃ then, 23g 1-benzyl-4-piperidone is dissolved in the 100ml ether, drips.Stir 2hr at 0 ℃ after adding, filter, the filtrate decompression evaporate to dryness gets oily matter, and this oily matter is crossed post with silica gel, with ethyl acetate-sherwood oil (1: 4) drip washing, gets pure oily product 20g.
1H?NMR(CDCl3，AM＝400)：2.10～2.20(2H，br)，2.30～2.50(2H，br)，
2.48～2.68(3H，br)，3.52(3H，s)，3.68(2H，s)，5.78(1H，s)，7.24～7.40(5H，m)
5-b:1-benzyl-4-piperidines formaldehyde
1-benzyl-4-methoxy methyne piperidinyl-1 the 8g that is made by 5-a is dissolved in the hydrochloric acid of 120ml 1N, refluxed under nitrogen 3 hours, and cooling, transfer to PH=8 with yellow soda ash, use ethyl acetate (100ml * 3) extraction then, with the saturated sodium chloride solution washing of 100ml, anhydrous magnesium sulfate drying.The pressure reducing and steaming solvent, remaining oily matter is purified with silicagel column, with ethyl acetate-sherwood oil (1: 4) drip washing, oily product 5-b 16.2g, place the freezing solid that is condensed into of refrigerator, MP=35～37 ℃.
1H?NMR(CDCl3，AM＝400)：1.64～1.80(2H，m)，1.84～2.00(2H，m)，
2.08～2.34(3H，m)，3.54(2H，s)，7.28～7.40(5H，m)，9.62(1H，br)
5-c:1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles
0.4ml Diisopropylamine is dissolved in the tetrahydrofuran (THF) of 20ml anhydrous and oxygen-free; be cooled to 0 ℃; the butyllithium cyclohexane solution that adds 1.3ml 2M; stir 20min, be chilled to-78 ℃, add the solution of 0.48g 1-methyl-2-ethanoyl-6-methoxyl group indoles at the 5ml anhydrous tetrahydro furan; controlled temperature is no more than-65 ℃; added the back restir 1 hour, 0.5g 1-benzyl-4-piperidines formaldehyde (being made by 5-b) is dissolved in and is added dropwise to above-mentioned reaction solution in the 5ml tetrahydrofuran (THF), adds the back and rises to ambient temperature overnight naturally.Then reaction solution is poured in the ammonium chloride solution of 50ml 10%,, merged organic layer, with the saturated sodium chloride solution washing of 100ml, anhydrous sodium sulfate drying with ethyl acetate extraction (50ml * 4).Purify with silicagel column, ethyl acetate-sherwood oil (1: 4) drip washing obtains 600mg 5-c, MP=119～120 ℃
1H?NMR(CDCl3，AM＝400)：1.56～1.90(4H，m)，2.04～2.36(3H，m)，
2.96～3.06(2H，m)，3.60(2H，s)，3.92(3H，s)，4.08(3H，s)，6.70-7.02(4H，m)，
7.20-7.40 (6H, m), 7.58 (1H, s) routine 6:1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) propionyl] indoles
270mg1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles (with reference to 5-c) is dissolved in the 10ml ethyl acetate, adds the Pd/C of 30mg 10%, under normal pressure, spend the night with hydrogen reducing.Filter then, boil off solvent, residue is purified with silicagel column, and ethyl acetate-sherwood oil (1: 1) drip washing obtains solid 240mg, MP=74～75 ℃
1H?NMR(CDCl3，AM＝400)：1.66～1.78(4H，m)，1.98～2.10(2H，m)，
2..90(2H，t)，2.90～3.02(2H，m)，3.60(2H，s)，3.88(3H，s)，4.043H，s)，
6.20 (1H, s), 6.30 (1H, d-d), 7.20～7.36 (6H, m), 7.52 (1H, d) routine 7:1-methyl-2-[3-(1-benzyl-4-piperidyl) acryl] indoles
Operating process such as routine 5-c just replace 1-methyl-2-ethanoyl-6-methoxyl group indoles with 1-methyl-2-ethanoyl indoles, obtain solid product, MP=96～97 ℃
1H?NMR(CDCl3，AM＝400)：1.56～1.64(2H，m)，1.80(2H，d)，2.04(2H，t)，
2.28 (1H, m), 2.92 (2H, d), 3.52 (2H, s), 4.08 (3H, s), 6.82～7.70 (12H, m) routine 8:1-methyl-2-[3-(1-benzyl-4-piperidyl) propionyl] indoles
Operating process such as example 6 are just with 1-methyl 2-[3-(1-benzyl-4-piperidyl) acryl] indoles replaces 1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles, obtain solid product, MP=57～58 ℃
1H?NMR(CDCl3，AM＝400)：1.32～1.46(3H，m)，1.68～1.76(4H，m)，
2.00～2.10(2H，m)，2.94～3.06(4H，m)，3.60(2H，s)，4.04(3H，s)，
7.10～7.38 (9H, m), 7.66 (1H, d) routine 9:1-benzenesulfonyl-3-[3-(1-benzyl-4-piperidyl) acryl] indoles
Operating process such as routine 5-c just replace 1-methyl-2-ethanoyl-6-methoxyl group indoles with 1-benzenesulfonyl-3-ethanoyl indoles, obtain solid product, MP=118～119 ℃
1H?NMR(CDCl3，AM＝400)：1.40～1.90(xH，m)，2.00～2.40(3H，m)，
2.90～3.14(2H，m)，3.48(2H，s)，3.54～3.72(2H，m)，6.72(1H，d)，7.02(1H，d-d)，
7.20～7.42(7H，m)，7.42～7.54(2H，t)，7.58(1H，t)，7.94(3H，m)，8.20(1H，s)，
8.34 (1H, d) routine 10:1-benzenesulfonyl-3-[3-(1-benzyl-4-piperidyl) propionyl] indoles
Operating process such as example 6 are just with 1-benzenesulfonyl-3-[3-(1-benzyl-4-piperidyl) acryl] indoles replaces 1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles, obtain solid product, MP=89～90 ℃
1H?NMR(CDCl3，AM＝400)：1.40～1.90(xH，m)，2.14～2.40(2H，m)，
2.90(2H，t)，3.04～3.30(2H，m)，3.48(2H，s)，3.68～3.90(2H，m)，
7.20～7.44(7H，m)，7.50(2H，t)，7.60(1H，t)，7.92(3H，m)，8.18(1H，s)，
8.28 (1H, d) routine 11:1-benzenesulfonyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles
Operating process such as routine 5-c just replace 1-methyl-2-ethanoyl-6-methoxyl group indoles with 1-benzenesulfonyl-2-ethanoyl-6-methoxyl group indoles, obtain solid product, MP=120～121 ℃
1H?NMR(CDCl3，AM＝400)：1.40～1.96(4H，m)，2.00～2.40(3H，m)，
3.02(2H，m)，3.62(2H，s)，3.92(3H，s)，6.60(1H，d)，6.90(2H，m)，7.04(1H，s)，
7.20～7.60 (11H, m), 7.66 (1H, d), 7.94 (2H, d) routine 12:1-benzenesulfonyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) propionyl] indoles
Operating process such as example 6; just with 1-benzenesulfonyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles replacement 1-methyl-6-methoxyl group-2-[3-(1-benzyl-4-piperidyl) acryl] indoles; obtain solid product, MP=100～102 ℃
1H?NMR(CDCl3，AM＝400)：1.40(2H，br)，1.60～1.80(3H，m)，2.10(2H，m)，
2.90(2H，t)，3.00(2H，m)，3.65(2H，s)，3.90(3H，s)，6.90(1H，d-d)，7.05(1H，s)，
7.22～7.60 (11H, m), 7.64 (1H, d), 7.94 (2H, d) routine 13:1-benzenesulfonyl indoles-3-(1-benzyl-4-piperidyl) ethyl ketone methoxy oximes
200mg 1-benzenesulfonyl-3-[3-(1-benzyl-4-piperidyl) propionyl] indoles is dissolved in the 3ml anhydrous pyridine, adds the 200mg methoxy-amine hydrochloride, stirred 2 hours at 50～60 ℃; cooling; pour in the frozen water, with ethyl acetate extraction (30mi * 3), organic layer washs with saturated sodium chloride solution; anhydrous sodium sulfate drying; boil off solvent, residue is purified with silicagel column, ethyl acetate-sherwood oil (1: 2) drip washing; obtain solid 160mg, MP=96～98 ℃
1H?NMR(CDCl3，AM＝400)：1.24～1.40(3H，m)，1.46～1.56(2H，m)，
1.66～1.76(2H，m)，1.92～2.04(2H，m)，2.68(2H，m)，2.94(2H，d)，3.52(2H，s)，
3.98 (3H, s), 7.20～8.26 (15H, m) routine 14:1-benzenesulfonyl indoles-3-sulphonyl (1-benzyl-4-piperidines) methylamines
14-a:1-benzenesulfonyl indoles-3-SULPHURYL CHLORIDE
The ClSO that 10ml is pure
3H is dissolved in the 50ml exsiccant methylene dichloride, is chilled to-20 ℃, drips the solution of 7g 1-benzenesulfonyl indoles in the 20ml methylene dichloride quickly; controlled temperature is no more than-10 ℃, adds in the 20min, keeps 20min at-10 ℃ then; pour into immediately in the 100g trash ice, use extracted with diethyl ether, saturated sodium chloride solution washing; anhydrous magnesium sulfate drying; boil off solvent, residue is purified with silicagel column, methylene dichloride-sherwood oil (1: 1) drip washing; obtain white solid 3.2g, MP=112～113 ℃
1H?NMR(CD
3COCD
3，AM＝400)：7.54～7.66(2H，m)，7.66～7.74(2H，m)，
7.74～7.86(1H，m)，7.90～7.96(1H，m)，8.18(1H，t)，8.30(2H，t)，
8.78(1H，m)
14-b:1-benzenesulfonyl indoles-3-sulphonyl (1-benzyl-4-piperidines) methylamine
350mg 1-benzenesulfonyl indoles-3-SULPHURYL CHLORIDE is dissolved in the 10ml methylene dichloride; cool off with ice-water bath; be added dropwise to the 270mg1-benzyl-solution of 4-piperidines methylamine in the 5ml methylene dichloride; add the 0.3ml triethylamine after adding again; 0 ℃ is stirred 30min; reaction solution is washed secondary with 20ml, washes once organic layer Anhydrous potassium carbonate drying again with the saturated sodium carbonate solution of 15ml.Boil off solvent, residuum is crossed post (with 200～300 purpose silica gel, pure ethyl acetate drip washing) and is got unformed solid 0.45g.
1H?NMR(CDCl
3，AM＝400)：1.28～1.40(2H，m)，1.46～1.58(1H，m)，
1.60～1.70(2H，m)，2.02～2.14(2H，m)，2.82(2H，m)，3.02(2H，m)，
3.68 (2H, s), 5.08 (1H, br), 7.20～8.12 (15H, m) routine 15:1-benzenesulfonyl indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamines
Operating process such as routine 14-b just replace 1-benzyl-4-piperidines methylamine with N-methyl isophthalic acid-benzyl-4-piperidinylmethylamine.Obtain unformed solid.
1H?NMR(CDCl
3，AM＝400)：1.18～1.46(2H，m)，1.48～1.80(xH，m)，
1.88～2.02(2H，m)，2.76(3H，s)，2.80～3.00(4H，m)，3.5(2H，s)，
7.20～8.10 (15H, m) routine 16:1-benzenesulfonyl indoles-3-sulphonyl (1-benzyl-4-piperidines) ethamine
Operating process such as routine 14-b just replace 1-benzyl-4-piperidines methylamine with 1-benzyl-4-piperidyl ethamine.Obtain unformed solid.
1H?NMR(CDCl
3，AM＝400)：1.16～1.50(5H，m)，1.64～2.00(xH，m)，
2.78～3.04 (4H, m), 3.56 (2H, s), 4.64 (1H, br), 7.20～8.18 (15H, m) routine 17:1-benzenesulfonyl indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) ethamine
Operating process such as routine 14-b just replace 1-benzyl-4-piperidines methylamine with N-methyl isophthalic acid-benzyl-4-piperidyl ethamine.Obtain unformed solid.
1H?NMR(CDCl
3，AM＝400)：1.30～1.50(5H，m)，1.66～1.74(2H，m)，
2.10 (2H, m), 2.76 (3H, s), 3.00～3.16 (4H, m), 3.68 (2H, s), 7.20～8.10 (15H, m) example 18: indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamine
600mg1-benzenesulfonyl indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamine is dissolved in the 15ml methyl alcohol; it is muddy to add water to firm generation; add 2ml methyl alcohol again; add 200mg potassium hydroxide solid then; stirring at room 3 hours; boil off methyl alcohol, add 10ml water and 20ml methylene dichloride, water layer is used dichloromethane extraction (20ml * 2) again; organic layer merges; with saturated sodium chloride solution washing, anhydrous sodium sulfate drying boils off solvent; residue is purified with silicagel column; methylene chloride-methanol (20: 1) drip washing obtains white solid 400mg, MP=169～170 ℃
1H?NMR(CDCl
3，AM＝400)：1.18～1.42(2H，m)，1.50～1.72(5H，m)，
1.86～2.00(2H，t)，2.72(3H，s)，2.88(2H，d)，3.50(2H，s)，7.20～7.92(10H，m)，
8.86 (1H, br) routine 19:1-skatole-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamine
30mg sodium hydrogen is suspended in the 15ml anhydrous tetrahydro furan, the ice-water bath cooling, 250mg indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamine is dissolved in the 8ml anhydrous tetrahydro furan and drips, added the back restir 1 hour, add the 95mg methyl-sulfate then, naturally rise to room temperature, stirred 3 hours, and poured in the 40ml water, with dichloromethane extraction (15 * 3), the saturated nacl aqueous solution washing, anhydrous sodium sulfate drying boils off solvent, and residue is purified with silicagel column, methylene chloride-methanol (20: 1) drip washing obtains unformed solid 260mg.
1H?NMR(CDCl
3，AM＝400)：1.20～1.36(2H，m)，1.50～1.76(5H，m)，
1.88～2.00(2H，m)，2.72(3H，s)，2.88(2H，d)，3.48(2H，s)，3.84(3H，s)，
7.20～7.92 (10H, m) example 20: indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) ethamine
Operating process such as example 18 just replace 1-benzenesulfonyl indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamine with 1-benzenesulfonyl indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) ethamine.Obtain unformed solid.
1H?NMR(CDCl
3，AM＝400)(HCl?salt)：1.28～1.48)2H，m，1.50～2.10(xH，m)，
2.50(2H，m)2.66(3H，s)，2.96(2H，m)，3.36(2H，m)，4.04(2H，m)，
7.20～7.90 (10H, m), 9.90 (1H, br), 11.90 (1H, br) routine 21:1-skatole-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) ethamine
Operating process such as example 19 just replace indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) methylamine with indoles-3-sulphonyl (N-methyl isophthalic acid-benzyl-4-piperidines) ethamine.Obtain unformed solid.Unformed
1H?NMR(CDCl
3，AM＝400)：1.16～1.48(5H，m)，1.56～1.70(xH，m)，1.86～
1.96(2H，m)，2.70(3H，s)，2.78～2.88(2H，d)，2.98～3.08(2H，t)，3.48(2H，s)，
3.86(3H，s)，7.20～7.92(10H，m)
Claims (15)
1, Indolylpiperidine compound, structure is as follows:
R wherein
1Be H, C
1-C
4Alkyl; Benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; X is C=O, C=N-ORb, S=O ,-SO
2-, wherein Rb is H, C
1-C
4Alkyl; Y is-NRa, O ,-CH
2, wherein Ra is H, C
1-C
4Alkyl, aryl, benzyl, C
1-C
4Alkyloyl, aroyl, m=1-2, n=0-4.
2, Indolylpiperidine compounds according to claim 1, it is characterized in that when X be C=O, Y is-during NRa, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; R
aBe H, C
1-C
4Alkyl, aryl, benzyl, C
1-C
4Alkyloyl, aroyl, m=1-2, n=0-4.
3, Indolylpiperidine compounds according to claim 1 is characterized in that working as X is C=O, when Y is O, and R
1Be H, C
1-C
4Alkyl; Benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
4, Indolylpiperidine compounds according to claim 1 is characterized in that working as X is C=O, and Y is-CH
2, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
5, Indolylpiperidine compounds according to claim 1, it is characterized in that when X be C=N-ORb, Y is-during NRa, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; Ra is H, C
1-C
4Alkyl, aryl, benzyl, C
1-C
4Alkyloyl, aroyl, m=1-2, n=0-4; Rb is H, C
1-C
4Alkyl.
6, Indolylpiperidine compounds according to claim 1 is characterized in that: when X is C=N-ORb, and when Y is O, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
7, Indolylpiperidine compounds according to claim 1 is characterized in that: when X is C=N-ORb, Y is-CH
2The time, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
8, Indolylpiperidine compounds according to claim 1, it is characterized in that when X be S=O, Y is-during NRa, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; Ra is H, C
1-C
4Alkyl, aryl, benzyl, C
1-C
4Alkyloyl, aroyl, m=1-2, n=0-4.
9, Indolylpiperidine compounds according to claim 1 is characterized in that working as X is S=O, during Y=O, and R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
10, Indolylpiperidine compounds according to claim 1 is characterized in that working as X is S=O, and Y is-CH
2The time, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
11, Indolylpiperidine compounds according to claim 1 is characterized in that as X being-SO
2, Y is-during NRa, and R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; Ra is H, C
1-C
4Alkyl, aryl, benzyl, C
1-C
4Alkyloyl, aroyl, m=1-2, n=0-4.
12, Indolylpiperidine compounds according to claim 1 is characterized in that as X being-SO
2, when Y is O, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
13, Indolylpiperidine compounds according to claim 1 is characterized in that as X being-SO
2, Y is-CH
2The time, R
1Be H, C
1-C
4Alkyl, benzenesulfonyl, picolyl, benzyl; R
2Be H, C
1-C
4Alkyl, C
1-C
4Alkoxyl group, amino, itrile group, nitro, hydroxyl; M=1-2, n=0-4.
14, Indolylpiperidine compound preparation method is characterized in that:
(1) when X be CO, Y=-NRa or O the time, 1-indolecarboxylic acid or 2-indolecarboxylic acid and chlorination reagent in inert solvent, react acyl chlorides;
(2) acyl chlorides gets the Indolylpiperidine compound with the condensation of substituted benzyl piperidinamines in the presence of alkali in inert solvent;
When X is CO, when Y is C:
1. substituted indole ketone and the condensation in the presence of alkali of substituted benzyl piperidines aldehyde get compounds ib;
2. compounds ib gets Compound I c through catalytic reduction;
3. Ic in protonic solvent under acid catalysis or in the organic bases with NH
2OR
bReact Id;
When X is-SO
2, Y is-during NRa,
A. compound VI I carries out the sulfonated SULPHURYL CHLORIDE that promptly gets compound VIII with chlorsulfonic acid
B. in the presence of alkali, get Ie at SULPHURYL CHLORIDE VIII and compound IV
Ie water under the effect of alkali be situated between If
If gets product Ig with halohydrocarbon, sulphonate, acyl chlorides in inert solvent in the presence of alkali
15, Indolylpiperidine compound is used in preparation treatment presenile dementia medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004048330A1 (en) * | 2002-11-28 | 2004-06-10 | Suven Life Sciences Limited | N-arylsulfonyl-3-substituted indoles having serotonin receptor affinity, process for their preparation and pharmaceutical composition containing them |
| WO2004055026A1 (en) * | 2002-12-18 | 2004-07-01 | Suven Life Sciences Limited | Tetracyclic 3-substituted indoles having serotonin receptor affinity |
| CN108299274A (en) * | 2018-02-08 | 2018-07-20 | 中国热带农业科学院海口实验站 | A kind of natural indoles, preparation method and application |
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|---|---|---|---|---|
| FI95572C (en) * | 1987-06-22 | 1996-02-26 | Eisai Co Ltd | Process for the preparation of a medicament useful as a piperidine derivative or its pharmaceutical salt |
| TW197435B (en) * | 1990-11-22 | 1993-01-01 | Takeda Pharm Industry Co Ltd | |
| TW263504B (en) * | 1991-10-03 | 1995-11-21 | Pfizer | |
| SE9103752D0 (en) * | 1991-12-18 | 1991-12-18 | Astra Ab | NEW COMPOUNDS |
| CA2092112A1 (en) * | 1992-03-23 | 1993-09-24 | Nobuyoshi Iwata | Indole and indazole derivatives, for the treatment and prophylaxis of cerebral disorders, their preparation and their use |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004048330A1 (en) * | 2002-11-28 | 2004-06-10 | Suven Life Sciences Limited | N-arylsulfonyl-3-substituted indoles having serotonin receptor affinity, process for their preparation and pharmaceutical composition containing them |
| EA011320B1 (en) * | 2002-11-28 | 2009-02-27 | Сувен Лайф Сайенсиз Лимитед | N-arylsulfonyl-3-substituted indoles having serotonin receptor affinity, process for their preparation and pharmaceutical composition containing them |
| US7875605B2 (en) | 2002-11-28 | 2011-01-25 | Suven Life Sciences Limited | N-arylsulfonyl-3-substituted indoles having serotonin receptor affinity, process for their preparation and pharmaceutical composition containing them |
| WO2004055026A1 (en) * | 2002-12-18 | 2004-07-01 | Suven Life Sciences Limited | Tetracyclic 3-substituted indoles having serotonin receptor affinity |
| EA009367B1 (en) * | 2002-12-18 | 2007-12-28 | Сувен Лайф Сайенсиз Лимитед | 5-THIA-5-DIOXO-4b AZA INDENO [2,1-a] INDENE DERIVATIVES HAVING SEROTONIN RECEPTOR AFFINITY |
| CN100378109C (en) * | 2002-12-18 | 2008-04-02 | 苏文生命科学有限公司 | Tetracyclic 3-substituted indoles having serotonin receptor affinity |
| US7781476B2 (en) | 2002-12-18 | 2010-08-24 | Suven Life Sciences Limited | Tetracyclic 3-substituted indoles having serotonin receptor affinity |
| CN108299274A (en) * | 2018-02-08 | 2018-07-20 | 中国热带农业科学院海口实验站 | A kind of natural indoles, preparation method and application |
| CN108299274B (en) * | 2018-02-08 | 2021-01-15 | 中国热带农业科学院海口实验站 | Natural indole, preparation method and application thereof |
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