CN1829697A - Aryl-heteroaromatic products, compositions containing same and use thereof - Google Patents
Aryl-heteroaromatic products, compositions containing same and use thereof Download PDFInfo
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- CN1829697A CN1829697A CNA2004800218006A CN200480021800A CN1829697A CN 1829697 A CN1829697 A CN 1829697A CN A2004800218006 A CNA2004800218006 A CN A2004800218006A CN 200480021800 A CN200480021800 A CN 200480021800A CN 1829697 A CN1829697 A CN 1829697A
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- C07—ORGANIC CHEMISTRY
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- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
Aryl-heteroaromatic products, compositions containing same and use thereof. The invention provides new chemical compounds, in particular new aryl-heteroaromatic products, compositions containing same and use thereof as drugs, in particular in oncological therapies.
Description
The present invention relates to new compound, relate in particular to new aryl-heteroaromatic products, contain their composition and as the purposes of medicine.
Or rather, according to first aspect, the present invention relates to have antitumour activity, particularly effect has and suppresses active new aryl-heteroaromatic product to tubulin polymerization.
The aryl relevant with this paper-heteroaromatic product is equivalent to following general formula (I):
The compound of A=C wherein, X=N, Y=C-phenyl and E=CH is known:
Isoxazole derivative also is known:
CAS number: [336186-17-5]
Di Stilo etc. are at Medicinal Chemistry Research (1994), and 3 (9), the Prazosin analogue with vasorelaxation performance is disclosed among the 554-566:
1,2, the 5-oxadiazole randomly is the form of N-oxide compound.R is a phenyl.Compound with [CAS number] expression: [157066-46-1], [157066-44-9], [157066-43-8] and [157066-42-7].
The heterogeneous ring compound of the claimed inhibitor as factor Xa of patent application WO 01/19798, this inhibitor for example can be used for treating thrombosis and are used to suppress solidifying of biological sample.Disclosed compound is not included within the definition of The compounds of this invention, except that following compounds:
Ermondi etc. are at Farmaco, disclose in 53,519 (1998) to be potential α
1The Prazosin analogue of-adrenoceptor inhibitor.It is 5-(4-(heteroaryl) piperazine-1-base carbonyl)-1-phenylpyrazole that a kind of Prazosin analogue is wherein arranged:
In fact, be astoundingly found to be equivalent to following general formula (I) compound to tubulin polymerization effect to have a significant inhibition active:
Wherein:
1) A is N or C;
2) L-G-R1 is selected from
3) X and Y are independently from each other CR3, N, NR3, O or S;
4) E is CR4, N, NR4 or S;
5) R1 and R2 are independently from each other the aryl of aryl, heteroaryl, replacement and the heteroaryl of replacement;
6) L is selected from C=O, C=S and C=N (R7);
7) R3 and R4 are independently from each other H, alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, O-R7, S-R7, SO-R7, SO
2-(R7), N (R7) (R8), halogen, aryl, heteroaryl, the cycloalkyl of replacement, the aryl of replacement and the heteroaryl of replacement;
8) R5 and R6 are independently from each other H and (C
1-C
3) alkyl;
9) R7 and R8 are independently from each other H, (C
1-C
3) (the C of alkyl and replacement
1-C
3) alkyl;
Its racemic form, the form that is rich in a kind of enantiomorph, the form that is rich in a kind of diastereomer, its tautomer, its prodrug and pharmacologically acceptable salt thereof, condition are that the compound of formula (I) is not one of following compounds:
N=0,1 or 2 and the R=phenyl.
General formula (I) compound below preferred:
Wherein: A is N or C; L-G-R1 is selected from
Preferred E wherein is that NR4 and R4 are the compounds of H.
Preferred R1 substituting group can be selected from phenyl; Be selected from the following phenyl that group replaced by at least one: halogen, CF
3, CN, NO
2, (C
1-C
3) alkyl, O-R10, S-R10, N (R10) (R11), CO-O-R10, CO-N (R10) (R11), NH-CO-R10, wherein R10 and R11 are independently from each other H, (C
1-C
3) alkyl, halogenated (C
1-C
3) alkyl, (C
1-C
3) alkyl-OH, (C
1-C
3) alkyl-NH
2, (C
1-C
3) alkyl-COOH, (C
1-C
3) alkyl-OCH
3, (C
1-C
3) alkyl-NHCH
3Pyridyl; Be selected from halogen, (C by at least one
1-C
3) alkyl, O-R12, S-R12 or N (R12) pyridyl that group replaced (R13), wherein R12 and R13 are independently from each other H or (C
1-C
3) alkyl.
More preferably R1 is by halogen or (C on the 3-position
1-C
3) alkyl, (C
1-C
3) alkoxyl group, (C
1-C
3) alkylamino, CONH
2, CO-NH-(CH
2)
2-OH or NH-CO-CH
3The phenyl that replaces; Or 3-pyridyl; By halogen, (C
1-C
3) alkyl or (C
1-C
3) the alkoxyl group 2-or the 3-pyridyl that replace.
When R1 is the phenyl that replaces, the preferred combined optional that replaces is from 2, the dibasic phenyl of 3-, 2, the phenyl, 3 that the dibasic phenyl of 5-, 3-replace, the dibasic phenyl of 5-and 3, the dibasic phenyl of 4-more preferably is selected from the phenyl, 3 that 3-replaces, the dibasic phenyl of 5-and 3, the dibasic phenyl of 4-.
When R1 is the 2-pyridyl, the preferred 2-pyridyl or 4 that is selected from 4-or 6-replacement, the dibasic 2-pyridyl of 6-of replacing.
When R1 was the 3-pyridyl, the preferred replacement was the 3-pyridyl that 2-or 5-replace.
Very preferably R1 be on the 3-position by chlorine or the phenyl that on 3-and 5-position, replaced by two methoxyl groups.
Very preferably R1 is the phenyl that is replaced by cyano group, formamido-, methoxyl group or hydroxymethyl on the 3-position.
Preferred R2 substituting group is selected from phenyl; Be selected from the following phenyl that group replaced by at least one: halogen, alkyl, O-R10, S-R10 and N (R10) (R11), wherein R10 and R11 are independently from each other H, alkyl and haloalkyl; Or 3-pyridyl.
According to second aspect, the present invention relates to pharmaceutical composition, it comprises and the pharmaceutically acceptable vehicle compound of blended first aspect present invention mutually.
Compound of the present invention can be advantageously used for the reagent that suppresses the tubulin polymerization effect, as the reagent that suppresses tumor cell proliferation, be used to promote that the cell cluster that is derived from vascular tissue breaks, perhaps be used to produce the medicine that is used for the treatment of pathological conditions, preferred cancer.
Usually, wherein L be the general formula of the present invention (Ia) of C (O) or compound (Ib) can according to the heteroaryl carboxylic acid of scheme 1 by the general formula (II) (wherein A, X, Y, E and R2 are as defined above) that will be at the ortho position of carboxyl functional group be replaced by aryl or heteroaryl respectively with 1 of the bridged piperazine derivatives of general formula (IIIa) or general formula (IIIb), 2,3, the 6-5,6-tetrahydropyridine derivative carries out linked reaction and makes, and wherein R1 is as defined above:
Scheme 1
The heteroaryl carboxylic acid of general formula (II) (wherein A, X, Y, E and R2 are as defined above) can buy, and perhaps can obtain according to general synthetic method well known by persons skilled in the art.
The bridged piperazine derivatives of general formula (IIIa) (wherein R1, R5 and R6 are as defined above) or can buy perhaps can make according to ordinary method well known by persons skilled in the art.
According to scheme 2, in these methods, the N1-aryl (heteroaryl) that has the piperazine of protecting group on 4-nitrogen turns into being particularly preferred in the present invention:
Scheme 2
It generally is the Hartwig-Buchwald type that the aryl of piperazine (heteroaryl) is changed reaction, and it can be according to Biorg.Med.Chem.Lett., 11,1375 (2001) or Biorg.Med.Chem., and the condition described in 10,3817 (2002) is carried out.
When R5 and R6 represent hydrogen atom, the another kind of method of particularly preferred in the context of the present invention synthesizing aryl (heteroaryl) piperazine comprises reacts aryl (heteroaryl) amine and two (2-hydroxyl-or 2-halogenated ethyl) amine under greater than 100-120 ℃ temperature, referring to scheme 3:
Scheme 3
Particularly advantageously be in the presence of microwave at Synth.Comm., 28,1175 (1998) or Tetrahedron Lett, react under 38,6875 (1997) the described conditions.
1,2,3,6-5,6-tetrahydropyridine derivative (IIIb) (wherein R1, R5 and R6 are as defined above) or can buy perhaps can make according to ordinary method well known by persons skilled in the art.
According to scheme 4, in these methods, organometallic aryl (heteroaryl) the derivative for example reaction of organic-magnesium derivative, organolithium derivative or organic cerium derivative and piperidin-4-one-derivative (the protected base of its nitrogen-atoms replaces) is particularly advantageous.
Scheme 4
Especially can be at J.Med.Chem., 38,1998 (1995) or E.P.306764 or J.Med.Chem., react under 28,311 (1985) the described conditions.
When R5 and R6 represent hydrogen atom; according to scheme 5; N-Boc-1; 2; 3; the pinacol ester of 6-tetrahydro pyridyl-4-dihydroxyl borane and aryl or heteroaryl halogenide; preferred bromide or iodide are at Tetrahedron Lett; 41; Suzuki-type coupling under 3705 (2000) the described conditions is particularly preferred in the context of the present invention: be appreciated that; the Boc protecting group can be replaced with matched any other protecting group of reaction conditions, and tetramethyl ethylene ketone dihydroxyl borane ester can also by with matched any other the boron derivative of described condition; acid or ester replace.
Scheme 5
Wherein L be the general formula of the present invention (Ia) of C (S) or compound (Ib) generally can according in the vulcanization process well known by persons skilled in the art any respectively by L wherein be the general formula (Ia) of C (O) or (Ib) sulfuration of compound obtain, reaction is carried out according to scheme 6:
Scheme 6
Especially preferably utilize Lawesson reagent to carry out sulfuration in the context of the present invention, reaction is according to Bull.Soc.Chim.Belg., and 87,293 (1978) carry out.
Wherein L is that the general formula of the present invention (Ia) of C (NH) or compound (Ib) can utilize the whole bag of tricks well known by persons skilled in the art to be prepared from the nitrile derived from the compound of general formula (II) according to the reaction sequence of scheme 7 usually:
Scheme 7
Usually need the not really active nitrile of activation, can activate with aluminum chloride, reaction is according to J.Chem.Soc.1947, and 1110 carry out; Perhaps with the cuprous iodide activation, reaction is according to Tetrahedron Lett., and 34,6395 (1993) carry out; Perhaps by nitrile is changed into imido ether, then with piperazine or 1,2,3,6-tetrahydropyridine or piperidine derivative reaction are reacted according to Eur.J.Med.Chem., and 24,427 (1989) carry out.
Wherein L is that the compound of the identical or different general formula of the present invention (Ia) of C (NR7) and R7 and hydrogen atom can be that the compound of the general formula (Ia) of C (O) and/or C (S) utilizes the whole bag of tricks well known by persons skilled in the art to be prepared from L wherein usually, and reaction is carried out according to the reaction sequence of scheme 8:
Scheme 8
In the context of the present invention, when X was Sauerstoffatom, earlier preferred especially and oxalyl chloride reacted (it generates X ' is the intermediate of chlorine atom), then with amine R7-NH
2React, reaction is according to Pol.J.Chem., and 58,117 (1984) carry out; And when X is sulphur atom, especially preferably at first react (it generates X ' is the intermediate of methylthio group) with methyl iodide, then with amine R7-NH
2Reaction, reaction is according to Eur.J.Med.Chem, and 12,365 (1977) carry out.
More preferably, in the context of the present invention, compound of the present invention can also make on solid phase, referring to reaction scheme 9:
Scheme 9
The general synthetic method that proposes in the scheme 1 to 9 illustrated explanatoryly The compounds of this invention possible preparation method and without any restriction.Can use a lot of other synthetic route, particularly be recorded in Comprehensive Heterocyclic Chemistry, 5 (Part 4A), those in (Pergamon Press) by A.Katritsky etc.
Following examples have illustrated compound of the present invention and without any restriction explanatoryly.With various products or according to the described method purifying of embodiment, perhaps under the general condition of the following stated, pass through the LC/MS purifying:
By the LC/MS purifying
Product is passed through the LC/MS purifying with Waters FractionLynx system, and this system is made up of valve, Waters996 type diode-array detector, Waters ZMD type mass spectrograph and the Gilson 204 type fraction collectors of Waters 600 type gradient pumps, Waters 515 type regenerative pumps, Waters Reagent Manager dilution pumps, Waters 2700 type automatic samplers, two Rheodyne LabPro types.System is controlled by Waters FractionLynx software.Also can be at two Waters Symmetry post (C
18, 5 μ M, 19 * 50mm, catalog number (Cat.No.) 186000210) on separate, post is regenerated with 95/5 (v/v) water/acetonitrile mixture that contains 0.07% (v/v) trifluoroacetic acid, another post is used for separating simultaneously.Pillar is carried out wash-out with 5% to the 95% acetonitrile flow velocity with 10mL/ minute in the linear gradient of the water that comprises 0.07% (v/v) trifluoroacetic acid that contains 0.07% (v/v) trifluoroacetic acid.Outlet at separator column, isolate millesimal effluent with LC Packing Accurate,, be sent to detector then with the flow velocity dilution of methyl alcohol with 0.5mL/ minute, ratio with 75% is sent to diode-array detector, and remaining 25% is sent to mass spectrograph.Remaining effluent (999/1000) is sent to the fraction collector, wherein, just effluent is abandoned as long as the quality of expection product is not arrived by the FractionLynx software detection.The molecular formula of expection product is input in the FractionLynx software, when the quality signal that detects meets ion [M+H]
+And/or meet [M+Na]
+The time, this software will begin to collect product.In some cases, the LC/MS result according to analyzing meets when detecting [M+2H]
++Strong ion the time, the value of half of the molecular mass that is equivalent to calculate (MW/2) also is imported in the Fraction Lynx software.Under these conditions, when detecting ion [M+2H]
++And/or [M+Na+H]
++Quality signal the time, also can begin to collect.With product collection in the glass test tube of weighing in advance.After the collection, in Savant AES 2000 or Genevac HT8 centrifugal evaporator, steam solvent, the test tube after the solvent evaporation is weighed to determine product quality.
LC/MS analyzes and carries out on the Micromass LCT type instrument that is connected on HP 1100 instruments.The abundance of product utilizes HP G1315A diode-array detector and Sedex 65 light scattering detectors in the 200-600nm wavelength region to measure.Mass spectrum obtains in 180 to 800 scope.Data are utilized Micromass MassLynx software analysis.Be separated in Hypersil BDS C18,3 μ m posts (carry out on 50 * 4.6mm), with 5% to 90% acetonitrile that contains 0.05% (v/v) trifluoroacetic acid (TFA) in the water that contains 0.05% (v/v) TFA in 3.5 minutes the flow velocity with 1mL/ minute carry out linear gradient elution.The bulk analysis time that comprises the starting time again of post is 7 minutes.
Embodiment 1:
[4-(3-chloro-phenyl-) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl) ketone
Step 1: in the three-necked flask of 100ml, with 3.5g 1-phenyl-1H-imidazoles-(it can be according to Tetrahedron Lett. (2000) 41 for 5-base ethyl formate, 5453-56 makes) be dissolved in 50ml ethanol, add 25ml water and 16.2ml 85% potassium hydroxide aqueous solution then, then mixture was at room temperature stirred 20 hours.Behind the concentrating under reduced pressure, in reaction medium, add 100ml water, then with 75ml diethyl ether washing three times.By adding hydrochloric acid water is adjusted to pH=3-4, and with 100ml washed with dichloromethane three times.Add 10ml methyl alcohol with the water vacuum concentration and in resistates, filter then.In filtrate, add the 25ml isopropyl ether at last, leach product and use 2ml isopropyl ether washing 2 times.Obtain the 2.5g 1-phenyl-1H-imidazoles-5-base formic acid of brown solid shape thus, it is directly used in following step.
Step 2: under argon atmospher, 342 μ l oxalyl chlorides and several dimethyl formamides are joined successively in the 25ml dichloromethane solution of the 0.5g 1-phenyl-1H-imidazoles-5-base-formic acid in the three-necked flask of 100ml, at room temperature stirred 2 hours.Resulting solution transferred in the dropping funnel and with it be added drop-wise in the 25ml dichloromethane solution that comprises 560 μ l triethylamines and 132 μ l 4-dimethylaminopyridines of 575mg 1-(3-chloro-phenyl-) piperazine that under argon atmospher, is cooled to 0 ℃.After at room temperature stirring 20 hours, add 20ml water, go out organic phase, wash with water, with dried over mgso and concentrating under reduced pressure by settlement separate.Resistates by flash chromatography on silica gel purifying (70-230 order), is carried out wash-out with methylene dichloride, use the isopropyl ether crystallization then.Obtain the crystalloid 280mg[4-of oldlace (3-chloro-phenyl-) piperazine-1-yl thus] (1-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Fusing point (Kofler warm table)=70 ℃
1H NMR wave spectrum (400MHz, (CD
3)
2SO, under the temperature of 393K, δ ppm): 3.18 (t, J=5Hz:4H); 3.66 (t, J=5Hz:4H); (6.81 ddd, J=8-2 and 1Hz:1H); (6.85 ddd, J=8-2 and 1Hz:1H); 6.90 (t, J=2Hz:1H); 7.21 (t, J=8Hz:1H); (7.30 tt, J=7.5 and 1.5Hz:1H); (7.40 tt, J=7.5 and 1.5Hz:2H); (7.65 dd, J=7.5 and 1.5Hz:2H); 7.72 (s:1H).
Embodiment 2
[4-(3-chloro-phenyl-) piperazine-1-yl] (5-phenyl-1,3-oxazole-4-yl) ketone
According to the described method of the step 2 of embodiment 1, with 500mg 5-phenyl-1, the 3-oxazole-4-base formic acid and the 20ml dichloromethane solution of 0.25ml oxalyl chloride and the 20ml dichloromethane solution that comprises the 0.75ml triethylamine of 0.48ml 1-(3-chloro-phenyl-) piperazine at room temperature reacted 20 hours.By flash chromatography on silica gel purifying (70-230 order), carry out wash-out with the mixture (30-70 volume ratio) of ethyl acetate and hexanaphthene and obtain cream-coloured foamed 0.83g[4-(3-chloro-phenyl-) piperazine-1-yl] (5-phenyl-1,3-oxazole-4-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=367 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 3.12 (wide t, J=5Hz:2H); 3.30 (mt:2H); 3.56 (wide t, J=5Hz:2H); 3.82 (wide t, J=5Hz:2H); (6.82 the peak that dd is big, J=8 and 2Hz:1H); (6.91 dd, J=8 and 2Hz:1H); 6.97 (t, J=2Hz:1H); 7.24 (t, J=8Hz:1H); 7.46 (wide t, J=7.5Hz:1H); 7.52 (wide t, J=7.5Hz:2H); 7.76 (wide d, J=7.5Hz:2H); 8.60 (s:1H).
Embodiment 3
[4-(3-chloro-phenyl-) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone
Step 1: (they can be according to Tetrahedron Lett. (1994) with the basic ethyl formate of 350mg 4-phenyl-1H-imidazoles-5-according to the described method of the step 1 of embodiment 1,35,1635-38 makes) and 1.6ml 85% potassium hydroxide aqueous solution in 5ml ethanol and 2.5ml water, react 218mg 4-phenyl-1H-imidazoles of obtaining the beige solid shape-5-base formic acid, it is directly used in following step.
Step 2: 188mg 4-phenyl-1H-imidazoles-5-base formic acid and the 10ml dichloromethane solution of 128 μ l oxalyl chlorides and the 10ml dichloromethane solution that comprises 210 μ l triethylamines and 5 μ l 4-dimethylaminopyridines of 216mg 1-(3-chloro-phenyl-) piperazine were at room temperature reacted 20 hours according to the described method of the step 2 of embodiment 1.By flash chromatography on silica gel purifying (70-230 order), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio) and obtain cream-coloured foamed 150mg[4-(3-chloro-phenyl-) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Fusing point (Kofler warm table)=208 ℃
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 3.10 (non-resolved peakss: 4H); 3.64 (wide t, J=5Hz:4H); (6.83 dd, J=8 and 2Hz:1H); (6.90 dd, J=8 and 2Hz:1H); 6.96 (t, J=2Hz:1H); 7.24 (t, J=8Hz:1H); 7.35-7.50 (mt:4H); 7.54 (wide t, J=7.5Hz:2H); (8.09 wide s:1H).
Embodiment 4
[4-(3-chloro-phenyl-) piperazine-1-yl] (3-phenyl thiophene-2-yl) ketone
(they can be according to J.Org.Chem. (1967) with the basic formic acid of 77mg 3-phenyl thiophene-2-according to the described method of the step 2 of embodiment 1,32,463-4 makes) and the 4ml dichloromethane solution of 35 μ l oxalyl chlorides and the 4ml dichloromethane solution that comprises 62 μ l triethylamines of 62 μ l 1-(3-chloro-phenyl-) piperazines at room temperature reacted 36 hours.By with 50mg[4-(3-chloro-phenyl-) piperazine-1-yl that obtains the pale solid shape behind the minimum methylene dichloride crystallization purifying] (3-phenyl thiophene-2-yl) ketone, its feature is as follows: mass spectrum (EI): m/z=382 (M
+)
1H NMR wave spectrum (400MHz, (CD
3)
2SO, under the temperature of 363K, δ ppm): 2.92 (non-resolved peakss: 4H); 3.43 (mt:4H); 6.75-6.85 (mt:3H); 7.20 (t, J=8.5Hz:1H); 7.30-7.40 (mt:1H); 7.32 (d, J=5Hz:1H); 7.40-7.55 (mt:4H); 7.75 (d, J=5Hz:1H).
Embodiment 5
[4-(3-p-methoxy-phenyl) piperazine-1-yl] [2-(4-chloro-phenyl-) furans-3-yl] ketone
24.6mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 1.6mg I-hydroxybenzotriazole hydrate (HOBT) are joined in the 5ml dichloromethane solution of 26mg 3-(4-chloro-phenyl-) furans-2-base formic acid (it can obtain according to Coll.Czech.Chem.Commun. (1989) 54,215-24).After at room temperature stirring 10 minutes, add 24.7mg 1-(3-p-methoxy-phenyl) piperazine, then this reaction mixture was at room temperature stirred 24 hours.Carry out chromatogram purification with the 6g fine silica, mixture (50-50 volume ratio) with hexanaphthene and ethyl acetate carries out 8.9mg[4-(3-p-methoxy-phenyl) piperazine-1-yl that wash-out obtains not having the colored paint shape] [2-(4-chloro-phenyl-) furans-3-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=396 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.99 (non-resolved peakss: 2H); 3.24 (non-resolved peaks: 2H); 3.42 (mt:2H); 3.71 (s:3H); 3.81 (non-resolved peaks: 2H); 6.43 (wide d, J=8Hz:1H); 6.46 (mt:1H); 6.52 (wide d, J=8Hz:1H); 6.76 (d, J=1.5Hz:1H); 7.14 (t, J=8Hz:1H); 7.55 (d, J=8Hz:2H); 7.67 (d, J=8Hz:2H); 7.90 (d, J=1.5Hz:1H).
Embodiment 6
[4-(3-chloro-phenyl-) piperazine-1-yl] (3-phenyl-1H-pyrroles-2-yl) ketone
Step 1: 99mg 3-phenyl-1H-pyrroles-2-base ethyl formate (they can be according to Austr.J.Chem. (1994), 47,969-74 makes) is dissolved in the 5ml tetrahydrofuran (THF).Adding the 96.5mg lithium hydroxide monohydrate then also at room temperature stirred 20 hours.Behind the concentrating under reduced pressure, resistates is dissolved in 5ml water, adds then and the 1N hydrochloric acid soln, reach 6 until pH.Leach formed throw out and vacuum-drying.Obtain the 80mg 3-phenyl-1H-pyrroles-2-base formic acid of white solid, it is directly used in following step.
Step 2: in 10ml Stern test tube, under argon gas, begin to react by the 5ml dichloromethane solution of 80mg 3-phenyl-1H-pyrroles-2-base formic acid and 112 μ l oxalyl chlorides according to the described method of the step 2 of embodiment 1.Different with the step 2 of embodiment 1 is with the reaction medium concentrating under reduced pressure, then resulting acyl chlorides is dissolved in the 5ml tetrahydrofuran (THF), adds 76.3mg 1-(3-chloro-phenyl-) piperazine and 81.8 μ l triethylamines then, then mixture is at room temperature stirred 20 hours.Crude product is passed through the LC/MS purifying according to the method described above.Obtain cream-coloured foamed 120mg[4-(3-chloro-phenyl-) piperazine-1-yl thus] (3-phenyl-1H-pyrroles-2-yl)-ketone, its feature is as follows:
Mass spectrum (EI): m/z=365 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.90 (non-resolved peakss: 4H); 3.42 (non-resolved peaks: 4H); 6.34 (t, J=2.5Hz:1H); 6.80 (mt:2H); 6.86 (mt:1H); 6.95 (t, J=2.5Hz:1H); 7.10-7.25 (mt:2H); 7.30-7.40 (mt:4H); 11.50 (non-resolved peaks: 1H).
Embodiment 7
[4-(3-chloro-phenyl-) piperazine-1-yl] (1-methyl-3-phenyl-1H-pyrroles-2-yl)-ketone
In the Stern of 10ml test tube, 80mg[4-(3-chloro-phenyl-) piperazine-1-yl that embodiment 6 is obtained] (3-phenyl-1H-pyrroles-2-yl)-ketone is dissolved in the 5ml dimethyl formamide, adds the 10.5mg sodium hydride then, after 1 hour, adds 13.64 μ l methyl iodide.After at room temperature stirring 10 hours,, in resistates, add the 5ml methylene dichloride then with the reaction medium concentrating under reduced pressure.Leach insoluble impurities, filtrate decompression is concentrated.Resistates is passed through LC/MS purifying under these conditions.Obtain cream-coloured foamed 80mg [4-(3-chloro-phenyl-) piperazine-1-yl] (1-methyl-3-phenyl-1H-pyrroles-2-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=379 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.80-3.40 (big non-resolved peaks: 6H); 3.50-3.80 (big non-resolved peaks: 2H); 3.61 (s:3H); 6.32 (d, J=3Hz:1H); 6.79 (wide d, J=8Hz:2H); 6.85 (mt:1H); 6.95 (d, J=3Hz:1H); 7.10-7.25 (mt:2H); 7.25-7.40 (mt:4H).
Embodiment 8
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (3-phenyl-1H-pyrroles-2-yl) ketone
Begin to react according to the 5ml dichloromethane solution of the described method of the step 2 of embodiment 1 by 214mg 3-phenyl-1H-pyrroles-2-base formic acid and 210 μ l oxalyl chlorides.Resulting acyl chlorides is dissolved in the 5ml tetrahydrofuran (THF), adds 161mg 1-(3, the 5-Dimethoxyphenyl) piperazine and 153 μ l triethylamines, then mixture was at room temperature stirred 20 hours.Obtain cream-coloured foamed 51mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl behind the purifying according to the method described above by LC/MS] (3-phenyl-1H-pyrroles-2-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=391 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.70-2.95 (non-resolved peaks: 4H); 3.20-3.50 (non-resolved peaks: 4H); 3.68 (s:6H); 5.98 (s:3H); 6.34 (mt:1H); 6.93 (mt:1H); 7.22 (mt:1H); 7.55-7.40 (mt:4H); 11.49 (non-resolved peaks: 1H).
Embodiment 9
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl)-ketone
1g 4-phenyl-1H-imidazoles-5-base formic acid and the 1.2g 1-(3 that the step 1 of embodiment 3 is obtained according to embodiment 5 described methods, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 1.1g1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 0.79g I-hydroxybenzotriazole hydrate (HOBT) in the 90ml methylene dichloride, and reaction was at room temperature stirred 48 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95-5 volume ratio), obtain 1.3g[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of white crystals shape then with the crystallization of 25ml diisopropyl ether] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=392 (M
+)
Fusing point (Kofler warm table)=196 ℃.
Embodiment 10
[4-(pyridin-3-yl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone
(they can be according to Tetrahedron Lett. (1998) for 100mg 4-phenyl-1H-imidazoles-5-base formic acid that the step 1 of embodiment 3 is obtained according to embodiment 5 described methods and 87mg 1-(pyridin-3-yl) piperazine, 39 (7), 617-20 makes) in the 10ml methylene dichloride, in the presence of 112mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 79mg I-hydroxybenzotriazole hydrate (HOBT), to react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio), obtain 100mg[4-(pyridin-3-yl) piperazine-1-yl of white foam shape then with the crystallization of 5ml diisopropyl ether] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=333 (M
+).
Embodiment 11
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl)-ketone hydrochloride
According to embodiment 5 described methods the step 1 of embodiment 1 is obtained 580mg 1-phenyl-1H-imidazoles-5-base formic acid and 685mg 1-(3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 650mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 460mg I-hydroxybenzotriazole hydrate (HOBT) in the 50ml methylene dichloride, and reaction was at room temperature stirred 48 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95-5 volume ratio) and obtain 950mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl]-(1-phenyl-1H-imidazoles-5-yl) ketone, the mixture by the solution in diethyl ether with 50ml ethyl acetate and 2.5ml 1M hydrochloric acid carries out recrystallization and converts it into hydrochloride then.Obtain 900mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of white crystals shape thus] (1-phenyl-1H-imidazoles-5-yl) ketone hydrochloride, its feature is as follows:
Fusing point (Kofler warm table)=268 ℃.
Embodiment 12
[4-(3-acetylamino phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone
The 189mg 4-phenyl-1H-imidazoles-5-base formic acid and the 94 μ l oxalyl chlorides that the step 1 of embodiment 3 are obtained according to the described method of the step 2 of embodiment 1 react in comprising the 20ml methylene dichloride of several DMF; (they can be according to TetrahedronLett. (1994) with 76.3mg 1-(3-acetylamino phenyl) piperazine then; 35 (40); 7331-34 makes), 281 μ l triethylamines and 12mg 4-dimethylaminopyridine react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m); carry out wash-out with methylene dichloride and methanol mixture (97.5-2.5 volume ratio); obtain 180mg[4-(the 3-acetylamino phenyl) piperazine-1-yl of beige solid shape then with the crystallization of 5ml diisopropyl ether] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=389 (M
+).
Embodiment 13
[4-(3-cyano-phenyl) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl) ketone
(they can be according to TetrahedronLett. (2000) for 376mg 1-phenyl-1H-imidazoles-5-base formic acid that the step 1 of embodiment 1 is obtained according to embodiment 5 described methods and 520mg 1-(3-cyano-phenyl) piperazine, 56 (24), 4107-10 makes) in the 34ml methylene dichloride, in the presence of 422mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 297mg I-hydroxybenzotriazole hydrate (HOBT), to react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5-2.5 volume ratio), obtain 650mg[4-(3-cyano-phenyl) piperazine-1-yl of white solid then with the crystallization of 5ml diisopropyl ether] (1-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=357 (M
+).
Embodiment 14
[4-(3-cyano-phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone
(they can be according to TetrahedronLett. (2000) for 200mg 4-phenyl-1H-imidazoles-5-base formic acid that the step 1 of embodiment 3 is obtained according to embodiment 5 described methods and 276mg 1-(3-cyano-phenyl) piperazine, 56 (24), 4107-10 makes) in the 34ml methylene dichloride, in the presence of 224mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 158mg I-hydroxybenzotriazole hydrate (HOBT), to react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5-2.5 volume ratio), obtain 350mg[4-(3-cyano-phenyl) piperazine-1-yl of white solid then with the crystallization of 5ml diisopropyl ether] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=357 (M
+).
Embodiment 15
[4-(3-chloro-phenyl-) piperazine-1-yl] (4-phenyl-1H-pyrroles-3-yl) ketone
(they can be according to Med.Chem.Res. (1997) with the basic formic acid of 562mg 4-phenyl-1H-pyrroles-3-according to embodiment 5 described methods, 7 (2), 98-108 makes) and 590mg 1-(3-chloro-phenyl-) piperazine in the 90ml methylene dichloride, in the presence of 632mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 446mg I-hydroxybenzotriazole hydrate (HOBT), react, the reaction at room temperature stirred 72 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), mixture (50-50 volume ratio) with hexanaphthene and ethyl acetate carries out wash-out, obtain 900mg[4-(3-chloro-phenyl-) piperazine-1-yl of oldlace solid state then with the crystallization of 15ml diisopropyl ether] (4-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=365 (M
+).
Embodiment 16
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (4-phenyl-1H-pyrroles-3-yl) ketone
(they can be according to Med.Chem.Res. (1997) with the basic formic acid of 562mg 4-phenyl-1H-pyrroles-3-according to embodiment 5 described methods, 7 (2), 98-108 makes) and 667mg 1-(3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 632mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 446mg I-hydroxybenzotriazole hydrate (HOBT) in the 90ml methylene dichloride, and reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), mixture (60-40 volume ratio) with hexanaphthene and ethyl acetate carries out wash-out, obtain 1g[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of oldlace solid state then with the crystallization of 15ml Di Iso Propyl Ether]-(4-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=391 (M
+).
Embodiment 17
[4-(3-formamyl phenyl) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl) ketone
600mg[4-(3-cyano-phenyl) piperazine-1-yl that embodiment 13 is obtained] the 20ml methanol solution that comprises the 0.5N aqueous sodium hydroxide solution of (1-phenyl-1H-imidazoles-5-yl) ketone refluxed 72 hours under argon atmospher in the three-necked flask of 100ml.When the heating beginning, methanol solution comprises 3.7ml 0.5N aqueous sodium hydroxide solution, refluxes after 20 hours, adds 3.7ml 0.5N aqueous sodium hydroxide solution.After the cooling, concentrated solvent is dissolved in resistates 100ml methylene dichloride and 20ml methyl alcohol then.Wash with saturated ammonium chloride solution then, go out organic phase by settlement separate, with dried over mgso and concentrating under reduced pressure.With crude product by carrying out purifying with the 5ml re-crystallizing in ethyl acetate.Obtain 180mg[4-(the 3-formamyl phenyl) piperazine-1-yl of white crystals shape thus] (1-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=375 (M
+).
Embodiment 18
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-4-phenyl-1H-pyrroles-3-yl) ketone hydrochloride
(they can be according to Med.Chem.Res. (1997) with the basic formic acid of 201mg 1-methyl-4-phenyl-1H-pyrroles-3-according to embodiment 5 described methods, 7 (2), 98-108 makes) and 222mg 1-(3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 148mg I-hydroxybenzotriazole hydrate (HOBT) in the 20ml methylene dichloride, and reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), mixture (50-50 volume ratio) with hexanaphthene and ethyl acetate carries out wash-out, solution in diethyl ether obtains the 400mg[4-(3 of white crystals shape with the form crystallization of hydrochloride with 5ml methylene dichloride and 1ml 1M hydrochloric acid then, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-4-phenyl-1H-pyrroles-3-yl) ketone hydrochloride, its feature is as follows:
Mass spectrum (EI): m/z=441 (M
+).
Embodiment 19
[4-(3-chloro-phenyl-) piperazine-1-yl] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl)-ketone
(they can be according to Chem.Pharm.Bull. (1984) with 200mg 2-sulfydryl-5-phenyl-1H-imidazol-4 yl formic acid according to embodiment 5 described methods, 32 (7), 2536-43 makes) and 178.6mg 1-(3-chloro-phenyl-) piperazine in the 15ml methylene dichloride, in the presence of 192mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 135mg I-hydroxybenzotriazole hydrate (HOBT), react, the reaction at room temperature stirred 24 hours.Behind the concentrating under reduced pressure, add 20ml water.Leach formed throw out,, use 20ml diethyl ether washed twice and dry then with 20ml water washing three times.Obtain filbert pulverous 260mg[4-(3-chloro-phenyl-) piperazine-1-yl thus] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Fusing point (Kofler warm table)＞260 ℃
Mass spectrum (EI): m/z=398 (M
+).
Embodiment 20
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl) ketone
(they can be according to Chem.Pharm.Bull. (1984) with 200mg 2-sulfydryl-5-phenyl-1H-imidazol-4 yl-formic acid according to embodiment 5 described methods, 32 (7), 2536-43 makes) and 202mg 1-(3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 192mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 135mg I-hydroxybenzotriazole hydrate (HOBT) in the 15ml methylene dichloride, and reaction was at room temperature stirred 24 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio) and obtain yellow foamed 263mg 4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=424 (M
+).
Embodiment 21
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone
Step 1: in the three-necked flask of 250ml, 1.2g 2-phenyl-1H-pyrroles-3-base ethyl formate (it can be according to J.Chem.Soc.Perkin Trans 1 1994 (17), and 2355-56 makes) is dissolved in 80ml ethanol and 19.5ml 1N aqueous sodium hydroxide solution; Solution was refluxed 48 hours.Behind the concentrating under reduced pressure ethanol, reaction medium is dissolved in 25ml distilled water.The aqueous solution that obtains is washed three times with the 10ml ethyl acetate, carry out acidifying by adding 39.5ml 1N aqueous hydrochloric acid then.Leach formed throw out, with 5ml water washing three times, dry down in 45 ℃ in baking oven then.Obtain 1g 2-phenyl-1H-pyrroles-3-base formic acid thus, it is directly used in following step.
Step 2: according to 375mg 2-phenyl-1H-pyrroles-3-base formic acid and the 440mg 1-(3 of embodiment 5 described methods with above preparation, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 420mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 27mg I-hydroxybenzotriazole hydrate (HOBT) in the 30ml methylene dichloride, reaction was at room temperature stirred 72 hours, after 24 hours, add the 20ml methylene dichloride.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95-5 volume ratio) and obtain the foamed 300mg[4-of lilac (3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl)-ketone, its feature is as follows:
Mass spectrum (EI): m/z=391 (M
+).
Embodiment 22
[4-(3-formamyl phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl)-ketone
The 189mg 4-phenyl-1H-imidazoles-5-base formic acid and 278mg 1-(the 3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 98/00400) that the step 1 of embodiment 3 are obtained according to embodiment 5 described methods react in the presence of 422 μ l triethylamines, 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 148mg I-hydroxybenzotriazole hydrate (HOBT) in the 35ml methylene dichloride, react and at room temperature stir 20 hours.Leach formed throw out, use 2 * 5ml methylene dichloride, 2 * 20ml water, 2 * 20ml saturated sodium bicarbonate aqueous solution and 2 * 20ml water washing successively.To be deposited in the middle mashed prod that forms of mixture (50-50 volume ratio) of 10ml ethyl acetate and diisopropyl ether then.Obtain 230mg[4-(the 3-formamyl phenyl) piperazine-1-yl of oldlace solid state thus] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=375 (M
+).
Embodiment 23
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone
In the three-necked flask of 25ml, 210mg 4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 20 is obtained] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl) ketone is dissolved in 10ml methyl alcohol.Add the 32mg sodium methylate then, mixture was at room temperature stirred 10 minutes, add the solution of 77.3mg methyl iodide then and mixture was refluxed 3 hours.Add 32mg sodium methylate and 228mg methyl iodide then, then mixture was refluxed 24 hours.The concentrating under reduced pressure solvent adds 20ml water also with 2 * 20ml ethyl acetate extraction in reaction medium.With the organic phase that merges with dried over mgso and concentrating under reduced pressure.With the cream-coloured foam (160mg) that obtains by flash chromatography purifying (60 on 25g silica gel; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio).Obtain 68mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of white foam shape by the fraction that reclaims wash-out between 880 to 960ml] (2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=438 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm):
Embodiment 24
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (N-methyl-2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone
React according to embodiment 23 described methods, but the fraction that reclaims wash-out between 420 to 500ml obtains the 27mg 4-(3 of colourless white paint shape, the 5-Dimethoxyphenyl) piperazine-1-yl] (N-methyl-2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=452 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm).
Embodiment 25
[4-(3-formamyl phenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone
The 195mg 2-phenyl-1H-pyrroles-3-base formic acid and 280mg 1-(the 3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 98/00400) that the step 1 of embodiment 21 are obtained according to embodiment 5 described methods react in the presence of 420 μ l triethylamines, 210mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 150mg I-hydroxybenzotriazole hydrate (HOBT) in the 35ml methylene dichloride, react and at room temperature stir 20 hours.Leach resulting throw out, use 2 * 5ml methylene dichloride, 2 * 20ml water, 2 * 20ml saturated sodium bicarbonate aqueous solution and 2 * 20ml water washing successively.Then throw out is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (90-10 volume ratio).Obtain 125mg[4-(the 3-formamyl phenyl) piperazine-1-yl of beige solid shape thus] (2-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=374 (M
+).
Embodiment 26
[4-(3-chloro-phenyl-) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone
The 189mg 2-phenyl-1H-pyrroles-3-base formic acid and 200mg 1-(3-chloro-phenyl-) piperazine that the step 1 of embodiment 21 are obtained according to embodiment 5 described methods react in the presence of 210mg1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 13mg I-hydroxybenzotriazole hydrate (HOBT) in the 15ml methylene dichloride, react and at room temperature stir 72 hours.Leach resulting throw out, use 2 * 5ml methylene dichloride, 2 * 20ml water, 2 * 20ml saturated sodium bicarbonate aqueous solution and 2 * 20ml water washing successively.Then throw out is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95-5 volume ratio).Obtain 125mg[4-(3-chloro-phenyl-) piperazine-1-yl of peachiness-beige solid shape thus] (2-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=365 (M
+).
Embodiment 27
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-2-phenyl-1H-pyrroles-3-yl)-ketone
In the three-necked flask of 100ml, 900mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 21 is made] (2-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 20ml pyridine.After being cooled to 0 ℃, adding 140mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and descend stirring 1 hour at 0 ℃.Add 160 μ l methyl iodide then and mixture was at room temperature stirred 20 hours.Decompression steams pyridine, adds 35ml methylene dichloride and 10ml water in resistates.Organic phase is washed with water, with dried over mgso and concentrating under reduced pressure.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95-5 volume ratio), obtain 420mg[4-(3-Dimethoxyphenyl) piperazine-1-yl of white crystals shape then with 25ml diethyl ether recrystallization] (1-methyl-2-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=405 (M
+)
Fusing point (Kofler warm table)=130 ℃.
Embodiment 28
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-hydroxyl-5-phenyl-1H-imidazol-4 yl) ketone
(they can be according to Heterocycles (1984) with 150mg 2-hydroxyl-5-phenyl-1H-imidazol-4 yl formic acid according to embodiment 5 described methods, 22 (8), 1763-9 makes) and 180mg 1-(3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 155mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 10mg I-hydroxybenzotriazole hydrate (HOBT) in the 25ml methylene dichloride, and reaction was at room temperature stirred 24 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio), obtain 260mg 4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of white crystals shape then with 15ml diethyl ether recrystallization] (2-hydroxyl-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=408 (M
+)
Fusing point (Kofler warm table)=130 ℃.
Embodiment 29
[4-(3-p-methoxy-phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone
The 188mg 4-phenyl-1H-imidazoles-5-base formic acid and 192mg 1-(3-p-methoxy-phenyl) piperazine that the step 1 of embodiment 3 are obtained according to embodiment 5 described methods react in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 148mg I-hydroxybenzotriazole hydrate (HOBT) in the 20ml methylene dichloride, react and at room temperature stir 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with pure ethyl acetate, use mixture (10/90 volume ratio) crystallization of ethyl acetate and diisopropyl ether to obtain 130mg[4-(3-p-methoxy-phenyl) piperazine-1-yl of beige solid shape then] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=362 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.80-3.80 (a series of roomy non-resolved peakss: 8H) altogether; 3.72 (s:3H); (6.40 wide dd, J=8 and 1.5Hz:1H); (6.45 wide s:1H); 6.51 (wide d, J=8Hz:1H); 7.13 (t, J=8Hz:1H); 7.30 (wide t, J=7.5Hz:1H); 7.42 (wide t, J=7.5Hz:2H); 7.62 (wide d, J=7.5Hz:2H); 7.82 (s:1H).
Embodiment 30
[4-(3-difluoro-methoxy phenyl) piperazine-1-yl] (5-phenyl-1H-imidazol-4 yl) ketone
Step 1:4-(3-difluoro-methoxy phenyl) piperazine-1-base t-butyl formate
With the 1-boc piperazine (500.1mg that buys, 2.685mmol) and the 3-difluoro-methoxy bromobenzene (598.8mg that buys, 2.685mmol) mixture in toluene (20ml) places with argon gas and keep inert 50ml three neck round-bottomed flasks, add part (R)-(+)-2 then, 2 '-two (diphenylphosphine)-1,1 '-dinaphthalene (56.850mg, 91.2 μ mol) and acid chloride (II) (20.4mg, 91.2 μ mol).Reaction mixture is stirred and refluxed 16 hours.After turning back to 20 ℃,, use ethyl acetate (2 * 30ml) extractions then with reaction mixture water (20ml) dilution.Organic extract liquid is merged, use dried over mgso, filter and reduction vaporization.The compound that obtains is passed through silica gel chromatography purifying (AIT short column, Ref.FC-25 Si-BP-SUP, 20-40 μ m, eluent methylene dichloride, flow velocity 20ml/min).The fraction that will contain expecting compound merges, then reduction vaporization.Separate obtaining 4-(3-difluoro-methoxy phenyl) piperazine-1-base t-butyl formate (253mg), its feature is as follows:
LC/MS analyzes: tr=4.18 minute, and M+H
+329.31
Step 2:1-(3-difluoro-methoxy phenyl) piperazine hydrochloride
(253mg, 3.8mmol) solution in the mixture of diox (1016 μ l) and hydrochloric acid (963 μ l) places the round-bottomed flask of 10ml with 4-(3-difluoro-methoxy phenyl) piperazine-1-t-butyl formate.Reaction mixture was stirred 48 hours down at 20 ℃.Leach formed solid, and washing (diisopropyl ether, 10ml) and drying under reduced pressure.Separate obtaining 1-(3-difluoro-methoxy phenyl) piperazine hydrochloride, discriminated union characterizes (189mg), directly uses it for following steps.
Step 3: the 376mg 4-phenyl-1H-imidazoles-5-base formic acid and 602mg 1-(the 3-difluoro-methoxy phenyl) piperazine dihydrochloride that the step 1 of embodiment 3 are obtained according to embodiment 5 described methods react in the presence of 0.618ml triethylamine, 422mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 296mg I-hydroxybenzotriazole hydrate (HOBT) in the 50ml methylene dichloride, react and at room temperature stir 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio), separate out 455mg[4-(the 3-difluoro-methoxy phenyl) piperazine-1-yl of amorphous beige solid shape then with the diisopropyl ether precipitation] (5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=398 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.90-3.90 (a series of wide non-resolved peakss: 8H) altogether; (6.58 wide dd, J=8 and 1.5Hz:1H); (6.68 wide s:1H); (6.80 wide dd, J=8 and 1.5Hz:1H); 7.20 (t, J=75Hz:1H); 7.25 (t, J=8Hz:1H); 7.30 (wide t, J=7.5Hz:1H); 7.43 (wide t, J=7.5Hz:2H); 7.63 (wide d, J=7.5Hz:2H); 7.82 (s:1H).
Embodiment 31
[4-(3-chloro-phenyl-) piperazine-1-yl] [1-(2-dimethyl aminoethyl)-4-phenyl-1H-pyrroles-3-yl] ketone hydrochloride
200mg[4-(3-chloro-phenyl-) piperazine-1-yl that embodiment 15 is made] (4-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 6ml pyridine.After being cooled to 0 ℃, add 49.3mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches, mixture was stirred 15 minutes down at 0 ℃.Add 79mg (2-chloroethyl) dimethyl amine hydrochloride then and mixture is descended heating 3 hours at 60 ℃, at room temperature stirred then 20 hours.The concentrating under reduced pressure pyridine, in resistates, add the 50ml ethyl acetate and with organic phase with 3 * 25ml water washing, with dried over mgso and concentrating under reduced pressure.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio), obtain the foamed 80mg[4-of light brown (3-chloro-phenyl-) piperazine-1-yl after the diethyl ether solution acidifying with 1 equivalent 1N hydrogenchloride] [1-(2-dimethyl aminoethyl)-4-phenyl-1H-pyrroles-3-yl] ketone hydrochloride, its feature is as follows:
Mass spectrum (EI): m/z=436 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.60-3.10 (wide non-resolved peaks: 4H); (2.81 wide s:6H); 3.20-3.70 (wide non-resolved peaks: 4H); 3.56 (mt:2H); 4.37 (t, J=7Hz:2H); 6.82 (mt:2H); (6.87 wide s:1H); 7.10-7.25 (mt:4H); 7.33 (mt:4H).
Embodiment 32
3-{3-[4-(3-chloro-phenyl-) piperazine-1-base carbonyl]-4-phenylpyrrole-1-yl }-propionic acid
200mg[4-(3-chloro-phenyl-) piperazine-1-yl that embodiment 15 is made] (4-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 49mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 15 minutes at 0 ℃.Add 91mg 3-methyl bromide c then and mixture is descended heating 3 hours at 60 ℃, at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine, in resistates, add the 50ml ethyl acetate and with organic phase with 3 * 25ml water washing, with dried over mgso and concentrating under reduced pressure.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (99-1 volume ratio), reclaim 115mg 3-{3-[4-(3-chloro-phenyl-) piperazine-1-base-carbonyl that second stage branch obtains amorphous beige solid shape]-4-phenylpyrrole-1-yl } propionic acid, its feature is as follows:
Mass spectrum (EI): m/z=437 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.70-3.60 (a series of non-resolved peakss: 8H) altogether; 2.80 (t, J=7Hz:2H); 4.16 (t, J=7Hz:2H); 6.80 (mt:2H); 6.86 (wide t, J=2Hz:1H); 7.06 (d, J=2Hz:1H); 7.10-7.25 (mt:1H); 7.13 (d, J=2Hz:1H); 7.20 (t, J=8Hz:1H); 7.33 (mt:4H).
Embodiment 33
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methanesulfinyl-5-phenyl-1H-imidazol-4 yl) ketone
984mg metachloroperbenzoic acid (MCPBA) is joined the 1.1g[4-(3 that embodiment 23 obtains in 0 ℃ temperature range, the 5-Dimethoxyphenyl) piperazine-1-yl] in the 25ml dichloromethane solution of (2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone, then mixture was at room temperature stirred 20 hours.After 10% sodium bicarbonate aqueous solution and water washing, with the organic phase dried over mgso, concentrating under reduced pressure also passes through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5/2.5 volume ratio).In first fraction, obtain 275mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous pink solid shape thus] (2-methanesulfinyl-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=454 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.94 (non-resolved peakss: 2H); 3.08 (s:3H); 3.20 (non-resolved peaks: 2H); 3.46 (non-resolved peaks: 2H); 3.70 (s:6H); 3.76 (non-resolved peaks: 2H); 6.00 (t, J=2Hz:1H); 6.06 (d, J=2Hz:2H); 7.37 (wide t, J=7.5Hz:1H); 7.47 (wide t, J=7.5Hz:2H); 7.67 (wide d, J=7.5Hz:2H); 13.95 (non-resolved peaks: 1H).
Embodiment 34
3-{3-[4-(3-chloro-phenyl-) piperazine-1-base carbonyl]-4-phenylpyrrole-1-yl }-methyl propionate
React according to embodiment 32 described methods, but collect first fraction.With this elutriated fraction with 132 μ l 1M hcl acidifyings after, collect 53mg 3-{3-[4-(3-chloro-phenyl-) piperazine-1-carbonyl obtain amorphous beige solid shape]-4-phenylpyrrole-1-yl the methyl propionate hydrochloride, its feature is as follows:
Mass spectrum (EI): m/z=451 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.60-3.10 and 3.30-3.80 (be respectively wide non-resolved peaks and non-resolved peaks: 8H) altogether; 2.92 (t, J=7Hz:2H); 3.64 (s:3H); 4.20 (t, J=7Hz:2H); 6.80 (mt:2H); 6.87 (t, J=2Hz:1H); 7.06 (d, J=2.5Hz:1H); 7.13 (d, J=2.5Hz:1H); 7.15-7.25 (mt:1H); 7.20 (t, J=8Hz:1H); 7.34 (mt:4H).
Embodiment 35
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-hydroxymethyl-4-phenyl-1H-pyrroles-3-yl) ketone
37% aqueous solution and the 0.66ml 1N sodium hydroxide of 2.98ml formaldehyde are joined 235mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 16 makes] in the 4ml ethanolic soln of (4-phenyl-1H-pyrroles-3-yl) ketone.After at room temperature stirring 20 hours, with the reaction mixture concentrating under reduced pressure, then to wherein adding 50ml water and, using 2 * 25ml water washing then with 3 * 25ml ethyl acetate extraction.With organic phase with dried over mgso and concentrating under reduced pressure.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio).Obtain 145mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous white solid thus] (1-hydroxymethyl-4-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=421 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.85 (non-resolved peakss: 4H); 3.46 (non-resolved peaks: 4H); 3.68 (s:6H); 5.25 (s:2H); 5.98 (s:3H); 6.63 (non-resolved peaks: 1H); 7.10 (d, J=2Hz:1H); 7.17 (d, J=2Hz:1H); 7.20 (mt:1H); 7.34 (mt:4H).
Embodiment 36
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(2-hydroxyethyl)-4-phenyl-1H-pyrroles-3-yl] ketone
Step 1: 391.5mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 16 is made] (4-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 90mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 241mg (2-bromine oxethyl)-tertiary butyl dimethylsilane then and mixture is descended heating 3 hours at 60 ℃, at room temperature stirred then 20 hours.The concentrating under reduced pressure pyrido adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.With dried over mgso and concentrating under reduced pressure, then by flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5-2.5 volume ratio) and obtain orange buttery 400mg{1-[2-(t-butyldimethylsilyl oxygen base) ethyl]-4-phenyl-1H-pyrroles-3-yl } [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=549 (M
+)
Step 2: the tetrahydrofuran solution of 5.82ml 1M four-N-butyl Neutral ammonium fluoride is joined 400mg{1-[2-(t-butyldimethylsilyl oxygen base) ethyl]-4-phenyl-1H-pyrroles-3-yl } in the 12ml tetrahydrofuran solution of [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] ketone.20 ℃ down stir 20 hours after, add the 50ml ethyl acetate and with mixture with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (99/1 volume ratio).Obtain 180mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous yellow solid shape thus] [1-(2-hydroxyethyl)-4-phenyl-1H-pyrroles-3-yl]-ketone, its feature is as follows:
Mass spectrum (EI): m/z=435 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.85 (non-resolved peakss: 4H); 3.47 (non-resolved peaks: 4H); 3.69 (s:6H); 3.72 (mt:2H); 3.99 (t, J=7.5Hz:2H); 4.96 (t, J=5Hz:1H); (5.98 wide s:3H); 7.04 (d, J=2Hz:1H); 7.09 (d, J=2Hz:1H); 7.16 (mt:1H); 7.34 (mt:4H).
Embodiment 37
3-[4-(1-methyl-4-phenyl-1H-pyrroles-3-base-carbonyl) piperazine-1-yl] benzamide
(they can be according to reference Med.Chem.Res. (1997) with the basic formic acid of 201mg 1-methyl-4-phenyl-1H-pyrroles-3-according to embodiment 5 described methods; 7 (2); 98-108 makes) and 278mg1-(3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 9800400) in the 25ml methylene dichloride, in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 148mg I-hydroxybenzotriazole hydrate (HOBT), react, the reaction at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out, obtain 240mg 3-[4-(1-methyl-4-phenyl-1H-pyrroles-3-base-carbonyl) piperazine-1-yl of amorphous white solid with methylene dichloride and methanol mixture (95/5 volume ratio)] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=388 (M
+)
1H mass spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.65-3.15 (wide non-resolved peaks: 4H); 3.50 (non-resolved peaks: 4H); 3.69 (s:3H); 6.98 (mt:1H); 7.01 (d, J=2Hz:1H); 7.04 (d, J=2Hz:1H); 7.10-7.40 (mt:9H); 7.86 (non-resolved peaks: 1H).
Embodiment 38
[4-(2-hydroxyl-3,5-Dimethoxyphenyl) piperazine-1-yl] (2-methanesulfinyl-5-phenyl-1H-imidazol-4 yl) ketone
React according to embodiment 33 described methods, but the fraction of collecting second wash-out.Obtain 45mg[4-(2-hydroxyl-3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous purple solid state thus] (2-methanesulfinyl-5-phenyl-1H-imidazol-4 yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=470 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.68 (non-resolved peakss: 2H); 2.97 (non-resolved peaks: 2H); 3.08 (s:3H); 3.45 (non-resolved peaks: 2H); 3.68 (s:3H); 3.75 (s:3H); 3.79 (non-resolved peaks: 2H); 6.05 (wide d, J=2.5Hz:1H); 6.32 (d, J=2.5Hz:1H); 7.38 (wide t, J=7.5Hz:1H); 7.48 (wide t, J=7.5Hz:2H); 7.65 (wide d, J=7.5Hz:2H); (7.73 wide s:1H); 13.92 (wide non-resolved peaks: 1H).
Embodiment 39
3-[4-(3-phenyl-1H-pyrroles-2-base carbonyl) piperazine-1-yl] benzamide
Step 1: the 115ml toluene solution of 3.25g 1-boc-piperazine is placed the 250ml three-necked flask, add 369.4mg (R)-(+)-2 then, 2 '-two (diphenylphosphine)-1,1 '-dinaphthalene, 3.176g 3-bromobenzyl nitrile, 133.2mg acid chloride and 2.516g sodium tert-butoxide.Heated 16 hours down with the reaction mixture stirring and at 80 ℃, then with the dilution of 110ml water.Water by settlement separate, is used the 120ml ethyl acetate extraction then.Organic phase is merged, use dried over mgso, filter and reduction vaporization.With the compound that obtains by silica gel chromatography purifying (20-40 μ m, last sample solvent: methylene dichloride, use 75/25v/v cyclohexane/ethyl acetate wash-out then, flow velocity 20ml/min is up to compound crystallization on post for AIT short column, Ref.FC-150-Si-BP-SUP).Silicagel column is divided into 8 equal portions, and the silica gel with each part extracts with ethyl acetate (20ml) then, generates various fractions.The fraction that will contain expecting compound merges, then reduction vaporization.Obtain 3.08g 4-(3-cyano-phenyl)-piperazine-1-base t-butyl formate thus, its feature is as follows:
Infrared spectrum (KBr): 3070; 2979; 2223; 1684; 1599; 1373; 1489; 1427; 1393; 1368; 1364; 1243; 1160; 1126; 993; 953; 785 and 686cm
-1
Mass spectrum: EI:m/z=287, M
+M/z=231, (M-C
4H
8)
+M/z=157C
10H
9N
2 +M/z=57C
4H
9 +Base peak
Step 2: 3.81g 4-(3-cyano-phenyl) piperazine-100ml methanol solution of 1-base-t-butyl formate that obtains more than inciting somebody to action places the round-bottomed flask of 250ml, adds 24ml 1M aqueous sodium hydroxide solution then.With reaction mixture refluxed 36 hours, reduction vaporization then.In resistates, add 150ml ethyl acetate and 150ml water and pass through settlement separate.With water 100ml ethyl acetate extraction.Organic extract liquid is merged, use dried over mgso, filter and reduction vaporization, in the compound that obtains, add the mixture of ethyl acetate (15ml) and heptane (10ml).The solid that forms is leached, and washing (1/1 ethyl acetate/heptane, 10ml) and drying under reduced pressure.Obtain 2.01g 4-(the 3-formamyl phenyl) piperazine-1-base t-butyl formate of beige solid shape thus, its feature is as follows:
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 1.45 (s:9H); 3.17 (mt:4H); 3.48 (mt:4H); (7.11 dt, J=7.5 and 2Hz:1H); 7.20-7.35 (mt:3H); (7.44 the s:1H of non-constant width); 7.90 (non-resolved peaks: 1H).
Mass spectrum: EI:m/z=305M
+M/z=249, (M-C
4H
8)
+M/z=163, C
9H
11N
2O
+, base peak; M/z=57C
4H
9 +
Step 3: the 8ml dioxane solution of 2.01g 4-(3-formamyl phenyl) piperazine-1-base t-butyl formate is placed the 100ml round-bottomed flask, add 8ml 4M hydrochloric acid De dioxane solution then and mixture is descended stirring 16 hours at 20 ℃.The solid that forms is leached, with ether washing and drying under reduced pressure.Obtain 1.57g 3-(piperazine-1-yl) benzamide thus, its feature is as follows:
LC/MS:Tr=1.48 minute, M+H
+M/z 206.28.
Step 4: under agitation 500mg 3-phenyl-1H-pyrroles that the step 1 of embodiment 6 is obtained-2-base formic acid, 563.2mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 397mg I-hydroxybenzotriazole (HOBT) and 710.2mg 3-(piperazine-1-yl) mixture of benzamide in the 40ml methylene dichloride place the 100ml three-necked flask that is placed under the argon gas, add the 1.24ml triethylamine then.Reaction mixture was stirred 16 hours down at 20 ℃, then with 50ml methylene dichloride and the dilution of 50ml water.After separating by sedimentation, extract with the 20ml methylene dichloride.Organic extract liquid is merged, use dried over mgso, filter and reduction vaporization.Add ethyl acetate (15ml) and methyl alcohol (5ml) in the crude product compound that obtains, dissolving was placed 48 hours down at 20 ℃ then.The solid that forms is leached, with ethyl acetate (5ml) and ether washing and drying under reduced pressure.Obtain the 778mg actual product thus, the mixture recrystallization with 80mg wherein uses ethyl acetate (5ml) and methyl alcohol (5ml) filters, with ethyl acetate (5ml) washing and drying.Separate thus and obtain 55mg 3-[4-(3-phenyl-1H-pyrroles-2-base carbonyl) piperazine-1-yl] benzamide, its feature is as follows:
1H NMR wave spectrum (300MHz, (CD
3)
2SO d6, δ ppm): 2.92 (non-resolved peakss: 4H); 3.44 (non-resolved peaks: 4H); 6.34 (t, J=2.5Hz:1H); 6.94 (t, J=2.5Hz:1H); 6.98 (d mt, J=7.5Hz:1H); 7.15-7.40 (mt:9H); 7.86 (non-resolved peaks: 1H); 11.49 (non-resolved peaks: 1H).
Mass spectrum: EI:m/z=374M
+M/z=212C
13H
12N
2O
+M/z=175C
10H
11N
2O
+Base peak; M/z=170C
11H
8NO
+
Fusing point: 259 ° (Kofler warm table).
Embodiment 40
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-3-phenyl-1H-pyrroles-2-yl)-ketone hydrochloride
The 99.9mg[4-(3 that embodiment 8 is obtained, the 5-Dimethoxyphenyl) piperazine-1-yl] the 1ml dimethyl formamide solution of (3-phenyl-1H-pyrroles-2-yl) ketone places 5ml Weathon reactor, adds 38.8mg salt of wormwood and 17.5 μ l methyl iodide then.Reaction mixture stirring under 20 ℃ is spent the night.Because reaction remains unfulfilled,, continue reaction 60 minutes down at 20 ℃ so add the 20mg sodium hydride and add 18 μ l methyl iodide.With reaction mixture water (15ml) dilution, use ethyl acetate (15ml) extraction then.(2 * 10ml) extract with ethyl acetate with water.Organic extract liquid is merged, use dried over mgso, filter and reduction vaporization.The compound that obtains is passed through silica gel chromatography purifying (26 * 135 short columns, Ref.1511-1000,10g silica gel, 15-40 μ m, eluent 9/1v/v cyclohexane/ethyl acetate, flow velocity 10ml/min).The fraction that will contain expecting compound merges, and reduction vaporization is developed the compound that obtains 15 hours with ether (5ml) then.The solid that forms is leached, with ether washing and drying under reduced pressure.Separate thus and obtain 62.8mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-3-phenyl-1H-pyrroles-2-yl) ketone (62.8mg, 56%), its feature is as follows:
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.70-3.40 (several wide non-resolved peakss: 4H) altogether; 3.61 (s:3H); 3.69 (s:6H); 3.60-4.00 (non-resolved peaks: 4H); 5.98 (s:3H); 6.31 (d, J=3Hz:1H); 6.94 (d, J=3Hz:1H); 7.20 (mt:1H); 7.25-7.40 (mt:4H).
Mass spectrum: EI m/z=405M
+M/z=192, C
11H
14NO
2 +, base peak; M/z=184, C
12H
10NO
+
Embodiment 41
1-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-base-carbonyl]-4-phenylpyrrole-1-yl }-ethyl ketone
With 98 μ l N, N-diisopropyl ethyl amine (DIPEA), 62mg 4-dimethylaminopyridine (DMAP) and 40 μ l Acetyl Chloride 98Min.s join 200mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 18 makes] in the 15ml dichloromethane solution of (4-phenyl-1H-pyrroles-3-yl)-ketone.After at room temperature stirring 20 hours, in reaction medium, add 25ml water and 25ml methylene dichloride, use the 25ml water washing then once.With organic phase with dried over mgso and concentrating under reduced pressure.The yellow oil that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (98/2 volume ratio).Obtain 120mg 1-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-base-carbonyl of amorphous beige solid shape thus]-4-phenylpyrrole-1-yl }-ethyl ketone, its feature is as follows:
Mass spectrum (EI): m/z=433 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.65 (s:3H); 2.68 (non-resolved peaks: 2H); 3.10 (non-resolved peaks: 2H); 3.20-3.35 (non-resolved peaks: 2H); 3.68 (non-resolved peaks: 2H); 3.68 (s:6H); (6.00 wide s:3H); (7.30 tt, J=7.5 and 1.5Hz:1H); 7.40 (wide t, J=7.5Hz:2H); 7.48 (wide d, J=7.5Hz:2H); 7.68 (d, J=2Hz:1H); 7.79 (d, J=2Hz:1H).
Embodiment 42
(2-amino-4-phenyl thiazole-5-yl) [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl]-ketone
Step 1: 4ml 1N aqueous sodium hydroxide solution and 10ml ethanol are joined in the solution of 260mg 2-amino-4-phenyl thiazole-5-base-ethyl formate (it can make according to WO 03/024948).After at room temperature placing 72 hours, with the reaction mixture concentrating under reduced pressure, with resistates 1N hcl acidifying, until reaching pH 1.With formed solid filtering, obtain the 210mg 2-amino-4-phenyl thiazole-5-base formic acid of white solid thus, its feature is as follows:
Mass spectrum (EI): m/z=220 (M
+)
Step 2: 192mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 135mg I-hydroxybenzotriazole hydrate (HOBT) are joined in the 25ml dichloromethane solution of 200mg 2-amino-4-phenyl thiazole-5-base formic acid and 202mg 1-(3, the 5-Dimethoxyphenyl) piperazine.Mixture was at room temperature stirred 20 hours, by flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5/2.5 volume ratio), [4-(3 to solidify the 245mg (2-amino-4-phenyl thiazole-5-yl) that obtains amorphous beige solid shape with diisopropyl ether then, the 5-Dimethoxyphenyl) piperazine-1-yl]-ketone, its feature is as follows:
Mass spectrum (EI): m/z=424 (M
+)
1H NMR wave spectrum (300MHz, (CD
3)
2SO, δ ppm): 2.84 (non-resolved peakss: 4H); 3.42 (non-resolved peaks: 4H); 3.68 (s:6H); 5.98 (s:3H); 7.25-7.45 (mt:5H); 7.56 (wide d, J=7.5Hz:2H).
Embodiment 43
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl-5-phenyl-3H-imidazol-4 yl) ketone
Step 1: 1g potassium hydroxide particle is joined in the solution of 3.5g 2-methyl-5-phenyl-1H-imidazol-4 yl ethyl formate (it can obtain according to patent application WO 95/04724) in 30ml distilled water and 60ml ethanol.Refluxed 20 hours, and turned back to room temperature then, with the reaction mixture concentrating under reduced pressure, with resistates 1N hcl acidifying.To obtain the 3g 2-methyl-5-phenyl-1H-imidazol-4 yl formic acid of beige solid shape behind the formed solid filtering, its feature is as follows:
Mass spectrum (EI): m/z=202 (M
+)
Step 2: with 146mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 103mg I-hydroxybenzotriazole hydrate (HOBT) and 154mg 1-(3, the 5-Dimethoxyphenyl) piperazine joins in the 15ml dichloromethane solution of 140mg 2-methyl-5-phenyl-1H-imidazol-4 yl formic acid, then this reaction mixture is at room temperature stirred 20 hours.After adding 25ml methylene dichloride and 25ml water, organic phase by settlement separate, is washed with water, then with dried over mgso and concentrating under reduced pressure.By silica gel flash column chromatography purifying (60; 35-70 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio), obtain the 100mg[4-(3 of amorphous white solid thus, the 5-Dimethoxyphenyl) piperazine-1-yl]-(2-methyl-5-phenyl-3H-imidazol-4 yl) ketone, its feature is as follows: mass spectrum (EI): m/z=406 (M
+).
Embodiment 44
3-[4-(2-sulfydryl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzamide
(they can be according to Chem.Pharm.Bull. (1984) with the basic formic acid of 440mg 2-sulfydryl-4-phenyl-1H-imidazoles-5-according to embodiment 5 described methods; 32 (7); 2536-43 makes) and 560mg 1-(3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 98/00400) in the 75ml methylene dichloride, in the presence of 421mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 297mg I-hydroxybenzotriazole hydrate (HOBT) and 0.7ml triethylamine, react, the reaction at room temperature stirred 20 hours.With flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 266mg3-[4-(2-sulfydryl-4-phenyl-1H-imidazoles-5-base-carbonyl) piperazine-1-yl that wash-out obtains amorphous yellow solid shape with methylene dichloride and methanol mixture (95/5 volume ratio)] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=407 (M
+).
Embodiment 45
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(thiazole-4-yl) methyl-4-phenyl-1H-pyrroles-3-yl] ketone
250mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 16 is made] (4-phenyl-1H-pyrroles-3-yl)-ketone is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 59mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 108mg 4-5-chloromethyl thiazole hydrochloride then and mixture is descended heating 6 hours at 60 ℃, at room temperature stirred then 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.With dried over mgso and concentrating under reduced pressure, then by flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (98-2 volume ratio), obtain the 170mg[4-(3 of amorphous reddish brown-yellow solid shape then with the diisopropyl ether crystallization, the 5-Dimethoxyphenyl) piperazine-1-yl]-[1-(thiazole-4-yl) methyl-4-phenyl-1H-pyrroles-3-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=488 (M
+).
Embodiment 46
4-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] carbonyl-4-phenyl-1H-pyrroles-1-yl }-butyric acid
250mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 16 is made] (4-phenyl-1H-pyrroles-3-yl)-ketone is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 59mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 96 μ l 4-bromo-butyric acid ethyl esters then and mixture is descended heating 8 hours at 60 ℃, at room temperature stirred then 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.By add 1N hydrochloric acid with aqueous phase as acidified to pH 4, use 3 * 25ml dichloromethane extraction then." methylene dichloride " that merges is evaporated to mutually dried, with resistates diisopropyl ether crystallization.Obtain 142mg 4-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous yellow solid shape thus] carbonyl-4-phenyl-1H-pyrroles-1-yl } butyric acid, its feature is as follows:
Mass spectrum (EI): m/z=477 (M
+).
Embodiment 47
2-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] carbonyl-4-phenyl-1H-pyrroles-1-yl } acetate
250mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 16 is made] (4-phenyl-1H-pyrroles-3-yl)-ketone is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 59mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 60.5 μ l ethyl bromoacetate then and mixture is descended heating 6 hours at 60 ℃, at room temperature stirred then 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.By add 1N hydrochloric acid with aqueous phase as acidified to pH 4, use 3 * 25ml dichloromethane extraction then." methylene dichloride " that merges is evaporated to mutually dried, with resistates by flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95-5 volume ratio).Obtain 42mg 2-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous orange solids shape thus] carbonyl-4-phenyl-1H-pyrroles-1-yl } acetate, its feature is as follows:
Mass spectrum (EI): m/z=449 (M
+).
Embodiment 48
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(pyridin-3-yl) methyl-4-phenyl-1H-pyrroles-3-yl] ketone
250mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 16 is made] (4-phenyl-1H-pyrroles-3-yl)-ketone is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 57mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 161.6mg 3-bromo methyl cycloheptapyridine hydrochloride then and mixture is descended heating 6 hours at 60 ℃, at room temperature stirred then 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.Behind dried over mgso and concentrating under reduced pressure, by flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (98-2 volume ratio), obtain the 75mg[4-(3 of amorphous light yellow solid shape then with the diisopropyl ether crystallization, the 5-Dimethoxyphenyl) piperazine-1-yl]-[1-(pyridin-3-yl) methyl-4-phenyl-1H-pyrroles-3-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=482 (M
+).
Embodiment 49
2-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] carbonyl-2-phenyl-1H-pyrroles-1-yl } methyl acetate
350mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 8 is made] (2-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 15ml pyridine.After being cooled to 0 ℃, adding 54mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 90 μ l methyl bromoacetates then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.The organic phase that merges is washed with water, with dried over mgso and be evaporated to dried.Resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5-2.5 volume ratio).Obtain 230mg 2-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous orange solids shape thus] carbonyl-2-phenyl-1H-pyrroles-1-yl } methyl acetate, its feature is as follows:
Mass spectrum (EI): m/z=463 (M
+).
Embodiment 50
3-[4-(1-methyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide
According to embodiment 5 described methods 430mg 1-methyl-2-phenyl-1H-pyrroles-3-base formic acid (it can make according to the step 1 of embodiment 21) and 420mg 1-(3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 98/00400) are reacted in the presence of 320mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 20mg I-hydroxybenzotriazole hydrate (HOBT) and 0.6ml triethylamine in the 50ml methylene dichloride, reaction was at room temperature stirred 20 hours.By with the 260mg 3-[4-that obtains the white crystals shape behind the 13ml diisopropyl ether crystallization purifying (1-methyl-2-phenyl-1H-pyrroles-3-base-carbonyl) piperazine-1-yl] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=407 (M
+)
Fusing point (Kofler warm table)=172 ℃.
Embodiment 51
3-[4-(2-hydroxy-4-phenyl-1H-imidazoles-5-base-carbonyl) piperazine-1-yl] benzamide
(it can be according to Heterocycles 1984 with the basic formic acid of 410mg 2-hydroxy-4-phenyl-1H-imidazoles-5-according to embodiment 5 described methods; 22 (8); 1763-69 makes) and 610mg 1-(3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 98/00400) in the 50ml methylene dichloride, in the presence of 420mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 27mg I-hydroxybenzotriazole hydrate (HOBT) and 0.82ml triethylamine, react, the reaction at room temperature stirred 48 hours.By using 20ml 1, obtain 500mg 3-[4-(2-hydroxy-4-phenyl-1H-imidazoles-5-base-carbonyl) piperazine-1-yl of white crystals shape behind the 2-glycol dimethyl ether crystallization purifying] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=391 (M
+)
Fusing point (Kofler warm table)=202 ℃.
Embodiment 52
3-[4-(2-sulfydryl-4-phenyl-1H-imidazoles-5-base-carbonyl) piperazine-1-yl]-benzonitrile
(they can be according to Chem.Pharm.Bull. (1984) with 300mg 2-sulfydryl-4-phenyl-1H-imidazoles-5-base-formic acid according to embodiment 5 described methods, 32 (7), 2536-43 makes) and 354mg 1-(3-cyano-phenyl) piperazine dihydrochloride (they can be according to Tetrahedron Lett (2000), 56 (24), 4107-10 makes) in the 50ml methylene dichloride at 287mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), react under the existence of 202mg I-hydroxybenzotriazole hydrate (HOBT) and 0.57ml triethylamine, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 431mg 3-[4-(2-sulfydryl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl that wash-out obtains amorphous white solid with methylene dichloride and methanol mixture (99/1 volume ratio)] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=389 (M
+)
Fusing point (Kofler warm table)=247 ℃
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.83-3.80 (m of non-constant width, 8H); 7.19 (td, J=1.0 and 7.5Hz, 1H); 7.23 (ddd, J=1.0-2.5 and 7.5Hz, 1H); 7.31 (dd, J=1.0 and 2.5Hz, 1H); 7.35-7.42 (m, 2H); 7.44 (wide t, J=7.5Hz, 2H); 7.51 (wide d, J=7.5Hz, 2H); 12.6 (wide m, 1H); 12.8 (wide, 1H).
Embodiment 53
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(2-hydroxyethyl)-2-phenyl-1H-pyrroles-3-yl] ketone
Step 1: 391.5mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 8 is made] (2-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 20ml pyridine.After being cooled to 0 ℃, adding 64.5mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 0.25ml (2-bromine oxethyl)-tertiary butyl dimethylsilane then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.With obtaining orange buttery 570mg{1-[2-(t-butyldimethylsilyl oxygen base) ethyl behind dried over mgso and the concentrating under reduced pressure]-2-phenyl-1H-pyrroles-3-yl } [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] ketone, it is directly used in following steps: its feature is as follows:
Mass spectrum (EI): m/z=549 (M
+)
Step 2: the tetrahydrofuran solution of 8ml 1M four-N-butyl Neutral ammonium fluoride is joined 550mg{1-[2-(t-butyldimethylsilyl oxygen base) ethyl]-2-phenyl-1H-pyrroles-3-yl } in the 20ml tetrahydrofuran solution of [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] ketone.20 ℃ down stir 20 hours after, add the 50ml ethyl acetate, with product with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95/5 volume ratio).With the 240mg[4-that obtains the white crystals shape behind the 15ml diethyl ether recrystallization (3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(2-hydroxyethyl)-2-phenyl-1H-pyrroles-3-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=435 (M
+)
Fusing point (Kofler warm table)=157 ℃.
Embodiment 54
3-[4-(2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzamide
Step 1: 200mg 4-phenyl-2-Trifluoromethyl-1 H-imidazoles-2-ethyl formate (it can make according to WO 95/04724) is dissolved in the 10ml tetrahydrofuran (THF).Add the 185mg lithium hydroxide monohydrate then and mixture was at room temperature stirred 20 hours.Behind the concentrating under reduced pressure, resistates is dissolved in 5ml water, adds the 1N hydrochloric acid soln then, until obtaining pH 6.The throw out that forms is leached and vacuum-drying, obtains the 160mg 4-phenyl-2-Trifluoromethyl-1 H-imidazoles-2-base formic acid of white solid thus, it is directly used in following steps:
Step 2: according to embodiment 5 described methods 120mg 2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base formic acid and 130mg 1-(3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO98/00400) are reacted in the presence of 99mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 70mg I-hydroxybenzotriazole hydrate (HOBT) and 0.20ml triethylamine in the 20ml methylene dichloride, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 79mg 3-[4-(2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl that gradient elution (from 99/1 to 95/5 volume ratio) obtains the white foam shape with methylene dichloride and alcoholic acid mixture] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=443 (M
+).
Embodiment 55
3-[4-(2-methylthio group-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzamide
The 150mg 3-[4-that embodiment 44 is obtained (2-sulfydryl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzamide forms suspension in 13ml methyl alcohol, add the 24mg sodium methylate then, and mixture is at room temperature stirred 20 minutes to dissolving fully.Add 25 μ l methyl iodide then and mixture is descended heating 1 hour 45 minutes at 40 ℃.With the methyl alcohol concentrating under reduced pressure, in resistates, add the mixture of entry and methylene dichloride then.Water is extracted once more with methylene dichloride.The organic phase that merges is washed with water, with dried over mgso and be concentrated into dried.Obtain 153mg 3-[4-(2-methylthio group-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl of yellow powder shape with the diisopropyl ether recrystallization]-benzamide, its feature is as follows:
Mass spectrum (EI): m/z=421 (M
+).
Embodiment 56
3-[4-(2-methylthio group-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzonitrile
The 200mg 3-[4-that embodiment 52 is obtained according to embodiment 55 described methods (2-sulfydryl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzonitrile, 33mg sodium methylate and 35 μ l methyl iodide react in 20ml methyl alcohol.With the 106mg3-[4-that obtains white powder behind the diisopropyl ether recrystallization (2-methylthio group-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=403 (M
+)
1H NMR wave spectrum (300MHz)-δ ppm d6-DMSO:2.61 (s, 3H); 3.03-3.37 (m of non-constant width, 4H); 3.46-3.80 (non-constant width m, 4H); 7.19 (wide d, J=8.0Hz, 1H); 7.22-7.44 (m, 6H); 7.58 (wide d, J=8.0Hz, 2H); 12.8 (wide m, 1H).
Embodiment 57
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-hydroxy-4-phenyl-1H-imidazoles-5-yl) ketone
Step 1: 850mg 4-tertiary butyl ketonic oxygen base-1-(3-hydroxymethyl phenyl) piperazine (it can make according to WO 00/15646) is dissolved in the 40ml diox.Add 3.64ml 4N hydrochloric acid De dioxane solution then and mixture is descended stirring 1 hour at 0 ℃.The throw out that forms is leached, with diethyl ether washing and drying under reduced pressure.Obtain 770mg 1-(the 3-hydroxymethyl phenyl) piperazine dihydrochloride of yellow powder shape, it is directly used in following steps.
Step 2: (it can be according to Heterocycles 1984 with the basic formic acid of 145mg 2-hydroxy-4-phenyl-1H-imidazoles-5-according to embodiment 5 described methods, 22 (8), 1763-6998-108 makes) and 188mg1-(3-hydroxymethyl phenyl) piperazine dihydrochloride in the 25ml methylene dichloride, in the presence of 150mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 105mg I-hydroxybenzotriazole hydrate (HOBT) and 0.22ml triethylamine, react, the reaction at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (90/10 volume ratio), obtain 145mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl of white crystals shape then with the crystallization of 5ml diethyl ether] (2-hydroxy-4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=378 (M
+)
Fusing point (Kofler warm table)=173 ℃
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:3.10 (wide m, 4H); 3.62 (wide m, 4H); 4.44 (d, J=5.0Hz, 2H); 5.09 (wide t, J=5.0Hz, 1H); 6.79 (m, 2H); 6.90 (t, J=2.0,1H); 7.18 (t, J=8.0Hz, 1H); 7.21 (s, 2H); 7.36 (wide t, J=8.0Hz, 1H); 7.42 (wide t, J=8.0Hz, 2H); 7.75 (wide d, J=8.0Hz, 1H).
Embodiment 58
3-[4-(4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide
(it can be according to Med.Chem.Res.1997 with the basic formic acid of 1.404g 4-phenyl-1H-pyrroles-3-according to embodiment 5 described methods; 7 (2); 98-108 makes) and 2.086g 1-(3-formamyl phenyl) piperazine dihydrochloride (it can make according to WO 98/00400) in the 100ml methylene dichloride, in the presence of 1.582g1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 1.115g I-hydroxybenzotriazole hydrate (HOBT) and 2.32ml triethylamine, react, the reaction at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 1.70g 3-[4-(4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl that gradient elution (from 95/5 to 90/10 volume ratio) obtains the cream-coloured powder shape with methylene dichloride and methanol mixture] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=374 (M
+).
Embodiment 59
3-[4-(2-methyl-5-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzamide
422mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 297mg I-hydroxybenzotriazole hydrate (HOBT) are joined in the 50ml dichloromethane solution of 404mg 2-methyl-5-phenyl-1H-imidazol-4 yl formic acid.After at room temperature stirring 10 minutes, add 0.85ml triethylamine (TEA) and 556mg 3-piperazine-1-yl-benzamide dihydrochloride (it can obtain according to patent application WO 98/00400), then this reaction mixture was at room temperature stirred 20 hours.After adding 50ml methylene dichloride and 50ml water, organic phase by settlement separate, is washed with water, then with dried over mgso and concentrating under reduced pressure.By silica gel flash column chromatography purifying (60; 35-70 μ m), carry out 425mg3-[4-(2-methyl-5-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl that wash-out obtains amorphous white solid with methylene dichloride and methanol mixture (90/10 volume ratio)] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=389 (M
+).
Embodiment 60
3-[4-(2-methyl-5-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzonitrile
422mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 297mg I-hydroxybenzotriazole hydrate (HOBT) are joined in the 50ml dichloromethane solution of 404mg 2-methyl-5-phenyl-1H-imidazol-4 yl formic acid.After at room temperature stirring 10 minutes, add 0.62ml triethylamine (TEA) and 520mg 3-piperazine-1-base benzonitrile dihydrochloride (it can obtain according to patent application WO99/31096), then this reaction mixture was at room temperature stirred 20 hours.After adding 50ml methylene dichloride and 50ml water, organic phase by settlement separate, is washed with water, then with dried over mgso and concentrating under reduced pressure.By silica gel flash column chromatography purifying (60; 35-70 μ m), carry out 585mg3-[4-(2-methyl-5-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl that wash-out obtains amorphous white solid with methylene dichloride and methanol mixture (95/05 volume ratio)] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=371 (M
+).
Embodiment 61
3-[4-(4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile
(it can be according to Med.Chem.Res.1997 with the basic formic acid of 375mg 2-hydroxy-4-phenyl-1H-imidazoles-5-according to embodiment 5 described methods, 7 (2), 98-108 makes) and 520mg 1-(3-cyano-phenyl) piperazine dihydrochloride (it can be according to Tetrahedron Lett.2000,56 (24), 4107-10 makes) in the 50ml methylene dichloride at 422mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), react under the existence of 297mg I-hydroxybenzotriazole hydrate (HOBT) and 0.62ml triethylamine, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 555mg 3-[4-(4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl that wash-out obtains the pale powder shape with methylene dichloride and methanol mixture (95/5 volume ratio)] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=356 (M
+).
Embodiment 62
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-trifluoromethyl-4-phenyl-1H-imidazoles-5-yl) ketone
200mg 2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base formic acid and the 174mg (3 that the step 1 of embodiment 54 is made according to embodiment 5 described methods, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 165mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 116mg I-hydroxybenzotriazole hydrate (HOBT) in the 30ml methylene dichloride, and reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out gradient elution (from 100/0 to 99.5/0.5 volume ratio) with methylene dichloride and methanol mixture, obtain the 87mg[4-(3 of white crystals shape then with 5ml diethyl ether recrystallization, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-trifluoromethyl-4-phenyl-1H-imidazoles-5-yl)-ketone, its feature is as follows:
Mass spectrum (EI): m/z=460 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO is under 373K: 3.10 (wide m, 4H); 3.62 (wide m, 4H); 3.73 (m, 6H); 6.01 (t, J=2.0Hz, 1H); 6.06 (d, J=2.0Hz, 2H); 7.38 (wide t, J=8.0Hz, 1H); 7.46 (wide t, J=8.0Hz, 2H); 7.68 (wide d, J=8.0Hz, 1H); 13.9 (wide m, 1H).
Embodiment 63
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-ethanoyl-2-phenyl-1H-pyrroles-3-yl) ketone
300mg [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone that embodiment 21 is obtained is dissolved in the 15ml pyridine.After being cooled to 0 ℃, adding 46mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 80 μ l ethanoyl chlorine then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.The organic phase that merges is washed with water, with dried over mgso and be evaporated to dried.Resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97-3 volume ratio).With the 135mg[4-that obtains the white crystals shape behind the 10ml diethyl ether recrystallization (3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-ethanoyl-2-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=433 (M
+)
Fusing point (Kofler warm table)=150 ℃.
Embodiment 64
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(3-pyridyl) methyl-2-phenyl-1H-pyrroles-3-yl] ketone
300mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 21 is obtained] (2-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 15ml pyridine.After being cooled to 0 ℃, adding 61mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 291mg 3-bromo methyl cycloheptapyridine hydrobromate then and mixture was at room temperature stirred 20 hours.Add 61mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) and 291mg 3-bromo methyl cycloheptapyridine then and mixture is descended heating 6 hours at 60 ℃.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.The organic phase that merges is washed with water, with dried over mgso and be evaporated to dried.Resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (96.5-3.5 volume ratio).Obtain orange foamed 50mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl thus] [1-(3-pyridyl) methyl-2-phenyl-1H-pyrroles-3-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=482 (M
+).
Embodiment 65
3-[4-(2-methoxycarbonyl methyl-4-phenyl-1H-pyrroles-3-carbonyl) piperazine-1-yl] benzamide
The 374mg 3-[4-that embodiment 58 is made (4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide is dissolved in 10ml anhydrous dimethyl formamide (DMF).After being cooled to 0 ℃, adding 44mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add the 168mg methyl bromoacetate then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.With dried over mgso and concentrating under reduced pressure, resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carries out wash-out, use the crystallization of 10ml diethyl ether then with methylene dichloride and methanol mixture (96.5-3.5 volume ratio).Obtain 400mg 3-[4-(the 2-methoxycarbonyl methyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl of amorphous beige solid shape thus] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=446 (M
+).
Embodiment 66
3-[4-(1-hydroxyethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide
Step 1: the 374mg 3-[4-that embodiment 58 is made (4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide is dissolved in 10ml anhydrous dimethyl formamide (DMF).After being cooled to 0 ℃, adding 44mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 263mg (2-bromine oxethyl)-tertiary butyl dimethylsilane then and mixture was at room temperature stirred 20 hours.In reaction medium, add 50ml water, use 3 * 25ml ethyl acetate extraction then.Behind dried over mgso and concentrating under reduced pressure, resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carries out wash-out, use the crystallization of 10ml diethyl ether then with methylene dichloride and methanol mixture (96.5-3.5 volume ratio).Obtain 405mg3-{4-[1-(the t-butyldimethylsilyl oxygen base) ethyl-4-phenyl-1H-pyrroles-3-base-carbonyl of beige solid shape thus] piperazine-1-yl } benzamide, directly use it for following steps.
Step 2: the tetrahydrofuran solution of 6ml 1M four-N-butyl Neutral ammonium fluoride is joined 400mg3-{4-[1-(t-butyldimethylsilyl oxygen base) ethyl-4-phenyl-1H-pyrroles-3-base carbonyl] piperazine-1-yl } in the 12ml tetrahydrofuran solution of benzamide.20 ℃ stir 20 hours after, add the 50ml ethyl acetate and with product with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio).Obtain 210mg 3-[4-(1-hydroxyethyl-4-phenyl-1H-pyrroles-3-base-carbonyl) piperazine-1-yl of amorphous beige solid shape with 15ml diisopropyl ether recrystallization] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=418 (M
+).
Embodiment 67
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-yl) ketone
Step 1: 13g 2-sulfydryl-4-phenyl-1H-imidazoles-5-base ethyl formate (it can be according to Chem.Pharm.Bull.1984,32 (7), 2536-43 makes) is dissolved in 500ml methyl alcohol.After being cooled to 0 ℃, adding the 3.4g sodium methylate in batches and stirred 30 minutes, mixture is turned back to room temperature.Mixture is cooled to 0 ℃ once more, drips the 25ml methanol solution of 3.3g methyl iodide, then mixture was refluxed 8 hours.With the methyl alcohol concentrating under reduced pressure, in resistates, add 150ml ethyl acetate and 150ml water.Organic phase by settlement separate, is washed with water, with dried over mgso and concentrating under reduced pressure.Obtain orange buttery 13g 2-methylthio group-4-phenyl-1H-imidazoles-5-base-ethyl formate thus, directly use it for next procedure, its feature is as follows:
Mass spectrum (EI): m/z=262 (M
+)
Step 2: 7g 2-methylthio group-4-phenyl-1H-imidazoles-5-base ethyl formate is dissolved in 200ml methyl alcohol, adds 24.6g oxone down at 10-20 ℃ then
Or potassium peroxide (2KHSO
5.KHSO
4.K
2SO
4) the 100ml aqueous solution.After at room temperature stirring 20 hours, add 200ml water and with mixture with 3 * 100ml ethyl acetate extraction.The organic phase that merges is washed with water, with the saturated sodium-chloride water solution washing, with dried over mgso and concentrating under reduced pressure.Obtain the 6g 2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-base ethyl formate of white solid thus, it is directly used in next procedure, its feature is as follows:
Mass spectrum (EI): m/z=294 (M
+)
Step 3: 1.5g 2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-base ethyl formate is dissolved in 20ml methyl alcohol, adds the 10ml aqueous solution of 0.37g potassium hydroxide then and mixture was at room temperature stirred 72 hours.Behind the concentrating under reduced pressure methyl alcohol, add 20ml water in resistates, making pH by adding 1N aqueous hydrochloric acid is 2.Formed throw out is leached, water and diisopropyl ether washing successively, dry down in 50 ℃ in baking oven then.Obtain the 1.2g 2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-base formic acid of pale solid shape thus, it is directly used in following step, its feature is as follows:
Mass spectrum (EI): m/z=266 (M
+)
Step 4: according to embodiment 5 described methods with 444mg 2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-base formic acid and 333mg (3; the 5-Dimethoxyphenyl) piperazine reacts in the presence of 316mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 223mg I-hydroxybenzotriazole hydrate (HOBT) in the 37.5ml methylene dichloride, and reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m); mixture (50/50 volume ratio) with hexanaphthene and ethyl acetate carries out wash-out; obtain the 450mg[4-(3 of beige solid shape then with 20ml diisopropyl ether recrystallization; the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=470 (M
+).
Embodiment 68
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone
170mg 1-(the 3-hydroxymethyl phenyl) piperazine dihydrochloride that 121mg 4-phenyl-1H-imidazol-4 yl formic acid that the step 1 of embodiment 3 is obtained according to embodiment 5 described methods and the step 1 of embodiment 57 make reacts in the presence of 135mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 95mg I-hydroxybenzotriazole hydrate (HOBT) and 198 μ l triethylamines, and reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 52mg[4-(3-hydroxymethyl-phenyl) piperazine-1-yl that gradient elution (from 98/2 to 95/5 volume ratio) obtains the white foam shape with methylene dichloride and methanol mixture] (4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=362 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm-d6-DMSO:2.83-3.91 (non-constant width m, 8H); 4.44 (s, 2H); 5.06 (non-constant width m, 1H); 6.78 (m, 2H); 6.90 (wide s, 1H); 7.17 (t, J=7.5Hz, 1H); 7.31 (wide d, J=8.0Hz, 1H); 7.42 (wide t, J=8.0Hz, 2H); 7.62 (wide d, J=8.0Hz, 1H); 7.82 (s, 1H); 12.75 (non-constant width m, 1H).
Embodiment 69
[4-(3,5-hydroxymethyl phenyl) piperazine-1-yl] (1-methyl-4-phenyl-1H-pyrroles-3-yl) ketone
(they can be according to Med.Chem.Res. (1997) with the basic formic acid of 133mg 1-methyl-4-phenyl-1H-pyrroles-3-according to embodiment 5 described methods, 7 (2), 98-108 makes) and 175mg 1-(the 3-hydroxymethyl phenyl) piperazine dihydrochloride that makes of the step 1 of embodiment 57 in the 25ml methylene dichloride, in the presence of 139mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 98mg I-hydroxybenzotriazole hydrate (HOBT) and 204 μ l triethylamines, react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (from 98/2 to 95/5 volume ratio), obtain the 140mg[4-(3 of cream-coloured powder shape then with the diisopropyl ether crystallization, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-4-phenyl-1H-pyrroles-3-yl) ketone hydrochloride, its feature is as follows:
Mass spectrum (EI): m/z=375 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.58-3.20 (non-constant width m, 4H); 3.35-3.65 (non-constant width m, 4H); 3.69 (s, 3H); 4.41 (d, J=5.5Hz, 2H); 5.06 (t, J=5.5Hz, 1H); 6.70 (roomy dd, J=2.0 and 7.5Hz, 1H); 6.75 (wide d, J=7.5Hz, 1H); 6.81 (t, J=2.0Hz, 1H); 7.00 (d, J=2.5Hz, 1H); 7.05 (d, J=2.5Hz, 1H); 7.12-7.22 (m, 2H); 7.32 (m, 4H).
Embodiment 70
3-[4-(2-methyl sulphonyl-4-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzonitrile
(it can be according to Tetrahedron Lett.2000 for 600mg 2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-base formic acid that the step 3 of embodiment 67 is made according to embodiment 5 described methods and 528mg 1-(3-cyano-phenyl) piperazine dihydrochloride; 56 (24); 4107-10 makes) in the 50ml methylene dichloride, in the presence of 428mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 301mg1-hydroxy benzotriazole hydrate (HOBT) and 627 μ l triethylamines, to react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out, obtain 610mg 3-[4-(2-methyl sulphonyl-4-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl of white crystals shape then with the diisopropyl ether crystallization with ethyl acetate] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=435 (M
+)
Fusing point (Koffer warm table)=198 ℃.
Embodiment 71
3-[4-(2-methyl sulphonyl-4-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzamide
The 600mg 2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-base formic acid and 564mg 1-(the 3-formamyl phenyl) piperazine dihydrochloride that the step 3 of embodiment 67 are made according to embodiment 5 described methods react in the presence of 428mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 301mg I-hydroxybenzotriazole hydrate (HOBT) and 627 μ l triethylamines in the 68ml methylene dichloride, react and at room temperature stir 20 hours.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out, obtain 180mg 3-[4-(2-methyl sulphonyl-4-phenyl-1H-imidazol-4 yl-carbonyl) piperazine-1-yl of amorphous beige solid shape to wherein adding diisopropyl ether with ethyl acetate] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=453 (M
+).
Embodiment 72
3-[4-(1-hydroxymethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile
The 500mg 3-[4-that embodiment 61 is obtained (4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile is dissolved in 10ml ethanol, add 7ml 37% formalin and 1.543m1 1N aqueous sodium hydroxide solution then successively, mixture was at room temperature stirred 8 days.In reaction mixture, add 50ml ethyl acetate and 50ml water.Organic phase by settlement separate, is washed with water, with dried over sodium sulfate and concentrating under reduced pressure.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out, obtain 375mg 3-[4-(1-hydroxymethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl of amorphous white solid to wherein adding diisopropyl ether then with ethyl acetate] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=386 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.65-3.20 (non-constant width m, 4H); 3.30-3.65 (non-constant width m, 4H); 5.23 (wide s, 2H); 6.62 (wide s, 1H); 7.10 (d, J=2.5Hz, 1H); 7.16 (m, 4H); 7.24 (dd, J=1.5 and 2.5Hz, 1H); 7.31 (m, 4H); 7.35 (dd, J=7.5 and 8.5Hz, 1H).
Embodiment 73
2-[4-(3-formamyl phenyl) piperazine-1-base carbonyl]-3-phenylpyrrole-1-yl } acetate
Step 1: with 4M hydrochloric acid De dioxane solution (11.6ml) join 2.6g 4-(3-cyano-phenyl) piperazine-1-base t-butyl formate (obtain in) De diox (15ml) solution according to the described method of the step 1 of embodiment 39, then with reaction mixture 20 ℃ of stirrings.React after 16 hours, add another part 4M hydrochloric acid De dioxane solution (11ml), then mixture was stirred 20 days under identical temperature.3-(piperazine-1-yl) benzonitrile (2.2g) that forms is leached, dry then with ether (15ml) washing.
Step 2: 417.2mg 3-(piperazine-1-yl) mixture of benzonitrile in the 30ml methylene dichloride that 300mg 3-phenyl-1H-pyrroles-2-base formic acid, 307mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 216mg I-hydroxybenzotriazole (HOBT) and the abovementioned steps that the step 1 of embodiment 6 is obtained obtains places the 100ml three-necked flask that is placed under the argon gas, adds the 0.74ml triethylamine then.Reaction mixture was stirred 16 hours down at 20 ℃, then with 50ml methylene dichloride and the dilution of 50ml water.After settlement separate, extract with the 20ml methylene dichloride.Organic extract liquid is merged,, use dried over mgso, filter and reduction vaporization with saturated ammonium chloride solution (20ml) washing.The crude compound that obtains by silica gel chromatography purifying (Bondelut short column, ref 15111.1000, the diameter of 26mm, 20g silica gel 15-40 micron), is carried out wash-out with flow velocity 12ml/min with the 60/40volv/vol mixture of hexanaphthene and ethyl acetate.The fraction that will contain expecting compound merges and reduction vaporization.Separate and obtain 3-[4-(3-phenyl-1H-pyrroles-2-base carbonyl) piperazine-1-yl] benzonitrile (260mg).
Step 3: utilize the 130.1mg 3-[4-that obtains previously (3-phenyl-1H-pyrroles-2-base carbonyl) piperazine-1-yl] dimethyl formamide (1.5ml) solution of benzonitrile, add 13mg sodium hydride and 61.4mg methyl bromoacetate then and with mixture 20 ℃ of reactions 1.5 hours down.Because reaction is not finished, so add another part sodium hydride (14mg) and another part methyl bromoacetate (43 μ l).React after 1 hour, reaction mixture is handled in accordance with the following methods: water (20ml) and ethyl acetate (20ml) dilution, by settlement separate, with ethyl acetate (2 * 15ml) extractions.Organic extract liquid is merged, use dried over mgso, then reduction vaporization.(the AIT short column refFC-25Si-HP), carries out wash-out with the 90/10vol/vol mixture of methylene dichloride and methyl alcohol with the flow velocity of 10ml/min by the silica gel chromatography purifying with the compound that obtains.The fraction that will contain expecting compound merges, and reduction vaporization obtains { 2-[4-(3-cyano-phenyl) piperazine-1-base carbonyl]-3-phenylpyrrole-1-yl } methyl acetate (95.5mg) then.
Step 4: the solution of 0.1M sodium hydroxide (491 μ l) and methyl alcohol (3ml) joined contain 95mg{2-[4-(3-cyano group-phenyl) piperazine-1-base carbonyl that obtains previously]-3-phenylpyrrole-1-yl } in the 50ml round-bottomed flask of methyl acetate.With reaction mixture stirring and refluxing 48 hours.Because reaction is not finished,, keep simultaneously refluxing and spend the night so add another part sodium hydroxide (250 μ l).Reaction mixture is evaporated to dried, then by reversed phase high efficiency chromatogram (volume injected 5ml DMSO, C18 100-10,250 * 40mm Nucleodur post, ref 762020, sequence number 3051181, lot number 2023), utilize water/acetonitrile gradient (to comprise 0.07% trifluoroacetic acid, from 95/5 to 5/95, volumetric ratio was with the flow velocity wash-out of 75ml/min 52 minutes) purifying.The fraction that will contain expecting compound merges evaporation then.Collect resulting solid and with the development of 3ml ether, leach and drying obtains { 2-[4-(3-formamyl phenyl) piperazine-1-base carbonyl]-3-phenylpyrrole-1-yl } acetate (22mg).
Fusing point: 132 ℃ (Kofler warm table).
Embodiment 74
3-[4-(2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile
(it can be according to Tetrahedron Lett.2000 for 500mg 2-phenyl-1H-pyrroles-3-base formic acid that the step 2 of embodiment 21 is made according to embodiment 5 described methods and 700mg 1-(3-cyano-phenyl) piperazine dihydrochloride, 56 (24), 4107-10 makes) in the 50ml methylene dichloride, in the presence of 560mg1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 36mg I-hydroxybenzotriazole hydrate (HOBT) and 1.1ml triethylamine, to react, reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out, obtain 450mg3-[4-(2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl of white crystals shape then with the diethyl ether crystallization with methylene dichloride and alcoholic acid mixture (95/5 volume ratio)] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=356 (M
+)
Fusing point (Kofler warm table)=80 ℃.
Embodiment 75
3-[4-(2-hydroxy-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzonitrile
(it is according to Heterocycles 1984 with the basic formic acid of 137mg 2-hydroxy-4-phenyl-1H-imidazoles-5-according to embodiment 5 described methods, 22 (8), 1763-69 makes) and 192mg 1-(3-cyano-phenyl) piperazine dihydrochloride (it is according to Tetrahedron Lett.2000,56 (24), 4107-10 makes) in the 25ml methylene dichloride in 141mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), react under the existence of 9mg I-hydroxybenzotriazole hydrate (HOBT) and 0.28ml triethylamine, reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying alkali (60; 30-75 μ m), carry out wash-out, obtain 185mg 3-[4-(2-hydroxy-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl of white crystals shape then with the diethyl ether crystallization with methylene dichloride and alcoholic acid mixture (95/5 volume ratio)] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=373 (M
+)
Fusing point (Kofler warm table)=198 ℃
1H NMR wave spectrum (300MHz)-δ ppm d6-DMSO:3.23 (wide m, 4H); 3.61 (wide m, 4H); 7.17-7.46 (m, 9H); 7.75 (wide d, J=8.0Hz, 2H).
Embodiment 76
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-methyl-4-phenyl-1H-imidazoles-5-yl) ketone
Step 1: will be according to Heteroatom.Chemistry 1996,7 (3), the 3.5g2-methyl that 187-94 makes-4-phenyl-1H-imidazoles-5-base ethyl formate is dissolved in 60ml ethanol, adds the 30ml aqueous solution of 1g potassium hydroxide then and mixture refluxed to stir 20 hours.Behind the concentrating under reduced pressure methyl alcohol, add 20ml water in resistates, making pH by adding 1N aqueous hydrochloric acid is 2.The throw out that forms is leached, and water and diisopropyl ether are washed successively, obtain 3g 2-methyl-4-phenyl-1H-imidazoles-5-base formic acid of beige solid shape then in baking oven in 50 ℃ of following dryings, and it is directly used in following step, and its feature is as follows:
Mass spectrum (EI): m/z=202 (M
+)
Step 2: according to embodiment 5 described methods 265mg (3-hydroxy phenyl) piperazine dihydrochloride that the step 1 of 202mg 2-methyl-4-phenyl-1H-imidazoles-5-base formic acid and embodiment 57 obtains is reacted in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 148mg I-hydroxybenzotriazole hydrate (HOBT) and 422 μ l triethylamines in the 25ml methylene dichloride, react and at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio), obtain 60mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl of amorphous beige solid shape to wherein adding the 20ml diisopropyl ether then] (2-methyl-4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=376 (M
+).
Embodiment 77
3-[4-(1-hydroxyethyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl]-benzamide
Step 1: the 450mg 3-[4-that embodiment 25 is made (2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide is dissolved in the 20ml anhydrous pyridine.After being cooled to 0 ℃, adding 72mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 0.28ml (2-bromine oxethyl)-tertiary butyl dimethyl-silane then and mixture was at room temperature stirred 20 hours, stirred 4 hours down at 60 ℃ then.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.Behind dried over mgso and concentrating under reduced pressure, resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (90-10 volume ratio).Obtain orange buttery 95mg3-{4-[1-(t-butyldimethylsilyl oxygen base) ethyl-2-phenyl-1H-pyrroles-3-base carbonyl thus]-piperazine-1-yl } benzamide, it is directly used in following step:
Step 2: the tetrahydrofuran solution of 1.4ml 1M four-N-butyl Neutral ammonium fluoride is joined 95mg3-{4-[1-(t-butyldimethylsilyl oxygen base) ethyl-2-phenyl-1H-pyrroles-3-base carbonyl] piperazine-1-yl-the 3.5ml tetrahydrofuran solution of benzamide in.20 ℃ down stir 20 hours after, add the 50ml ethyl acetate, with product with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (90/10 volume ratio).Obtain cream-coloured foamed 65mg 3-[4-(1-hydroxyethyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl thus] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=418 (M
+).
Embodiment 78
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-sulfydryl-4-phenyl-1H-imidazoles-5-yl) ketone
(it is according to Chem.Pharm.Bull.1984 with the basic formic acid of 265mg 2-sulfydryl-4-phenyl-1H-imidazoles-5-according to embodiment 5 described methods, 32 (7), 2536-43 obtains) and 220mg (3-hydroxy phenyl) piperazine dihydrochloride that obtains of the step 1 of embodiment 57 in the 25ml methylene dichloride, in the presence of 211mg1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 148mg I-hydroxybenzotriazole hydrate (HOBT) and 309 μ l triethylamines, react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio), obtain 175mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl of amorphous beige solid shape to wherein adding the 20ml diisopropyl ether then] (2-sulfydryl-4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=394 (M
+).
Embodiment 79
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-methylthio group-4-phenyl-1H-imidazoles-5-yl) ketone
530mg (3-hydroxy phenyl) piperazine dihydrochloride that 521mg 2-sulfydryl-4-phenyl-1H-imidazoles-5-base formic acid that the step 1 of embodiment 67 is obtained according to embodiment 5 described methods and the step 1 of embodiment 57 obtain reacts in the presence of 422mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 297mg I-hydroxybenzotriazole hydrate (HOBT) and 613 μ l triethylamines in the 50ml methylene dichloride, reacts and at room temperature stirs 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out, obtain cream-coloured foamed 100mg 4-(3-hydroxymethyl phenyl) piperazine-1-yl to wherein adding the 20ml diisopropyl ether then with ethyl acetate] (2-methylthio group-4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=408 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO is under the temperature of 353K: 2.63 (wide s, 3H); 3.47-3.74 (non-constant width m, 8H); 4.46 (wide s, 2H); 4.81 (wide m, 1H); 6.78 (wide d, J=7.5Hz, 2H); 6.90 (wide s, 1H); 7.17 (t, J=7.5Hz, 1H); 7.30 (wide t, J=7.5Hz, 1H); 7.41 (t, J=7.5Hz, 2H); 7.61 (wide d, J=7.5Hz, 2H); 12.6 (wide m, 1H).
Embodiment 80
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (1-methyl-2-phenyl-1H-pyrroles-3-yl)-ketone
(they can be according to Med.Chem.Res. (1997) with the basic formic acid of 157mg 1-methyl-2-phenyl-1H-pyrroles-3-according to embodiment 5 described methods, 7 (2), 98-108 makes) and 227mg (3-hydroxy phenyl) piperazine dihydrochloride that obtains of the step 1 of embodiment 57 in the 50ml methylene dichloride, in the presence of 165mg1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 12mg I-hydroxybenzotriazole hydrate (HOBT) and 240 μ l triethylamines, react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 115mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl that wash-out obtains the white foam shape with methylene dichloride and methanol mixture (95-5 volume ratio)] (1-methyl-2-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=375 (M
+).
Embodiment 81
3-[4-(1-hydroxyethyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl]-benzonitrile
Step 1: the 430mg 3-[4-that embodiment 74 is made (2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile is dissolved in the 20ml anhydrous pyridine.After being cooled to 0 ℃, adding 72mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 0.28ml (2-bromine oxethyl)-tertiary butyl dimethylsilane then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.Behind dried over mgso and concentrating under reduced pressure, resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (90-10 volume ratio).Obtain 550mg 3-{4-[1-(the t-butyldimethylsilyl oxygen base) ethyl-2-phenyl-1H-pyrroles-3-base carbonyl of yellow oily thus]-piperazine-1-yl } benzonitrile, it is directly used in following step.
Step 2: the tetrahydrofuran solution of 8ml 1M four-N-butyl Neutral ammonium fluoride is joined 550mg3-{4-[1-(t-butyldimethylsilyl oxygen base) ethyl-2-phenyl-1H-pyrroles-3-base carbonyl] piperazine-1-yl-the 35ml tetrahydrofuran solution of benzonitrile in.20 ℃ down stir 20 hours after, add the 50ml ethyl acetate, with product with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (90/10 volume ratio).With obtaining the crystalloid 140mg 3-[4-of canescence (1-hydroxyethyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl behind the 7.5ml diethyl ether recrystallization] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=400 (M
+)
Fusing point (Kofler warm table)=158 ℃.
Embodiment 82
3-[4-(2-amino-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzonitrile
(it can be according to US 3 with the basic formic acid of 200mg 2-amino-4-phenyl-thiazole-5-according to embodiment 5 described methods, 282,927 make) and 252.6mg 1-(3-cyano-phenyl) piperazine dihydrochloride (it can be according to Tetrahedron Lett.2000,56 (24), 4107-10 makes) in the 20ml methylene dichloride, in the presence of 191.5mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 135mg I-hydroxybenzotriazole hydrate (HOBT) and 281 μ l triethylamines, to react, reaction was at room temperature stirred 20 hours.By with obtaining light yellow crystalloid 200mg3-[4-(2-amino-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl behind the 30ml alcohol crystal purifying] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=389 (M
+)
Fusing point (Kofler warm table)=246 ℃
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.96 (wide m, 4H); 3.44 (wide m, 4H); 7.18 (m, 2H); 7.25 (t, J=2.0Hz, 1H); 7.30-7.44 (m, 6H); 7.55 (wide d, J=8.0Hz, 2H).
Embodiment 83
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-trifluoromethyl-4-phenyl-1H-imidazoles-5-yl) ketone
265mg 1-(the 3-hydroxymethyl phenyl) piperazine dihydrochloride that 256mg 2-trifluoromethyl-4-phenyl-1H-imidazol-4 yl formic acid that the step 1 of embodiment 54 is obtained according to embodiment 5 described methods and the step 1 of embodiment 57 obtain reacts in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 148mg I-hydroxybenzotriazole hydrate (HOBT) and 309 μ l triethylamines in the 25ml methylene dichloride, and reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (97.5/2.5 volume ratio), obtain 250mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl of amorphous beige solid shape to wherein adding diisopropyl ether then] (2-trifluoromethyl-4-phenyl-1H-imidazoles-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=430 (M
+).
Embodiment 84
3-[4-(2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzonitrile
(it can be according to Tetrahedron Lett.2000 for 256mg 2-trifluoromethyl-4-phenyl-1H-imidazol-4 yl formic acid that the step 1 of embodiment 54 is obtained according to embodiment 5 described methods and 260mg 1-(3-cyano methyl phenyl) piperazine dihydrochloride, 56 (24), 4107-10 makes) in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 149mg I-hydroxybenzotriazole hydrate (HOBT) and 309 μ l triethylamines, to react, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5/2.5 volume ratio), obtain 80mg 3-[4-(2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl of amorphous beige solid shape to wherein adding diisopropyl ether then] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=425 (M
+).
Embodiment 85
3-[4-(2-amino-4-phenyl-thiazole-5-base carbonyl) piperazine-1-yl] benzamide
(it can be according to US 3 with the basic formic acid of 200mg 2-amino-4-phenyl thiazole-5-according to embodiment 5 described methods; 282; 927 make) and 258mg 1-(3-formamyl phenyl) piperazine dihydrochloride in the 30ml methylene dichloride, in the presence of 192mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 135mg I-hydroxybenzotriazole hydrate (HOBT) and 281 μ l triethylamines, react, the reaction at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 100mg 3-[4-(2-amino-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl that gradient elution (from 95/5 to 90/10 volume ratio) obtains white solid with methylene dichloride and methanol mixture] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=407 (M
+)
Fusing point (Kofler warm table)=236 ℃.
Embodiment 86
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone
265mg 1-(the 3-hydroxymethyl phenyl) piperazine dihydrochloride that 256mg 2-phenyl-1H-pyrroles-3-base formic acid that the step 2 of embodiment 21 is made according to embodiment 5 described methods and the step 1 of embodiment 57 make reacts in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 149mg I-hydroxybenzotriazole hydrate (HOBT) and 309 μ l triethylamines, reacts and at room temperature stirs 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95/5 volume ratio) and obtain cream-coloured foamed 250mg[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=361 (M
+).
Embodiment 87
3-[4-(1-hydroxyethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl]-benzonitrile
Step 1: the 500mg 3-[4-that embodiment 61 is made (4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile is dissolved in 15ml anhydrous dimethyl formamide (DMF).After being cooled to 0 ℃, adding 62mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 370mg (2-bromine oxethyl)-tertiary butyl dimethylsilane then and mixture was at room temperature stirred 20 hours.In reaction medium, add 50ml water, use 3 * 25ml ethyl acetate extraction then.Behind dried over mgso and concentrating under reduced pressure, resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with ethyl acetate.Obtain 700mg 3-{4-[1-(tertiary butyl dimethyl-silyl oxygen base) ethyl-4-phenyl-1H-pyrroles-3-base carbonyl of yellow oily thus] piperazine-1-yl } benzonitrile, it is directly used in following step:
Step 2: the tetrahydrofuran solution of 10ml 1M four-N-butyl Neutral ammonium fluoride is joined 720mg3-{4-[1-(t-butyldimethylsilyl oxygen base) ethyl-4-phenyl-1H-pyrroles-3-base carbonyl] piperazine-1-yl-the 15ml tetrahydrofuran solution of benzonitrile in.20 ℃ down stir 20 hours after, add the 50ml ethyl acetate, with product with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (92.5/7.5 volume ratio).Obtain 400mg 3-[4-(1-hydroxyethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl of beige solid shape to wherein adding diethyl ether] benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=400 (M
+).
Embodiment 88
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-amino-4-phenyl thiazole-5-yl)-ketone
(it can be according to US 3 with the basic formic acid of 324mg 2-amino-4-phenyl thiazole-5-according to embodiment 5 described methods, 282,927 make) and 390mg 1-(3-hydroxymethyl phenyl) piperazine dihydrochloride in the 30ml methylene dichloride, in the presence of 310mg 1-(3 dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 219mg I-hydroxybenzotriazole hydrate (HOBT) and 455 μ l triethylamines, react, the reaction at room temperature stirred 72 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio), use mixture (80/20 volume ratio) recrystallization of 10ml water and Virahol to obtain 130mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl of yellow crystal shape then] (2-amino-4-phenyl thiazole-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=394 (M
+)
Fusing point (Kofler warm table)=176 ℃.
Embodiment 89
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (1-hydroxyethyl-2-phenyl-1H-pyrroles-5-yl) ketone
Step 1: 240mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl that embodiment 86 is made] (2-phenyl-1H-pyrroles-3-yl) ketone is dissolved in the 15ml anhydrous pyridine.After being cooled to 0 ℃, adding 40mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 160 μ l (2-bromine oxethyl)-tertiary butyl dimethylsilane then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 25ml water in resistates, use 3 * 15ml ethyl acetate extraction then.Behind dried over mgso and concentrating under reduced pressure, resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio).Obtain orange buttery 100mg[4-(3-hydroxymethyl phenyl) piperazine-1-yl thus] (1-(t-butyldimethylsilyl oxygen base) ethyl-2-phenyl-1H-pyrroles-5-yl) ketone, it is directly used in following step.
Step 2: the tetrahydrofuran solution of 1.5ml 1M four-N-butyl Neutral ammonium fluoride is joined 98mg[4-(3-hydroxymethyl phenyl) piperazine-1-yl] in the 5ml tetrahydrofuran solution of (1-(t-butyldimethylsilyl oxygen base) ethyl-2-phenyl-1H-pyrroles-5-yl) ketone.20 ℃ down stir 20 hours after, add the 50ml ethyl acetate, with product with 3 * 25ml water washing, with dried over mgso and be evaporated to dried.The resistates that obtains is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and alcoholic acid mixture (95/5 volume ratio).Obtain 70mg[4-(the 3-hydroxymethyl phenyl) piperazine-1-yl of white foam shape thus] (1-hydroxyethyl-2-phenyl-1H-pyrroles-5-yl)-ketone, its feature is as follows:
Mass spectrum (EI): m/z=405 (M
+).
Embodiment 90
[4-(3, the 5-3,5-dimethylphenyl) piperazine-1-yl] [2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-yl] ketone
Step 1: will be according to Pharmazie 1987,42 (6), the 2.3g 2-that 373-375 makes (2-methoxy ethyl) amino-4-phenyl thiazole-5-base ethyl formate is dissolved in 30ml ethanol, adds 7.8ml 1N aqueous sodium hydroxide solution then and mixture was refluxed 15 minutes.After being cooled to room temperature, adding 3.5ml 1N aqueous sodium hydroxide solution and mixture was refluxed 30 minutes.Behind the concentrating under reduced pressure ethanol, add 20ml water and also extract with the 20ml methylene dichloride.By add the 1N aqueous hydrochloric acid with aqueous phase as acidified to pH 2.The throw out that forms is leached, wash with water, use mixture (80/20 volume ratio) washing of methyl alcohol and methylene dichloride then.Obtain 0.6g 2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base formic acid of white solid thus, it is directly used in following step, its feature is as follows:
Mass spectrum (EI): m/z=278 (M
+)
Step 2: according to embodiment 5 described methods with 200mg 2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base formic acid and 160mg (3, the 5-3,5-dimethylphenyl) piperazine reacts in the presence of 151mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 107mg I-hydroxybenzotriazole hydrate (HOBT) in the 20ml methylene dichloride, and reaction was at room temperature stirred 72 hours.By flash chromatography on silica gel purifying (25g short column, 40-60 μ m), carry out wash-out with the mixture (50/50 volume ratio) of hexanaphthene and ethyl acetate and obtain yellow foamed 143mg[4-(3, the 5-3,5-dimethylphenyl) piperazine-1-yl] [2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-yl]-ketone, its feature is as follows:
Mass spectrum (EI): m/z=450 (M
+).
Embodiment 91
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-yl] ketone
200mg 2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base formic acid and the 160mg (3 that the step 1 of embodiment 90 is obtained according to embodiment 5 described methods, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 151mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 107mg I-hydroxybenzotriazole hydrate (HOBT) in the 20ml methylene dichloride, and reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (25g short column, 40-60 μ m), mixture (50/50 volume ratio) with hexanaphthene and ethyl acetate carries out the 190mg[4-(3 that wash-out obtains the white foam shape, the 5-Dimethoxyphenyl) piperazine-1-yl] [2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-yl] ketone, its feature is as follows:
Mass spectrum (EI): m/z=482 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.83 (wide m, 4H); 3.30 (s, 1H); 3.41 (wide m, 4H); 3.49 (q, J=5.5Hz, 2H); 3.54 (t, J=5.5Hz, 2H); 3.68 (s, 6H); 5.97 (wide s, 3H); 7.35 (tt, J=1.5 and 7.5Hz, 1H); 7.42 (wide t, J=7.5Hz, 2H); 7.56 (wide d, J=7.5Hz, 2H); 8.04 (wide t, J=5.5Hz, 1H).
Embodiment 92
3-{4-[1-(pyridin-3-yl) methyl-4-phenyl-1H-pyrroles-3-base carbonyl] piperazine-1-yl }-benzonitrile
The 300mg 3-[4-that embodiment 61 is obtained (4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile is dissolved in the 10ml pyridine.After being cooled to 0 ℃, adding 40mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) in batches and mixture is descended stirring 30 minutes at 0 ℃.Add 253mg 3-bromo methyl cycloheptapyridine hydrobromate then and mixture was at room temperature stirred 20 hours.Add 61mg sodium hydride (60% oil solution washs in advance by sedimentation in toluene) and 291mg 3-bromo methyl cycloheptapyridine then and mixture was at room temperature stirred 20 hours.The concentrating under reduced pressure pyridine adds 50ml water in resistates, use 3 * 25ml ethyl acetate extraction then.The organic phase that merges is washed with water, with dried over mgso and be evaporated to dried.Resistates is passed through flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (99-1 volume ratio).After wherein adding diisopropyl ether, obtain 180mg 3-{4-[1-(pyridin-3-yl) methyl-4-phenyl-1H-pyrroles-3-base carbonyl of amorphous beige solid shape] piperazine-1-yl } benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=447 (M
+)
1H NMR wave spectrum (300MHz)-δ ppm d6-DMSO:2.63-3.20 (non-constant width m, 4H); 3.30-3.63 (non-constant width m, 4H); 5.22 (wide s, 2H); 7.17 (m, 4H); 7.20 (d, J=2.5Hz, 1H); 7.24 (d, J=2.5Hz, 1H); 7.30-7.45 (m, 6H); 7.76 (t, J=2.0 and 8.0Hz, 1H); 8.55 (dd, J=2.0 and 5.0Hz, 1H); 8.61 (dd, J=1.0 and 2.0Hz, 1H).
Embodiment 93
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl-4-phenyl thiazole-5-yl)-ketone
(it can be according to Tetrahedron 2002 with the basic formic acid of 219mg 2-methyl-4-phenyl thiazole-5-according to embodiment 5 described methods, 58 (42), 8581-89 obtains) and 223mg (3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 148mg I-hydroxybenzotriazole hydrate (HOBT) in the 25ml methylene dichloride, and reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (25g short column, 40-60 μ m), carry out the 420mg[4-(3 that wash-out obtains the white foam shape with methylene dichloride and methanol mixture (97.5/2.5 volume ratio), the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl-4-phenyl thiazole-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=423 (M
+).
Embodiment 94
3-[4-(2-methyl-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide
(it can be according to Tetrahedron 2002 with the basic formic acid of 219mg 2-methyl-4-phenyl thiazole-5-according to embodiment 5 described methods; 58 (42); 8581-89 obtains) and 278mg (3-formamyl phenyl) piperazine dihydrochloride in the 25ml methylene dichloride, in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 148mg I-hydroxybenzotriazole hydrate (HOBT) and 309 μ l triethylamines, react, the reaction at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5/2.5 volume ratio), obtain 340mg 3-[4-(2-methyl-4-phenyl-thiazole-5-carbonyl)-piperazine-1-yl of amorphous beige solid shape to wherein adding diisopropyl ether then]-benzamide, its feature is as follows:
Mass spectrum (EI): m/z=406 (M
+)
1H NMR wave spectrum (300MHz)-δ ppm d6-DMSO:2.70 (wide m, 2H); 2.76 (s, 3H); 3.21 (wide m, 4H); 3.76 (wide m, 2H); 6.99 (ddd, J=1.5-2.5 and 7.5Hz, 1H); 7.23-7.34 (m, 4H); 7.39 (tt, J=2.0 and 7.5Hz, 1H); 7.45 (wide t, J=7.5Hz, 2H); 7.67 (wide d, J=7.5Hz, 2H); 7.87 (wide m, 1H).
Embodiment 95
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-hydroxy-4-phenyl thiazole-5-yl)-ketone
Step 1: will be according to Acta Poloniae Pharmaceutica 1984,41 (6), the 750mg 2-hydroxy-4-phenyl thiazole that 633-40 obtains-5-base ethyl formate is dissolved in 8ml ethanol, adds the 7.5ml2.5N aqueous sodium hydroxide solution then and mixture was refluxed 15 minutes.Behind the concentrating under reduced pressure ethanol, add 20ml water, mixture is acidified to pH 1 by adding the 1N aqueous hydrochloric acid.The throw out that forms is leached water and diisopropyl ether washing.Obtain the 0.6g 2-hydroxy-4-phenyl thiazole-5-base formic acid of yellow solid shape thus, it is directly used in following step, its feature is as follows:
Mass spectrum (EI): m/z=221 (M
+)
Step 2: according to embodiment 5 described methods with 400mg 2-hydroxy-4-phenyl thiazole-5-base formic acid and 402mg (3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 381mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 269mg I-hydroxybenzotriazole hydrate (HOBT) in the 50ml methylene dichloride, and reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out 730mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that wash-out obtains the thickness yellow oily with methylene dichloride and methanol mixture (95/5 volume ratio)] (2-methyl-4-phenyl thiazole-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=425 (M
+).
Embodiment 96
3-[4-{2-hydroxy-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide
The 200mg 2-hydroxy-4-phenyl thiazole-5-base formic acid and 251mg (the 3-formamyl phenyl) piperazine dihydrochloride that the step 1 of embodiment 95 are obtained according to embodiment 5 described methods react in the presence of 190mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 134mg I-hydroxybenzotriazole hydrate (HOBT) and 279 μ l triethylamines in the 25ml methylene dichloride, react and at room temperature stir 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out, obtain 25mg3-[4-(2-hydroxy-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl of amorphous yellow solid shape to wherein adding diisopropyl ether then with ethyl acetate] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=406 (M
+).
Embodiment 97
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methoxyl group-4-phenyl thiazole-5-yl)-ketone
500mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl that embodiment 95 is obtained] (2-hydroxyl 4-phenyl thiazole-5-yl) ketone is dissolved in 10ml methyl alcohol and is cooled to 0 ℃.Add the 77mg sodium methylate then and mixture was stirred 30 minutes, add 80.5 μ l methyl iodide then and mixture was stirred 2 hours down at 45 ℃, at room temperature stirred then 20 hours.Behind the concentrating under reduced pressure methyl alcohol, in resistates, add 50ml ethyl acetate and 50ml water.To wash with water by settlement separate organic phase, with dried over mgso and be evaporated to dried.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5/2.5 volume ratio), obtain the 495mg[4-(3 of amorphous yellow solid shape to wherein adding diisopropyl ether, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methoxyl group-4-phenyl thiazole-5-yl)-ketone, its feature is as follows:
Mass spectrum (EI): m/z=439 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.64 (wide m, 4H); 3.13 (s, 3H); 3.34 (wide m, 4H); 3.69 (s, 6H); 5.94 (d, J=2.5Hz, 2H); 5.99 (t, J=2.5Hz, 1H); 7.46-7.57 (m, 5H).
Embodiment 98
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (4-phenyl thiazole-5-yl) ketone
(it can be according to Acta Poloniae Pharmaceutica 1984 with the basic formic acid of 205mg 4-phenyl thiazole-5-according to embodiment 5 described methods, 41 (6), 633-40 obtains) and 223mg (3, the 5-Dimethoxyphenyl) piperazine reacts in the presence of 211mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl) and 148mg I-hydroxybenzotriazole hydrate (HOBT) in the 25ml methylene dichloride, and reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (97.5/2.5 volume ratio), obtain 390mg[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl of amorphous yellow solid shape to wherein adding diisopropyl ether then] (4-phenyl thiazole-5-yl) ketone, its feature is as follows:
Mass spectrum (EI): m/z=405 (M
+).
Embodiment 99
3-[4-(2-hydroxy-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide
(it can be according to Acta Poloniae Pharmaceutica 1984 with the basic formic acid of 308mg 4-phenyl thiazole-5-according to embodiment 5 described methods; 41 (6); 633-40 obtains) and 417mg (3-formamyl phenyl) piperazine dihydrochloride in the 37.5ml methylene dichloride, in the presence of 316mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 223mg I-hydroxybenzotriazole hydrate (HOBT) and 464 μ l triethylamines, react, the reaction at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (60; 30-75 μ m), carry out wash-out with methylene dichloride and methanol mixture (95/5 volume ratio), obtain 500mg 3-[4-(2-hydroxy-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl of amorphous beige solid shape to wherein adding diisopropyl ether then] benzamide, its feature is as follows:
Mass spectrum (EI): m/z=392 (M
+)
1H NMR wave spectrum (300MHz)-δ ppm d6-DMSO:2.70 (wide m, 2H); 3.20 (wide m, 4H); 3.79 (wide m, 2H); 6.98 (ddd, J=1.5-2.5 and 8.0Hz, 1H); 7.22-7.34 (m, 4H); 7.41 (tt, J=2.0 and 7.5Hz, 1H); 7.50 (wide t, J=7.5Hz, 2H); 7.71 (wide d, J=7.5Hz, 2H); 7.86 (wide m, and 1H) 9.31 (s, 1H).
Embodiment 100
3-{4-[2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base carbonyl] piperazine-1-yl }-benzonitrile
(it can be according to Tetrahedron Lett.2000 for 100mg 2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base formic acid that the step 1 of embodiment 90 is obtained according to embodiment 5 described methods and 93.5mg (3-cyano-phenyl) piperazine dihydrochloride, 56 (24), 4107-10 makes) in 13ml methylene dichloride and 0.4ml DMF in 75.5mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 53.5mg react under the existence of I-hydroxybenzotriazole hydrate (HOBT) and 103 μ l triethylamines, reaction was at room temperature stirred 20 hours.By flash chromatography on silica gel purifying (10g short column, 40-60 μ m), carry out 90mg[3-{4-[2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base carbonyl that wash-out obtains the white foam shape with methylene dichloride and methanol mixture (95/5 volume ratio)] piperazine-1-yl } benzonitrile, its feature is as follows:
Mass spectrum (EI): m/z=465 (M
+).
Embodiment 101
3-{4-[2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base carbonyl] piperazine-1-yl }-benzamide
93mg 2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base formic acid and 93mg (3-formamyl-phenyl) piperazine dihydrochloride that the step 1 of embodiment 90 are obtained according to embodiment 5 described methods react in the presence of 70.5mg 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCl), 50mg I-hydroxybenzotriazole hydrate (HOBT) and 103 μ l triethylamines in 17ml methylene dichloride and 0.4ml DMF, react and at room temperature stir 20 hours.By flash chromatography on silica gel purifying (10g short column, 40-60 μ m), carry out 60mg[3-{4-[2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base carbonyl that wash-out obtains the white foam shape with methylene dichloride and methanol mixture (95/5 volume ratio)] piperazine-1-yl } benzamide, its feature is as follows:
Mass spectrum (EI): m/z=465 (M
+)
1H NMR wave spectrum (400MHz)-δ ppm d6-DMSO:2.92 (wide m, 4H); 3.30 (concealed, 3H); 3.45 (wide m, 4H); 3.48 (q, J=5.5Hz, 2H); 3.55 (t, J=5.5Hz, 2H); 6.99 (ddd, J=1.0-2.5 and 8.0Hz, 1H); 7.22-7.35 (m, 5H); 7.42 (wide t, J=8.0Hz, 2H); 7.59 (wide d, J=8.0Hz, 2H); 7.86 (wide m, 1H); 8.03 (wide t, J=5.5Hz, 1H).
Inhibiting evaluation to tubulin polymerization
According to disclosed method (Shelanski etc., 1973, Proc.Natl.Acad.Sci.USA, 70,765-768.Weingarten etc., 1975, Proc.Natl.Acad.Sci.USA, 72,1858-1862) tubulin is purified from the pig brain.Say briefly, the pig brain is ground, then centrifugation in the extraction damping fluid.To be present in the tubulin of extraction in the supernatant liquor and carry out twice successive, go up and MAP (microtubule-associated protein) is separated at phosphorylated cotton P11 post (Whatman) by chromatography then 37 ℃ of poly-down circulations that are incorporated in 4 ℃ of following depolymerization.Separate the purity of the tubulin that obtains thus greater than 95%.It is stored in the damping fluid that is known as RB/230% glycerine, and its composition is 50mMMES-NaOH[2-(N-morpholino) ethyl sulfonic acid], pH 6.8; 0.25mM MgCl
20.5mM EGTA; 30% (v/v) glycerine, 0.2mM GTP (guanosine 5 '-triguaiacyl phosphate).
Monitor the polymerization of tubulin to microtubule by following turbidimetry: tubulin is adjusted to concentration in RB/230% glycerine damping fluid be 10 μ M (1mg/ml), to wherein adding 1mM GTP and 6mM MgCl
2By being in the sample pool of 1cm temperature to be increased to 37 ℃ by 6 ℃ to come initiated polymerization at path length, described sample pool is placed in UVIKON 931 spectrophotometers (Kontron) that the thermostatic control specimen holder is housed.Increase at 350nm place monitoring solution turbidity.
Product is dissolved in DMSO with the concentration of 10mM, before polymerization, it is joined in the tubulin solution with variable concentrations (0.5 to 10 μ M) then.With IC
50Be defined as the concentration of the product that can suppress 50% rate of polymerization.Its IC
50The product that is less than or equal to 25 μ M is considered to active very strong.
Compound of the present invention can be used for suppressing the propagation of tumor cell in vitro.
Be used for determining test to the inhibition of proliferation effect of HCT116 human colon tumor clone
The propagation of HCT116 cell in accordance with the following methods by measure [
14C]-combination of thymidine determines.HCT166 cell (taking from ATCC) is cultivated in DMEM substratum (Gibco), and described substratum contains 10% foetal calf serum and microbiotic (1% penicillin, 1% Streptomycin sulphate).In order to carry out proliferation test, the ratio of cell with 5000 cells/well is inoculated in the 96 hole cytostar micro plates (Amersham).Add subsequently [
14C]-thymidine (0.1 μ Ci/ hole) and product to be evaluated.Use the variable concentrations of the product of the highest 10 μ M; DMSO in substratum (solvent that is used for lysate) is should exceed 0.5% not.By being counted to measure, flat board is attached to intracellular radioactivity in insulation under 37 ℃ after 48 hours in Tri-Lux counter (Wallac).With IC
50Be defined as with untreated contrast and compare the concentration that can reduce by 50% radioactive product.Its IC
50Product less than 10 μ M is considered to have Cytotoxic.
Biological results
N.d: do not detect
Claims (39)
1, the compound of following formula (I):
Wherein:
1) A is N or C;
2) L-G-R1 is selected from
3) X and Y are independently from each other CR3, N, NR3, O or S;
4) E is CR4, N, NR4 or S;
5) R1 and R2 are independently from each other the aryl of aryl, heteroaryl, replacement and the heteroaryl of replacement;
6) L is selected from C=O, C=S and C=N (R7);
7) R3 and R4 are independently from each other alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, O-R7, S-R7, SO-R7, the SO of H, alkyl, replacement
2-(R7), N (R7) (R8), halogen, aryl, heteroaryl, the cycloalkyl of replacement, the aryl of replacement and the heteroaryl of replacement;
8) R5 and R6 are independently from each other H and (C
1-C
3) alkyl;
9) R7 and R8 are independently from each other H, (C
1-C
3) (the C of alkyl and replacement
1-C
3) alkyl;
Its racemic form, the form that is rich in a kind of enantiomorph, the form that is rich in a kind of diastereomer, its tautomer, its prodrug and pharmacologically acceptable salt thereof, condition are that formula (I) compound is not one of following compounds:
N=0,1 or 2 and the R=phenyl wherein;
N-(4-{4-[3-(2-chloro-phenyl-)-5-methyl-isoxazole-4-carbonyl]-piperazine-1-yl }-phenyl)-N-[3-(cyano group-benzyl)-3H-imidazol-4 yl methyl]-benzamide;
[4-(3, the 5-Dimethoxyphenyl)-piperazine-1-yl]-(5-methyl-3-phenyl-isoxazole azoles-4-yl)-ketone;
[4-(3-p-methoxy-phenyl)-piperazine-1-yl]-(2-phenyl-2H-pyrazole-3-yl)-ketone;
[4-(6-picoline-2-yl)-piperazine-1-yl]-(2-phenyl-2H-pyrazole-3-yl)-ketone;
[4-(3-hydroxyl-phenyl)-piperazine-1-yl]-(2-phenyl-2H-pyrazole-3-yl)-ketone;
1-(4-amino-6,7-dimethoxy-2-quinazoline-2-yl)-4-[(5-methyl-3-phenyl-isoxzzole-4-yl) carbonyl]-piperazine, CAS number [124953-56-6];
(5-{2,5-dimethyl-4-[(4-phenyl-Piperazine-1-yl) carbonyl]-furans-3-yl }-the 1H-benzimidazolyl-2 radicals-yl)-Urethylane, CAS number [104794-78-7];
1-{[4-(3, the 4-diamino-phenyl)-2,5-dimethyl-furans-3-yl]-carbonyl }-the 4-phenyl-Piperazine, CAS number [104794-73-2];
1-{[4-(4-amino-3-nitrophenyl)-2,5-dimethyl-furans-3-yl]-carbonyl }-the 4-phenyl-Piperazine, CAS number [104794-68-5];
1-[(2,5-dimethyl-4-phenyl-furans-3-yl)-carbonyl]-4-(pyridine-2-yl)-piperazine, CAS number [104794-40-3];
And CAS number following compound: 522598-56-7,505088-40-4,505088-33-5,497060-57-8,477863-64-2,445232-64-4,445232-62-2,445232-36-0,445232-14-4,442648-23-9,442564-97-8,442555-04-6,442196-99-8,442196-98-7,442196-94-3,442196-93-2,438197-21-8,438195-18-7,438195-01-8,425373-10-0,420844-92-4,420844-91-3,385391-47-9,378753-06-1,361372-16-9,355003-62-2,353507-94-5,350600-92-9,349614-20-6,346633-19-0,341001-40-9,341001-38-5,338979-25-2,332174-91-1,332174-90-0,332174-85-3,332174-83-1,331848-28-3,331848-07-8,331847-86-0,328105-24-4,326902-94-7,326902-93-6,326902-91-4,321532-07-4,321532-06-3,313393-06-5,313392-99-3,313392-70-0,313392-55-1,312537-31-8,312537-30-7,312536-58-6,312517-98-9,312512-02-0,309271-41-8,309271-38-3,309270-64-2,303135-76-4,301822-64-0,296792-68-2,278791-83-6,261178-26-1,260442-78-2,260392-36-7,260367-99-5,260367-97-3,260367-90-6,260367-86-0,259683-36-8,256417-32-0,255715-55-0 and 218158-18-0.
2, the described compound of claim 1, wherein R3 is selected from H, alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, O-R7, S-R7, SO-R7, SO
2-(R7), N (R7) (R8), halogen, aryl, heteroaryl, the cycloalkyl of replacement, the aryl of replacement, the heteroaryl of replacement and the alkyl of replacement.
3, the described compound of claim 2, wherein R3 is by the alkyl of F, OH or COOH replacement.
4, the described compound of claim 2, wherein R3 is selected from CF
3, CH
2OH, CH
2-CH
2OH, CH
2-CH
2-COOH, CH
2-COOH, O (R7), S (R7) and NH (R7), wherein R7 is selected from H, (C
1-C
3) alkyl and be selected from OH, O-(C
1-C
3) alkyl, SH, S-(C
1-C
3) alkyl, NH
2And NH-(C
1-C
3) (the C that replaces of the substituting group of alkyl
1-C
3) alkyl.
5, any one described compound in the claim 1 to 4, wherein L-G-R1 is
6, the described compound of any one in the claim 1 to 5, wherein E=NR4 and R4=H.
7, the described compound of any one in the claim 1 to 6, wherein R1 is selected from:
-phenyl;
-be selected from the following phenyl that group replaced by at least one: halogen, CF
3, CN, NO
2, (C
1-C
3) alkyl, O-R10, S-R10, N (R10) (R11), CO-O-R10, CO-N (R10) (R11), NH-CO-R10, wherein R10 and R11 are independently from each other H, (C
1-C
3) alkyl, halogenated (C
1-C
3) alkyl, (C
1-C
3) alkyl-OH, (C
1-C
3) alkyl-NH
2, (C
1-C
3) alkyl-COOH, (C
1-C
3) alkyl-OCH
3, (C
1-C
3) alkyl-NHCH
3
-pyridyl;
-be selected from halogen, (C by at least one
1-C
3) alkyl, O-R12, S-R12, N (R12) pyridyl that group replaced (R13), wherein R12 and R13 are independently from each other H and (C
1-C
3) alkyl.
8, the described compound of claim 7, wherein R1 is selected from:
-by (C
1-C
3) phenyl that replaces of alkyl-OH and
-by (C
1-C
3) pyridyl that replaces of alkoxyl group.
9, the described compound of claim 7, wherein R1 is selected from the phenyl that following substituting group replaces on the 3-position: halogen, (C
1-C
3) alkyl, (C
1-C
3) alkoxyl group, (C
1-C
3) alkylamino, CONH
2, CO-NH-(CH
2)
2-OH, NH-CO-CH
3, 3-pyridyl and be selected from halogen, (C
1-C
3) alkyl and (C
1-C
3) substituting group of the alkoxyl group 2-or the 3-pyridyl that replace.
10, the described compound of claim 7, wherein R1 is selected from 2, the dibasic phenyl of 3-, 2, the phenyl, 3 that the dibasic phenyl of 5-, 3-replace, the dibasic phenyl of 5-and 3, the dibasic phenyl of 4-.
11, the described compound of claim 10, wherein R1 is selected from the phenyl, 3 that 3-replaces, the dibasic phenyl of 5-and 3, the dibasic phenyl of 4-.
12, the described compound of claim 11, wherein R1 is selected from 3-chloro-phenyl-, 3,5-Dimethoxyphenyl, 3-acetylamino phenyl, 3-formamyl phenyl and 3-hydroxymethyl phenyl.
13, the described compound of claim 1 or claim 2, wherein R1 be selected from substituted 2-pyridyl on the 4-position, substituted 2-pyridyl on the 6-position, on 4-and 6-position substituted 2-pyridyl, substituted 3-pyridyl on the 2-position and on the 5-position substituted 3-pyridyl.
14, the described compound of claim 1 or claim 2, wherein R2 is selected from 3-pyridyl, phenyl and is selected from the following phenyl that group replaced: halogen, alkyl, O-R14, S-R14 and N (R14) (R15), wherein R14 and R15 are independently from each other H, alkyl and haloalkyl.
15, the described compound of claim 1 or claim 2, this compound is selected from:
[4-(3-chloro-phenyl-) piperazine-1-yl] (1-phenyl-1H-imidazoles-2-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (5-phenyl-1,3-oxazole-4-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (3-phenyl thiophene-2-yl) ketone,
[4-(3-p-methoxy-phenyl) piperazine-1-yl] [2-(4-chloro-phenyl-) furans-3-yl] ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (3-phenyl-1H-pyrroles-2-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (1-methyl-3-phenyl-1H-pyrroles-2-yl) ketone and
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (3-phenyl-1H-pyrroles-2-yl) ketone.
16, the described compound of claim 1 or claim 2, this compound is selected from:
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(pyridin-3-yl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-acetylamino phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-cyano-phenyl) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-cyano-phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (4-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (4-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3-formamyl phenyl) piperazine-1-yl] (1-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-4-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-sulfydryl-5-phenyl-1H-imidazol-4 yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3-formamyl phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (N-methyl-2-methylthio group-5-phenyl-1H-imidazol-4 yl) ketone,
[4-(3-formamyl phenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-2-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-hydroxyl-5-phenyl-1H-imidazol-4 yl) ketone,
[4-(3-p-methoxy-phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-difluoro-methoxy phenyl) piperazine-1-yl] (5-phenyl-1H-imidazol-4 yl) ketone,
[4-(3-chloro-phenyl-) piperazine-1-yl] [1-(2-dimethyl aminoethyl)-4-phenyl-1H-pyrroles-3-yl] ketone,
3-{3-[4-(3-chloro-phenyl-) piperazine-1-base carbonyl]-4-phenylpyrrole-1-yl } propionic acid,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methanesulfinyl-5-phenyl-1H-imidazol-4 yl) ketone,
3-{3-[4-(3-chloro-phenyl-) piperazine-1-base carbonyl]-4-phenylpyrrole-1-yl }-methyl propionate,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-hydroxymethyl-4-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(2-hydroxyethyl)-4-phenyl-1H-pyrroles-3-yl] ketone,
3-[4-(1-methyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide,
[4-(2-hydroxyl-3,5-Dimethoxyphenyl) piperazine-1-yl] (2-methanesulfinyl-5-phenyl-1H-imidazol-4 yl) ketone,
3-[4-(3-phenyl-1H-pyrroles-2-base carbonyl) piperazine-1-yl] benzamide,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-methyl-3-phenyl-1H-pyrroles-2-yl) ketone,
1-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-base carbonyl]-4-phenylpyrrole-1-yl }-ethyl ketone,
(2-amino-4-phenyl thiazole-5-yl) [4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl]-ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl-5-phenyl-3H-imidazol-4 yl) ketone,
3-[4-(2-sulfydryl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzamide,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(thiazole-4-yl) methyl-4-phenyl-1H-pyrroles-3-yl] ketone,
4-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] carbonyl-4-phenyl-1H-pyrroles-1-yl }-butyric acid,
2-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] carbonyl-4-phenyl-1H-pyrroles-1-yl }-acetate,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(pyridin-3-yl) methyl-4-phenyl-1H-pyrroles-3-yl] ketone,
2-{3-[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] carbonyl-2-phenyl-1H-pyrroles-1-yl } methyl acetate,
3-[4-(1-methyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide,
3-[4-(2-hydroxy-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzamide,
3-[4-(2-sulfydryl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl]-benzonitrile,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(2-hydroxyethyl)-2-phenyl-1H-pyrroles-3-yl] ketone,
3-[4-(2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzamide,
3-[4-(2-methylthio group-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzamide,
3-[4-(2-methylthio group-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzonitrile,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-hydroxy-4-phenyl-1H-imidazoles-5-yl) ketone,
3-[4-(4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide,
3-[4-(2-methyl-5-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzamide,
3-[4-(2-methyl-5-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzonitrile,
3-[4-(4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-trifluoromethyl-4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (1-ethanoyl-2-phenyl-1H-pyrroles-3-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [1-(3-pyridyl) methyl-2-phenyl-1H-pyrroles-3-yl] ketone,
3-[4-(2-methoxycarbonyl methyl-4-phenyl-1H-pyrroles-3-carbonyl) piperazine-1-yl] benzamide,
3-[4-(1-hydroxyethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl sulphonyl-4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3,5-hydroxymethyl phenyl) piperazine-1-yl] (1-methyl-4-phenyl-1H-pyrroles-3-yl) ketone,
3-[4-(2-methyl sulphonyl-4-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzonitrile,
3-[4-(2-methyl sulphonyl-4-phenyl-1H-imidazol-4 yl carbonyl) piperazine-1-yl] benzamide,
3-[4-(1-hydroxymethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile,
2-[4-(3-formamyl phenyl) piperazine-1-base carbonyl]-3-phenylpyrrole-1-yl } acetate,
3-[4-(2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile,
3-[4-(2-hydroxy-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzonitrile,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-methyl-4-phenyl-1H-imidazoles-5-yl) ketone,
3-[4-(1-hydroxyethyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzamide,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-sulfydryl-4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-methylthio group-4-phenyl-1H-imidazoles-5-yl) ketone,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (1-methyl-2-phenyl-1H-pyrroles-3-yl) ketone,
3-[4-(1-hydroxyethyl-2-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile,
3-[4-(2-amino-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzonitrile,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-trifluoromethyl-4-phenyl-1H-imidazoles-5-yl) ketone,
3-[4-(2-trifluoromethyl-4-phenyl-1H-imidazoles-5-base carbonyl) piperazine-1-yl] benzonitrile,
3-[4-(2-amino-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-phenyl-1H-pyrroles-3-yl) ketone,
3-[4-(1-hydroxyethyl-4-phenyl-1H-pyrroles-3-base carbonyl) piperazine-1-yl] benzonitrile,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (2-amino-4-phenyl thiazole-5-yl) ketone,
[4-(3-hydroxymethyl phenyl) piperazine-1-yl] (1-hydroxyethyl-2-phenyl-1H-pyrroles-5-yl) ketone,
[4-(3, the 5-3,5-dimethylphenyl) piperazine-1-yl] [2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-yl] ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] [2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-yl] ketone,
3-{4-[1-(pyridin-3-yl) methyl-4-phenyl-1H-pyrroles-3-base carbonyl] piperazine-1-yl } benzonitrile,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methyl-4-phenyl thiazole-5-yl) ketone,
3-[4-(2-methyl-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-hydroxy-4-phenyl thiazole-5-yl) ketone,
3-[4-(2-hydroxy-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (2-methoxyl group-4-phenyl thiazole-5-yl) ketone,
[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] (4-phenyl thiazole-5-yl) ketone,
3-[4-(2-hydroxy-4-phenyl thiazole-5-base carbonyl) piperazine-1-yl] benzamide,
3-{4-[2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base carbonyl] piperazine-1-yl benzonitrile and
3-{4-[2-(2-methoxy ethyl) amino-4-phenyl thiazole-5-base carbonyl] piperazine-1-yl } benzamide.
17, the compound of claim 1, wherein Y is CR3.
18, the compound of claim 17, wherein A is C; And X is N.
19, the compound of claim 17, wherein E is N.
20, the compound of claim 17, wherein E is S.
21, the compound of claim 17, wherein E is O.
22, the compound of claim 18, wherein E is N.
23, the compound of claim 18, wherein E is S.
24, the compound of claim 18, wherein E is O.
25, the compound of claim 1, wherein
Be pyrrole ring, wherein:
(i) when A is N, X and Y are independently from each other CR3, and E is CR4;
(ii) when X was N, A was C, and Y is that CR3 and E are CR4;
(iii) when Y was N, A was C, and X is that CR3 and E are CR4;
(iv) when E was N, A was C, and X and Y are independently from each other CR3.
26, the compound of claim 1, wherein when A was N, X was N.
27, the compound of claim 1, wherein
Be thiazole ring, wherein:
(i) when A is N, Y is S, and X is CR3, and E is CR4;
(ii) when X was N, A was C, and Y is CR3, and E is S;
(iii) when E was N, A was C, and X is S, and Y is CR3.
28, the compound of claim 1, wherein
Be imidazole ring, wherein:
(i) when A is N,
When (ia) Y was N, X was CR3, and E is CR4, or
(ib) X and Y are independently from each other CR3, and E is N;
(ii) when X was N, A was C, and Y is CR3, and E is NR4;
(iii) when E is N,
(iiia) Y is CR3, and X is NR3, and A is C, or
(iiib) X and Y are independently from each other CR3, and A is N.
29, the compound of claim 1, wherein R2 is unsubstituted phenyl.
30, the compound of claim 1, wherein R1 is selected from 3-p-methoxy-phenyl, 3,5-Dimethoxyphenyl and 3-formamyl phenyl.
31, the compound of claim 30, wherein R1 is a 3-formamyl phenyl.
32, the compound of claim 1, wherein X is that C and Y are CR3.
33, the described compound of claim 1 or claim 2, this compound is selected from the compound 1 to 101.
34, comprise any one the described compound in the aforementioned claim and the pharmaceutical composition of pharmaceutically acceptable vehicle.
35, the described compound of any one in the claim 1 to 33 is as the purposes of the reagent that suppresses tubulin polymerization.
36, the described compound of any one in the claim 1 to 33 is as the purposes of the reagent that suppresses tumor cell proliferation.
37, the described compound of any one in the claim 1 to 33 is used to promote to be derived from the cell cluster disruptive purposes of vascular tissue.
38, the described compound of any one in the claim 1 to 33 is used for the treatment of purposes in the medicine of pathological conditions in production.
39, the described purposes of claim 38, pathological conditions wherein is a cancer.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR03/06719 | 2003-06-04 | ||
| FR0306719A FR2855825B1 (en) | 2003-06-04 | 2003-06-04 | ARYL-HETEROAROMATIC PRODUCTS, COMPOSITIONS CONTAINING SAME AND USE THEREOF |
| FR04/04889 | 2004-05-06 |
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| Publication Number | Publication Date |
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| CN1829697A true CN1829697A (en) | 2006-09-06 |
| CN100427472C CN100427472C (en) | 2008-10-22 |
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| CNB2004800218006A Expired - Fee Related CN100427472C (en) | 2003-06-04 | 2004-06-03 | Aryl-heteroaromatic products, compositions containing same and use thereof |
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| Country | Link |
|---|---|
| CN (1) | CN100427472C (en) |
| FR (1) | FR2855825B1 (en) |
| GT (1) | GT200400113A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101607942B (en) * | 2008-06-17 | 2012-02-22 | 中国人民解放军第二军医大学 | Novel imidazolone anti-tumor compound and preparation method thereof |
| TWI415845B (en) * | 2006-10-03 | 2013-11-21 | Arena Pharm Inc | Pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
| CN104080783A (en) * | 2012-01-25 | 2014-10-01 | 株式会社益力多本社 | Pyrrole compound |
| CN108358864A (en) * | 2017-12-15 | 2018-08-03 | 五邑大学 | A kind of preparation method and application of 2- acyl groups -5- Ben Ji oxazole class Antitubulins |
| CN108707147A (en) * | 2018-06-20 | 2018-10-26 | 桑文军 | A kind of novel tubulin inhibitor and its application in antitumor drug |
| CN112521357A (en) * | 2020-08-31 | 2021-03-19 | 深圳瑞健生物科技有限公司 | Long-acting low-addiction HNK derivative and preparation method thereof |
| CN114195735A (en) * | 2020-09-02 | 2022-03-18 | 沈阳药科大学 | 1,2, 3-thiadiazole compound and use thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9707561A (en) * | 1995-04-07 | 1997-12-31 | Schering Corp | Carbonyl-piperazinyl and piperidinil compounds which inhibit farnesyl protein transferase. |
| DE10035908A1 (en) * | 2000-07-21 | 2002-03-07 | Asta Medica Ag | New heteroaryl derivatives and their use as medicines |
| DE10035928A1 (en) * | 2000-07-21 | 2002-03-07 | Asta Medica Ag | New heteroaryl derivatives and their use as medicines |
| DE10035927A1 (en) * | 2000-07-21 | 2002-03-07 | Asta Medica Ag | New heteroaryl derivatives and their use as medicines |
| FR2815032B1 (en) * | 2000-10-10 | 2003-08-08 | Pf Medicament | NOVEL AMINOPHENYL PIPERAZINE OR AMINO PHENYL PIPERIDE DERIVATIVES PRENYL TRANSFERASE PROTEIN INHIBITORS AND PREPARATIONS THEREOF |
| AU2003246571B2 (en) * | 2002-06-29 | 2008-06-26 | Zentaris Gmbh | Arylcarbonylpiperazines and heteroarylcarbonylpiperazines and the use thereof for treating benign and malignant tumour diseases |
-
2003
- 2003-06-04 FR FR0306719A patent/FR2855825B1/en not_active Expired - Fee Related
-
2004
- 2004-06-02 GT GT200400113A patent/GT200400113A/en unknown
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI415845B (en) * | 2006-10-03 | 2013-11-21 | Arena Pharm Inc | Pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
| CN101607942B (en) * | 2008-06-17 | 2012-02-22 | 中国人民解放军第二军医大学 | Novel imidazolone anti-tumor compound and preparation method thereof |
| CN104080783A (en) * | 2012-01-25 | 2014-10-01 | 株式会社益力多本社 | Pyrrole compound |
| CN108358864A (en) * | 2017-12-15 | 2018-08-03 | 五邑大学 | A kind of preparation method and application of 2- acyl groups -5- Ben Ji oxazole class Antitubulins |
| CN108707147A (en) * | 2018-06-20 | 2018-10-26 | 桑文军 | A kind of novel tubulin inhibitor and its application in antitumor drug |
| CN112521357A (en) * | 2020-08-31 | 2021-03-19 | 深圳瑞健生物科技有限公司 | Long-acting low-addiction HNK derivative and preparation method thereof |
| CN114195735A (en) * | 2020-09-02 | 2022-03-18 | 沈阳药科大学 | 1,2, 3-thiadiazole compound and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2855825A1 (en) | 2004-12-10 |
| FR2855825B1 (en) | 2008-08-22 |
| CN100427472C (en) | 2008-10-22 |
| GT200400113A (en) | 2005-12-22 |
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