CN103980195A - Amide-type phenylpiperazine derivative, and salt and application thereof in preparing medicine for treating benign prostatic hyperplasia - Google Patents
Amide-type phenylpiperazine derivative, and salt and application thereof in preparing medicine for treating benign prostatic hyperplasia Download PDFInfo
- Publication number
- CN103980195A CN103980195A CN201410175321.5A CN201410175321A CN103980195A CN 103980195 A CN103980195 A CN 103980195A CN 201410175321 A CN201410175321 A CN 201410175321A CN 103980195 A CN103980195 A CN 103980195A
- Authority
- CN
- China
- Prior art keywords
- base
- arh
- piperazinyl
- acid
- cdcl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ALZFIXZUUYUZFB-UHFFFAOYSA-N COc(cccc1)c1N1CCN(CC(CNC(c2cc3nccnc3cc2)=O)O)CC1 Chemical compound COc(cccc1)c1N1CCN(CC(CNC(c2cc3nccnc3cc2)=O)O)CC1 ALZFIXZUUYUZFB-UHFFFAOYSA-N 0.000 description 1
- IQCPIYYMPKHZFV-UHFFFAOYSA-N COc(cccc1)c1NCCNCCCNC(c(c1c2)n[nH]c1ccc2F)=O Chemical compound COc(cccc1)c1NCCNCCCNC(c(c1c2)n[nH]c1ccc2F)=O IQCPIYYMPKHZFV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 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 in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
- C07D311/84—Xanthenes 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 in position 9
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- 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
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an amide-type phenylpiperazine derivative, salt and anapplication thereof in preparing medicines for treating benign prostatic hyperplasia. The phenylpiperazine type compounds can selectively antagonize <1A>- or <1D>- adrenergic receptors. Researches indicate that an <1A>/<1D> selective antagonist has high urinary tract selectivity, and at the same time, is not liable to cause side effects of postural hypotension, exhaustion, drowsiness and the like are not . When being used as an antagonist of the <1A>- or <1D>- adrenergic receptors, the compounds, provided by the invention, can be used for treating benign prostatic hyperplasia.
Description
Technical field
The present invention relates to amides Phenylpiperazine derivatives and preparation method thereof and treat the application in benign prostate hyperplasia medicine in preparation.
Background technology
Benign prostatic hyperplasia (benign prostate hyperplasia, BPH) is the common multiple disease of middle-aging male, conventionally after 40 years old, starts to occur, and sickness rate increases progressively along with the increase at age.According to pertinent data, show, 50 years old male sex BPH sickness rate is more than 50%, and within 80 years old, male sex's sickness rate is up to 90%.The carrying out property enlargement meeting of body of gland causes lower urinary tract symptom (lower urinary tract symptoms, LUTS) generation, show as frequent micturition, urgent urination, uroschesis etc. are clinically blocked symptom, bring very large misery to many patients, seriously affected middle-aged and old qualities of life.Benign prostate hyperplasia therapeutic modality is mainly divided into operative treatment and pharmacological agent at present, wherein surgical eradication is considered to effect a radical cure the prefered method of BPH, but because this patient's age is generally excessive, physiological function a little less than, although good operation effect, case fatality rate is not high, but still can bring infringement in various degree to patient.Therefore, unless patient's hyperplasia of prostate arrives very serious stage, otherwise all with medicine, treat.
The medicine that is used for the treatment of at present benign prostate hyperplasia both at home and abroad mainly contains three major types: 1. α
1-adrenergic receptor antagonist, such medicine represents that medicine is Prazosin, terazosin, Doxazosin, perhexiline maleate, Tamsulosin and naftopidil; 2. 5α-reductase inhibitor, such medicine represents that medicine is finasteride, epristeride, dutasteride and epristeride; 3. plant amedica and Chinese patent medicine, Prostat, Tadenan, LONGBISHU.α wherein
1-adrenoceptor antagonists is rapid-action, and mitigation symptoms rapidly in the short period of time is the drug of first choice that treatment at present has manifest symptom BPH.
Pathological study shows, the interstitial of BPH hyperplasia is rich in α
1Asubtype acceptor, the LUTS that BPH causes be distributed in prostate gland, bladder and urethra near-end α
1Aand α
1Dsubtype acceptor is relevant, so specificity antagonism α
1A/ α
1Dhypotype can reach the shrinkage degree that alleviates unstriated muscle and sphincter vesicae in prostate gland interstitial, alleviates BPH symptom, improves LUTS.A large amount of experiments confirms traditional α
1receptor antagonist does not have α as Prazosin, terazosin, perhexiline maleate
1subtype-selective, to α
1Bhypotype produces the antagonistic action of equal extent, is the major cause that this class medicine produces postural hypotension, the side effect such as tired, sleepy.Therefore, exploitation has optionally α of high urinary tract
1A/ α
1D-adrenoceptor antagonists, has become the study hotspot of researching and developing the anti-benign prostatic hyperplasia medicine of efficient low side effect.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, amides Phenylpiperazine derivatives and salt thereof and the application in preparation treatment benign prostate hyperplasia medicine are provided
Amides Phenylpiperazine derivatives structure provided by the invention is as general formula (I) or (II):
R
1be selected from 1-isoquinolyl, 2-quinolyl, 2-quinoxalinyl, 6-quinoxalinyl, 1,4-benzodioxan-2-base, indazole-3-base, 1-methylindazole-3-base, 5-fluorine indazole-3-base, 5-bromo-indazole-3-base, 7-azaindole-3-base, imidazo [1,2-a] pyridin-3-yl, 1H-indenes-3-base, thionaphthene-3-base, 2-chloropyridine-3-base, 6-5-flumethiazine-3-base, 2-methoxypyridine-3-base, 2,6-dichloropyridine-3-base, 2-methoxypyridine-4-base, pyridine-2-base;
R
2be selected from 1-naphthyl, 2-naphthyl, 9-anthryl, 1-isoquinolyl, 2-quinolyl, 2-quinoxalinyl, 6-quinoxalinyl, 3, 4-methylenedioxyphenyl, 1, 4-benzodioxan-6-base, 1, 4-benzodioxan-2-base, xanthene-9-base, 4-benzopyrone-2-base, indol-3-yl, 1-benzylindole-3-base, 6-bromo indole-3-base, indazole-3-base, 1-methylindazole-3-base, 5-fluorine indazole-3-base, 5-bromo-indazole-3-base, 5-chloro-indole-2-base, 6-bromo indole-2-base, 7-azaindole-3-base, imidazo [1, 2-a] pyridin-3-yl, 1H-indenes-3-base, thionaphthene-3-base, phenyl, pyridin-3-yl, furans-2-base.
The present invention relates to formula (I) (II) compound and pharmacy acceptable salt thereof, these salt are selected from: the subsalt of organic acid and mineral acid, described organic acid and mineral acid are selected from hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, methylsulfonic acid, phenylformic acid, Phenylsulfonic acid, tosic acid, formic acid, acetic acid, propionic acid, oxysuccinic acid, tartrate, oxalic acid, succsinic acid, fumaric acid, toxilic acid and each seed amino acid etc.
The invention provides (II) preparation method of compound of above-claimed cpd formula (I).
The preparation method of formula (I) compound is as follows:
R wherein
1identical with the definition in above-mentioned formula (I) compound.
Concrete grammar: the compound of formula (B) is placed in to reaction flask, adds methylene dichloride to dissolve, add DIPEA (DIEA), stir 10 minutes.The compound and the condensing agent that add formula (A), stirring at room reaction is spent the night again.After having reacted, add 5% wet chemical to stir in reaction solution 5 minutes, dichloromethane extraction, gets organic layer, and organic layer is after anhydrous sodium sulfate drying, and column chromatography obtains the compound shown in formula (I).Wherein condensing agent is elected 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) as.
Wherein, formula (A) compound R
1cOOH is commercialization reagent, the compound of formula (B)
can adopt the conventional method in this area to synthesize obtains.
The compound of formula (B)
can adopt following synthetic method to obtain:
Wherein reaction raw materials 3-propantheline bromide hydrobromide, tert-Butyl dicarbonate, DMAP (DMAP), triethylamine, 1-(2-methoxyphenyl) piperazine, Anhydrous potassium carbonate, sodium iodide, trifluoroacetic acid, methylene chloride etc. all can have been bought from market.
Concrete preparation method is: 3-propantheline bromide hydrobromide and equivalent tert-Butyl dicarbonate are dissolved in appropriate dichloromethane solvent, drips Et
3n/DMAP/CH
2cl
2mixed solution, after titration, stirring reaction spends the night.After having reacted, reaction solution is used 0.5N dilute hydrochloric acid and saturated common salt water washing respectively once, anhydrous sodium sulfate drying, filtration, concentrating under reduced pressure obtain light yellow oily N-(3-bromopropyl) t-butyl carbamate crude product, and gained crude product does not react for next step through being further purified direct use.After N-(3-bromopropyl) t-butyl carbamate and 1-(2-methoxyphenyl) piperazine mix, with methylene dichloride, dissolve, add solid water-free salt of wormwood and potassiumiodide, stirring is spent the night.After having reacted, reacting liquid filtering, filtrate is after washing, dry, column chromatography obtains light yellow oil N-tertbutyloxycarbonyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine.N-tertbutyloxycarbonyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine is placed in back-pressure bottle, splashes into TFA/CH
2cl
2(v/v=1: 4) mixed solution.React after 3 hours and finish reaction, reaction solution is successively all washed once with 20%NaOH and saturated aqueous common salt, anhydrous sodium sulfate drying, filtering and concentrating obtains compound light yellow oil 3-[4-(2-the methoxyphenyl)-1-piperazinyl of formula (B)] propylamine.
The preparation method of formula (II) compound is as follows:
R wherein
2identical with the definition in above-mentioned formula (II) compound.
Concrete grammar: the compound of formula (D) is placed in to reaction flask, adds methylene dichloride to dissolve, add DIPEA (DIEA), stir 10 minutes.The compound and the condensing agent that add formula (C), stirring at room reaction is spent the night again.After having reacted, add 5% wet chemical to stir 5 minutes, dichloromethane extraction, gets organic layer, and organic layer is after anhydrous sodium sulfate drying, and column chromatography obtains the compound shown in formula (II).Wherein condensing agent is elected 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) as.
Wherein, formula (C) compound R
2cOOH is commercialization reagent, the compound of formula (D)
can adopt the conventional method in this area to synthesize obtains.
The compound of formula (D)
can adopt following synthetic method to obtain:
Wherein alkane, 1-(this base of 2-methoxy) piperazine, hydrazine hydrate in reaction raw materials potassium phthalimide, epoxy chlorine, solvent Virahol, ethanol all can have been bought from market.
Concrete preparation method is: potassium phthalimide and epoxy chloropropane mix, and 120 ℃ of return stirrings react about 12 hours.After having reacted, filter, ethanol cleans filter cake.Collect filtrate, concentrating under reduced pressure obtains white-yellowish solid, by re-crystallizing in ethyl acetate, obtains white solid N-(2,3-epoxypropyl) phthalic imidine.N-(2,3-epoxypropyl) phthalic imidine and 1-(2-methoxyphenyl) piperazine mix, and add Virahol, and 90 ℃ of back flow reaction are spent the night.After having reacted, obtain solid after removing solvent under reduced pressure, by ethyl acetate, repeatedly wash, obtain light yellow solid N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] } phthalic imidine.N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] } phthalic imidine is dissolved in appropriate ethanol, adds hydrazine hydrate.Stirring at normal temperature is spent the night.After having reacted, filter, filtrate is through saturated common salt water washing, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure obtains light yellow oil ,-4 ℃ of cooling compound white solid 2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyls that obtain formula (D)] propylamine.
Amides Phenylpiperazine derivatives of the present invention is antagonism α optionally
1A-or α
1D-adrenoceptor.Research shows α
1A/ α
1Dselective antagonist has high urinary tract selectivity, be difficult for to produce postural hypotension, the side effect such as tired out, sleepy simultaneously.Compound of the present invention is as α
1A/ α
1D-adrenoceptor antagonists, can be used for the treatment of benign prostate hyperplasia.
Embodiment
Formula (I) compound reaction expression:
The preparation of embodiment 1:N-(3-bromopropyl) t-butyl carbamate
By 3-propantheline bromide hydrobromide (5g, 22.84mmol) and tert-Butyl dicarbonate (5.98g, 27.40mmol) be dissolved in stirring at normal temperature in appropriate methylene dichloride, slowly drip triethylamine (9.5ml, 68.16mmol) and the methylene dichloride mixing solutions that is made into of DMAP (0.28g, 2.28mmol).Titration time is controlled as 1h, continues stirring at normal temperature 30min after titration.After reacting completely, reaction solution successively all washs once with 0.5N HCl and saturated aqueous common salt, organic layer is with after anhydrous sodium sulfate drying, and concentrating under reduced pressure obtains 4.17g light yellow oil after removing organic solvent, and gained crude product does not react for next step through being further purified direct use.
Embodiment 2:N-tertbutyloxycarbonyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] preparation of propylamine
The 4.17gN-that upper step is obtained (3-bromopropyl) t-butyl carbamate crude product and 1-(2-methoxyphenyl) piperazine (3.70g, 19.24mmol) are dissolved in the addition of C H
2cl
2, add Anhydrous potassium carbonate (2.66g, 19.24mmol) and sodium iodide (0.26g, 1.73mmol), stirring at normal temperature 1d.After having reacted, reaction solution is washed once, anhydrous Na SO
4dry, concentrating under reduced pressure obtains milk emulsus crude product 7.28g crude product.Crude product, through 300-400 order purification by silica gel column chromatography (eluent is sherwood oil: ethyl acetate=4: 1, add 5 ‰ triethylamines), obtains light yellow oil 5.69g, and embodiment 1 and embodiment 2 two-step reaction total recoverys are 71.3%.ESI-MS(m/z):350.3[M+H]
+.
Embodiment 3:3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine
By 500mg N-tertbutyloxycarbonyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine is dissolved in 40ml methylene dichloride, slowly drips 10ml trifluoroacetic acid, stirring at normal temperature 3h.After reacting completely, in reaction solution, add 20%NaOH solution, adjust PH to 13.Dichloromethane extraction twice, organic layer merges, and organic layer is with after anhydrous sodium sulfate drying, and concentrating under reduced pressure is removed light yellow oil after organic solvent, and products therefrom is not directly used in next step reaction through being further purified.ESI-MS(m/z):2502[M+H]
+。
Embodiment 4:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } isoquinoline 99.9-1-methane amide (I-01)
In 50ml reaction flask, add 3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine (100mg, 0.40mmol) and DIPEA (DIEA) (0.6ml), with 20ml methylene dichloride, dissolve.Continue to add isoquinoline 99.9-1-formic acid (69mg, 0.40mmol) and 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid (HATU) (152mg, 0.40mmol), stirring reaction 6h.After reacting completely, once with the washing of 5% solution of potassium carbonate and saturated common salt, organic layer is through anhydrous sodium sulfate drying successively for reaction solution, and column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) obtains golden yellow oily matter 127mg, yield 78.3%.
ESI-MS(m/z):405.3[M+H]
+,427.2[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ9.60-9.54(m,1H,ArH),9.15(brs,1H,amide-H),8.43(d,J=5.5Hz,1H,ArH),7.86-7.62(m,4H,ArH),7.03-6.82(m,4H,ArH),3.85(s,3H,-OCH
3),3.65(dd,J=12.4,5.9Hz,2H,NH-C
H 2CH
2CH
2-N),3.14(brs,4H,piperazinyl-H),2.72(brs,4H,piperazinyl-H),2.64(t,J=6.5Hz,2H,NH-CH
2CH
2C
H 2-N),1.95-1.85(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ166.29,152.36,149.06,141.47,140.36,137.36,130.37,128.45,127.95,126.98,126.73,124.03,122.87,121.03,118.15,111.32,57.58,55.38,53.59(2C),50.55(2C),39.42,25.63.
Embodiment 5:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } quinoline-2-formamide (I-02)
Synthetic method is with reference to embodiment 4, and raw material isoquinoline 99.9-1-formic acid is substituted with raw material quinoline-2-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 2, gradient elution) purifying, obtains white powder 135mg, yield 83.2%, fusing point 130-131 ℃.
ESI-MS(m/z):405.3[M+H]
+.
1H?NMR(500MHz,CDCl
3):δ8.58(brs,1H,amide-H),8.19(s,1H,ArH),7.87(d,J=20.0Hz,2H,ArH),7.72(s,1H,ArH),7.57(s,1H,ArH),6.86-6.71(m,5H,ArH),3.86(s,3H,-OCH
3),3.65(dd,J=12.4,5.9Hz,2H,NH-C
H 2CH
2CH
2-N),3.14(brs,4H,piperazinyl-H),2.79(brs,4H,piperazinyl-H),2.66(t,J=6.3Hz,2H,NH-CH
2CH
2C
H 2-N),1.97-1.87(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(125MHz,CDCl
3):δ166.32,156.79,153.01,141.10,139.73,133.00,130.61,127.87,127.61,127.59,127.40,123.55,119.27,119.09,118.01,114.69,56.83,55.38,52.13(2C),50.67(2C),39.22,26.47.
Embodiment 6:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } quinoxaline-2-methane amide (I-03)
Synthetic method is with reference to embodiment 4, raw material isoquinoline 99.9-1-formic acid is substituted with raw material quinoxaline-2-formic acid, through column chromatography (sherwood oil: acetone=1: 3-1: 1, gradient elution) purifying, product re-crystallizing in ethyl acetate, obtain golden yellow powder 102mg, yield 62.7%, fusing point 180-181 ℃.
ESI-MS(m/z):406.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.69(s,1H,ArH),9.16(brs,1H,amide-H),8.17(dd,J=8.5,1.1Hz,1H,ArH),8.09(dd,J=8.4,0.9Hz,1H,ArH),7.82(ddd,J=8.4,6.9,1.4Hz,1H,ArH),7.65(ddd,J=8.4,6.9,1.4Hz,1H,ArH),7.05-6.86(m,4H,ArH),3.87(s,3H,-OCH
3),3.70(dd,J=12.0,5.8Hz,2H,NH-C
H 2CH
2CH
2-N),3.27(brs,4H,piperazinyl-H),2.75(brs,4H,piperazinyl-H),2.67(t,J=6.2Hz,2H,NH-CH
2CH
2C
H 2-N),1.94-1.86(m,2H,NH-CH
2-C
H 2CH
2-N)。
13C?NMR(100MHz,CDCl
3):δ163.44,152.30,144.25,144.05,143.80,141.26,140.34,131.31,130.59,129.86,129.53,122.95,120.92,118.30,111.41,58.16,55.41,53.78(2C),50.51(2C),39.99,25.36。
Embodiment 7:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } quinoxaline-6-methane amide (I-04)
Synthetic method is with reference to embodiment 4, and raw material isoquinoline 99.9-1-formic acid is substituted with raw material quinoxaline-6-formic acid, through column chromatography (sherwood oil: acetone=1: 3-1: 1, gradient elution) purifying, obtains red-brown powder 104mg, yield 64.0%, fusing point 145-147 ℃.
ESI-MS(m/z):406.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.01(brs,1H,amide-H),8.83(dd,J=16.0,1.8,Hz,2H,ArH),8.58(d,J=1.9Hz,1H,ArH),8.29(dd,J=8.7,2.0Hz,1H,ArH),8.14(d,J=8.7Hz,1H,ArH),7.02-6.97(m,1H,ArH),6.91-6.81(m,3H,ArH),3.83(s,3H,-OCH
3),3.68(dd,J=10.7,5.6Hz,2H,NH-C
H 2CH
2CH
2-N),3.12(brs,4H,piperazinyl-H),2.76(brs,4H,piperazinyl-H),,2.71(t,J=5.6Hz,2H,NH-CH
2CH
2C
H 2-N),1.91-1.84(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ166.19,152.34,146.01,145.70,144.17,142.47,141.00?,136.43,129.94,128.76,128.17,123.19,120.87,118.62,111.19,58.91,55.38,53.76(2C),50.64(2C),41.60,23.82.
Embodiment 8:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-Isosorbide-5-Nitrae-benzodioxan-2-methane amide (I-05)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=1: 2) purifying, obtains white solid 89mg, yield 53.9%, fusing point 136-138 ℃ with raw material Isosorbide-5-Nitrae-benzodioxan-2-formic acid.
ESI-MS(m/z):412.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):7.77(brs,1H,amide-H),7.02-6.82(m,7H,ArH),6.78-6.73(m,1H,ArH),4.68-4.56(m,2H,
),4.11(dd,J=11.3,7.9Hz,1H,
),3.86(s,3H,-OCH
3),3.47(dd,J=12.0,5.9Hz,2H,NH-C
H 2CH
2CH
2-N),3.14(brs,4H,piperazinyl-H),2.65(brs,4H,piperazinyl-H),2.56-2.48(m,2H,NH-CH
2CH
2-C
H 2-N),1.79-1.71(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ166.95,152.25,143.36,141.82,141.13,122.94,122.36,121.83,120.99,118.37,117.60,117.52,111.29,73.42,65.97,57.68,55.39,53.72(2C),50.48(2C),39.29,25.21.
Embodiment 9:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1H-indazole-3-methane amide (I-06)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=1: 1) purifying, obtains white solid 93mg, yield 58.9%, fusing point 156-157 ℃ with raw material 1H-indazole-3-formic acid.
ESI-MS(m/z):394.4[M+H]
+,416.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ11.04(s,1H,indazolyl-
NH),8.42(d,J=8.2Hz,1H,ArH),8.26(t,J=5.2Hz,lH,amide-H),7.47-7.35(m,2H,ArH),7.23-7.29(m,lH,ArH),7.04-6.84(m,4H,ArH),3.85(s,3H,-OCH
3),3.62(dd,J=12.2,5.9Hz,2H,NH-C
H 2CH
2CH
2-N),3.19(brs,4H,piperazinyl-H),2.72(brs,4H,piperazinyl-H),2.62(t,J=6.5Hz,2H,NH-CH
2CH
2C
H 2-N),1.92-1.81(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ162.93,152.36,141.37,139.70,127.11,122.98,122.76,122.61,122.10,121.05,118.18,111.40,109.79,57.41,55.40,53.48(2C),50.40(2C),38.78,25.69.
Embodiment 10:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1-methylindazole-3-methane amide (I-07)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=4: 1) purifying, obtains white oily matter 92mg, yield 56.3% with raw material 1-methyl-benzdiazole-3-formic acid.
ESI-MS(m/z):408.4[M+H]
+,430.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ8.43-8.33(m,2H),7.41-7.31(m,2H,ArH),7.26-7.22(m,1H,amide-H),7.02-6.84(m,4H,ArH),3.96(s,3H,Indazole-C
H 3),3.85(s,3H,-OCH
3),3.63(dd,J=12.0,5.8Hz,2H,NH-C
H 2CH
2CH
2-N),3.20(brs,4H,piperazinyl-H),2.71(brs,4H,piperazinyl-H),2.62(t,J=6.3Hz,2H,NH-CH
2CH
2C
H 2-N),1.89-1.80(m,2H,NH-CH
2-C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ162.65,152.30,141.47,141.18,137.58,126.65,122.97,122.90,122.83,122.34,120.90,117.97,111.38,108.94,57.88,55.37,53.60(2C),50.51(2C),39.15,35.94,25.49.
Embodiment 11:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-5-fluorine indazole-3-methane amide (I-08)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=1: 1) purifying, obtains white solid 90mg, yield 54.5%, fusing point 172-174 ℃ with raw material 5-fluorine indazole-3-formic acid.
ESI-MS(m/z):412.3[M+H]
+,434.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ10.76(s,1H,indazolyl-N
H),8.38-8.33(m,1H,amide-H),8.08-8.03(m,1H,ArH),7.42-7.37(m,1H,ArH),7.20-7.14(m,1H,ArH),7.04-6.86(m,4H,ArH),3.85(s,3H,-OCH
3),3.62(dd,J=12.2,5.7Hz,2H,NH-C
H 2CH
2CH
2-N),3.20(brs,4H,piperazinyl-H),2.72(brs,4H,piperazinyl-H),2.63(t,J=6.4Hz,2H,NH-CH
2CH
2C
H 2-N),1.90-1.83(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ162.50,152.38,141.43,138.20,122.97,121.04,118.10,117.19,116.91,111.43,110.90,110.81,107.18,106.94,57.60,55.41,53.51(2C),50.43(2C),39.01,25.53.
Embodiment 12:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-5-bromo-indazole-3-methane amide (I-09)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=1: 1) purifying, obtains white powder 97mg, yield 51.2%, fusing point 211-213 ℃ with raw material 5-bromo-indazole-3-formic acid.
ESI-MS(m/z):472.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ11.40(s,1H,indazolyl-N
H),8.59(s,1H,ArH),8.31(t,J=5.3Hz,1H,amide-H),7.47-7.43(m,1H,ArH),7.33-7.29(m,1H,ArH),7.03-6.48(m,4H,ArH),3.84(s,3H,-OCH
3),3.61(dd,J=12.2,5.8Hz,2H,NH-C
H2CH2CH2-N),3.18(brs,4H,piperazinyl-H),2.71(brs,4H,piperazinyl-H),2.61(t,J=6.5Hz,2H,NH-CH
2CH
2C
H 2-N),1.89-1.82(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ162.47,152.34,141.30,140.01,139.07,130.35,125.24,123.59,123.03,121.05,118.15,116.00,111.42,111.29,57.45,55.40,53.45(2C),50.43(2C),38.95,25.57.
Embodiment 13:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-7-azaindole-3-methane amide (I-10)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=1: 1) purifying, obtains white powder 84mg, yield 53.2%, fusing point 146-147 ℃ with raw material 7-azaindole-3-formic acid.
ESI-MS(m/z):394.3[M+H]
+,416.3[M+Na]
+.
1H?NMR(500MHz,CDCl):δ11.70(s,1H,7-azaindolyl-N
H),8.54(d,J=7.8Hz,1H,ArH),8.22(d,J=4.3Hz,1H,ArH),7.91(s,1H,ArH),7.60(brs,1H,amide-H),7.15(dd,J=7.8,4.8Hz,1H,ArH),7.04-6.96(m,1H,ArH),6.91-6.81(m,3H,ArH),3.85(s,3H,-OCH
3),3.64(dd,J=10.9,5.3Hz,2H,NH-C
H2CH2CH2-N),3.10(brs,4H,piperazinyl-H),2.74(brs,4H,piperazinyl-H),2.65(t,J=5.8Hz,2H,NH-CH
2CH
2C
H 2-N),1.91-1.82(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(125MHz,CDCl
3):δ164.66,152.22,148.69,143.35,140.93,130.25,126.85,123.19,121.05,118.64,117.96,117.38,111.26,111.19,58.27,55.37,53.66(2C),50.61(2C),39.87,24.88.
Embodiment 14:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } imidazo [1,2-a] pyridine-3-carboxamide (I-11)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid with raw material imidazo [1,2-a] Nicotinicum Acidum, through column chromatography (pure ethyl acetate wash-out) purifying, obtain colorless oil 112mg, yield 71.0%.
ESI-MS(m/z):394.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.55-9.50(m,1H,ArH),8.10(s,1H,ArH),7.97(brs,1H,amide-H),7.66(d,J=9.0Hz,1H,ArH),7.33(s,1H,ArH),7.03-6.84(m,5H,ArH),3.86(s,3H,-OCH
3),3.61(dd,J=11.3,5.8Hz,2H,NH-C
H2CH2CH2-N),3.16(s,4H,piperazinyl-H),2.74(s,4H,piperazinyl-H),2.68-2.62(m,2H,NH-CH
2CH
2C
H 2-N),1.86(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):160.79,152.29,147.69,140.94,135.62,128.17,126.73,123.18,121.24,118.75,118.46,117.56,113.60,111.30,58.32,55.41,53.81(2C),50.76(2C),39.89,24.59.
Embodiment 15:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1H-indenes-3-methane amide (I-12)
Synthetic method is with reference to embodiment 4, and raw material isoquinoline 99.9-1-formic acid is substituted with raw material 1H-indenes-3-formic acid, through column chromatography (sherwood oil: acetone=5: 1-4: 1, gradient elution) purifying, obtains golden yellow oily matter 75mg, yield 47.8%.
ESI-MS(m/z):392.3[M+H]
+,414.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ7.96(d,J=7.6Hz,1H,ArH),7.84(brs,1H,amide-H),7.46(d,J=7.4Hz,1H,ArH),7.33(t,J=7.4Hz,1H,ArH),7.25-7.20(m,1H,ArH),7.04-6.76?(m,5H,ArH),3.85(s,3H,-OCH
3),3.59(dd,J=11.6,5.6Hz,2H,NH-C
H2-CH2CH2-N),3.45(d,J=1.6Hz,2H,
),3.01(brs,4H,piperaziny1-H),2.68(brs,4H,piperazinyl-H),2.62(t,J=6.1Hz,2H,NH-CH
2CH
2C
H 2-N),1.88-1.78(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ165.05,152.32,143.61,141.58,141.13,140.94,135.47,126.63,125.53,123.80,123.08,122.19,121.01,118.07,111.33,58.10,55.39,53.56(2C),50.66(2C),39.92,38.09,24.82.
Embodiment 16:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } thionaphthene-3-methane amide (I-13)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=4: 1-3: 1 with raw material 1-thionaphthene-3-formic acid, gradient elution) purifying, obtain white powder 105mg, yield 63.9%, fusing point 119-120 ℃.
ESI-MS(m/z):410.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.45(d,J=7.9Hz,1H,ArH),8.06(brs,1H,amide-H),7.89-7.82(m,2H,ArH),7.48-7.35(m,2H,ArH),7.03-6.75(m,4H,ArH),3.84(s,3H,-OCH
3),3.63(dd,J=11.4,5.7Hz,2H,NH-C
H2-CH2CH2-N),2.96(brs,4H,piperazinyl-H),2.68(brs,4H,piperazinyl-H),2.64(t,J=6.0Hz,2H,NH-CH
2CH
2C
H 2-N),1.89-1.80(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ164.07,152.32,141.02,140.30,136.98,132.74,128.62,125.03(2C),124.61,123.15,122.48,121.03,118.27,111.28,58.25,55.39,53.58(2C),50.63(2C),40.38,24.62.
Embodiment 17:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-2-chloro-nicotinamide (I-14)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: ethyl acetate=1: 1) purifying, obtains colorless oil 100mg, yield 64.0% with raw material 2-chlorine apellagrin.
ESI-MS(m/z):389.2[M+H]
+.
1HNMR(400MHz,CDCl
3):δ8.41(dd,J=4.8,2.0Hz,1H,ArH),8.16(brs,1H?amide-H),7.95(dd,J=7.6,2.0Hz,1H,ArH),7.29(dd,J=7.6,4.8Hz,1H,ArH),7.01-6.75(m,4H,ArH),3.84(s,3H,-OCH
3),3.61(dd,J=6.0,12.0Hz,2H,NH-C
H2-CH2CH2-N),2.93(brs,4H,piperazinyl-H),2.69(brs,4H,piperazinyl-H),2.64(t,J=6.2Hz,2H,NH-CH
2CH
2C
H 2-N),1.87-1.83(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ164.92,152.28,150.62,147.34,140.92,138.78,132.49,123.16,122.55,121.04,118.20,111.28,57.57,55.39,53.40(2C),50.56(2C),40.43,24.44.
Embodiment 18:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-6-trifluoromethyl niacinamide (I-15)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: ethyl acetate=1: 1) purifying, obtains white powder 92mg, yield 54.4%, fusing point 120-121 ℃ with raw material 6-trifluoromethyl nicotinic acid.
ESI-MS(m/z):423.2[M+H]
+.
1HNMR(400MHz,CDCl
3):δ9.15(d,J=1.8Hz,1H,ArH),8.83(brs,1H,amide-H),8.34(dd,J=8.1,1.7Hz,1H,ArH),7.73(d,J=8.2Hz,1H,ArH),7.06-6.99(m,1H,ArH),6.96-6.91(m,1H,ArH),6.90-6.85(m,2H,ArH),3.86(s,3H,-OCH
3),
3.65(dd,J=10.8,5.7Hz,2H,NH-C
H2-CH2CH2-N),3.07(brs,4H,piperazinyl-H),2.76(brs,4H,piperazinyl-H),2.71(t,J=5.7Hz,2H,NH-CH
2CH
2C
H 2-N),1.92-1.84(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ164.19,152.37,148.60,140.70,136.60,133.09,123.55,121.21,120.26,118.48,111.35,58.37,55.44,53.61(2C),50.66(2C),41.21,23.65.
Embodiment 19:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-2-methoxyl group niacinamide (I-16)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: ethyl acetate=1: 1) purifying, obtains white powder 83mg, yield 53.9%, fusing point 88-89 ℃ with raw material 2-methoxyl group nicotinic acid.
ESI-MS(m/z):385.1[M+H]
+.
1HNMR(400MHz,CDCl
3):δ8.49(dd,J=7.5,2.0Hz,1H,ArH),8.26(dd,J=4.8,2.0Hz,1H,ArH),8.05(brs,1H,amide-H),7.07-6.90(m,4H,ArH),6.87-6.84(m,1H,ArH),4.10(s,3H,pyridinyl-OC
H 3),3.86(s,3H,-OCH
3),3.56(dd,J=12.7,6.7Hz,2H,NH-C
H2-CH2CH2-N),3.11(brs,4H,piperazinyl-H),2.69(brs,4H,piperazinyl-H),2.55(t,J=7.2Hz,2H,NH-CH
2CH
2C
H 2-N),1.93-1.84(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ163.96,160.64,152.34,149.37,141.50,141.28,122.99,121.05,118.24,117.80,116.29,111.31,56.19,55.39,54.14,53.53(2C),50.56(2C),38.20,26.58.
Embodiment 20:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-2,6-bis-chloro-nicotinamides (I-17)
Synthetic method is with reference to embodiment 4, raw material isoquinoline 99.9-1-raw material 2 for formic acid, and 6-dichloro-nicotinic acid substitutes, through column chromatography (sherwood oil: ethyl acetate=1: 1) purifying, obtains golden yellow oily matter 98mg, yield 57.6%.
ESI-MS(m/z):423.2,425.0[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.25(brs,1H,amide-H),7.94(d,J=8.0Hz,1H,ArH),7.32(d,J=8.0Hz,1H,ArH),7.03-6.74(m,4H,ArH),3.84(s,3H,-OCH
3),?3.63-3.57(m,2H,NH-C
H2-CH2CH2-N),2.92(brs,4H,piperazinyl-H),2.66(brs,4H,piperazinyl-H),2.64-2.59(m,2H,NH-CH
2CH
2C
H 2-N),1.86-1.81(m,2H,NH-CH
2-C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ163.87,152.29,151.35,146.51,141.17,140.94,131.08,123.29,123.22,121.19,118.21,111.30,57.66,55.39,53.42(2C),50.72(2C),41.27,24.38.
Embodiment 21:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-2-methoxyl group Isonicotinamide (I-18)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: ethyl acetate=1: 1) purifying, obtains colorless oil 89mg, yield 57.8% with raw material 2-methoxyl group γ-picolinic acid.
ESI-MS(m/z):385.1[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.80(brs,1H,amide-H),8.21(d,J=5.3Hz,1H,ArH),7.29-7.26(m,1H,ArH),7.14(s,1H,ArH),7.05-6.85(m,4H,ArH),3.90(s,3H,pyridinyl-OC
H 3),3.86(s,3H,-OCH
3),3.59(dd,J=10.8,5.5Hz,2H,NH-C
H2-CH2CH2-N),3.10(brs,4H,piperazinyl-H),2.73(brs,4H,piperazinyl-H),2.66(t,J=5.6Hz,2H,NH-CH
2CH
2C
H 2-N),1.85-1.78(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ165.30,164.77,152.38,147.70,145.03,141.05,123.30,121.04,118.37,114.50,111.28,108.83,58.87,55.41,53.71,53.64(2C),50.66(2C),41.43,23.66.
Embodiment 22:N-{3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } pyridine-2-carboxamide (I-19)
Synthetic method, with reference to embodiment 4, substitutes raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: ethyl acetate=1: 1) purifying, obtains yellow oil 79mg, yield 55.6% with raw material pyridine-2-formic acid.
ESI-MS(m/z):355.1[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.06(brs,1H,amide-H),8.50(d,J=4.7Hz,1H,ArH),8.19(d,J=7.8Hz,1H,ArH),7.84-7.76(m,1H,ArH),7.41-7.34(m,1H,ArH),7.05-6.91(m,3H,ArH),6.90-6.84(m,1H,ArH),3.86(s,3H,-OCH
3),3.60(dd,J=12.3,5.9Hz,2H,NH-C
H2CH2CH2-N),3.19(brs,4H,piperazinyl-H),2.71(brs,4H,piperazinyl-H),2.61(t,J=6.4Hz,2H,NH-CH
2CH
2C
H 2-N),1.91-1.80(m,2H,NH-CH
2C
H 2CH
2-N).
13C?NMR(100MHz,CDCl
3):δ164.48,152.38,150.37,148.08,141.55,137.18,125.93,122.87,122.20,121.05,118.11,111.34,57.57,55.39,53.63(2C),50.49(2C),39.36,25.67.
Formula (II) compound reaction expression:
Embodiment 23:N-(2,3-epoxypropyl) phthalic imidine
Potassium phthalimide (5.9g, 40.0mmol) and epoxy chloropropane (30ml, 23.6eq) are mixed, and 120 ℃ of return stirrings 12 hours, react complete.Filter, ethanol cleans filter cake, and filtrate decompression concentrates to obtain white-yellowish solid crude product, and solid re-crystallizing in ethyl acetate, obtains white solid 5.61g, yield 86.7%.ESI-MS(m/z):190.1[M+H]
+
Embodiment 24:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] } phthalic imidine
N-(2,3-epoxypropyl) phthalic imidine (5.61g, 27.6mmol) and 1-(2-methoxyphenyl) piperazine (5.30g, 27.6mmol) mix, and add 150ml Virahol, and 90 ℃ of backflows are spent the night.React complete, remove solvent under reduced pressure and obtain solid, with the washing of ethyl acetate repeated ultrasonic, obtain light yellow solid 9.82g, yield 89.9%.Products therefrom does not react for next step through being further purified direct use.ESI-MS(m/z):396.3[M+H]
+,418.3[M+Na]
+
Embodiment 25:2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine
Take N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] } phthalic imidine (1.13g, 2.86mmol) is dissolved in appropriate ethanol, adds hydrazine hydrate 7ml.Normal temperature reaction overnight, reaction solution becomes clarification by muddiness, finally becomes again muddiness.After completion of the reaction, remove by filter filter cake, filtrate is used saturated aqueous common salt washed twice, and organic layer is with after anhydrous sodium sulfate drying, and concentrating under reduced pressure obtains light yellow oil, and-4 ℃ of conditions freezing 1 as a child obtained white solid 675mg, yield 89.05%.Products therefrom is not directly used in next step reaction through being further purified.
Embodiment 26:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1-naphthoamide (II-01)
By 2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propylamine (106mg, 0.40mmol) and DIPEA (DIEA) (4ml, 6eq), dissolve with 20ml methylene dichloride.Continue to add 1-naphthoic acid (69mg, 0.40mmol) and 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) (152mg, 0.40mmol), stirring at normal temperature 12h.After completion of the reaction, reaction solution is successively used 5% solution of potassium carbonate and saturated common salt water washing once, and organic layer is through anhydrous sodium sulfate drying, column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) obtain white powder 113mg, yield 71.5%, fusing point 56-57 ℃.
ESI-MS(m/z):420.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.34(dd,J=8.2,0.9Hz,1H,ArH),7.93-7.89(m,1H,ArH),7.88-7.84(m,1H,ArH),7.66-7.42(m,4H,ArH),7.03-6.84(m,4H,ArH),6.62(t,J=5.5Hz,1H,amide-H),4.05-3.98(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.81(ddd,J=13.8,5.5,3.5Hz,1H,NH-C
H 2CHOHCH
2-N),3.52-3.43(m,1H,NH-C
H 2-CHOHCH
2-N),3.07(brs,4H,piperazinyl-H),2.92-2.84(m,2H,piperazinyl-H),2.67-2.58(m,2H,piperazinyl-H),2.58-2.47(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ169.88,152.32,141.13,134.48,133.75,130.68,130.20,128.34,127.13,126.42,125.44,125.03,124.73,123.09,121.02,118.23,111.36,65.75,61.15,55.42,53.55(2C),50.72(2C),43.36.
Embodiment 27:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-2-naphthoamide (II-02)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid substitutes with raw material 2-naphthoic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 121mg, yield 76.5%, fusing point 91-93 ℃.
ESI-MS(m/z):420.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.33(s,1H,ArH),7.96-7.83(m,4H,ArH),7.60-7.49(m,2H,ArH),7.03-6.90(m,4H,ArH),6.89-6.84(m,1H,amide-H),4.06-3.98(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.80(ddd,J=13.8,5.9,3.5Hz,1H,NH-C
H 2CHOHCH
2-N),3.53-3.44(m,1H,NH-C
H 2CHOHCH
2-N),3.09(brs,4H,piperazinyl-H),2.93-2.83(m,2H,piperaziny-1-H),2.68-2.60(m,2H,piperazinyl-H),2.59-2.46(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ167.80,152.33,141.13,134.8,132.67,131.67,128.97,,128.47,127.76,127.66,127.49,126.76,123.67,123.10,121.03,118.23,111.36,65.80,61.18,60.38,55.42,53.56(2C),50.72(2C),43.53.
Embodiment 28:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-9-anthracene methane amide (II-03)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid substitutes with raw material 9-anthroic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 143mg, yield 80.8%, fusing point 177-179 ℃.
ESI-MS(m/z):470.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.47(s,1H,ArH),8.13-8.08(m,2H,ArH),8.00(d,J=7.7Hz,2H,ArH),7.54-7.44(m,4H,ArH),7.03-6.97(m,1H,ArH),6.94-6.84(m,3H,ArH),6.66(t,J=5.5Hz,1H,amide-H),4.11-4.04(m,1H,-C
HOH),3.95(ddd,J=13.7,5.5,3.6Hz,1H,NH-C
H 2CHOHCH
2-N),3.87(s,3H,-OCH
3),3.64-3.55(m,1H,NH-C
H 2CHOHCH
2-N),3.04(brs,4H,piperazinyl-H),2.93-2.85(m,2H,piperazinyl-H),2.67-2.62(m,2H,piperazi-nyl-H),2.61-2.51(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ169.84,152.32,141.11,131.90,131.14,128.55(2C),128.30,128.09,126.71(2C),125.51(2C),125.15(2C),123.11,121.03,118.23,111.35,65.68,61.30,55.43,53.57(2C),50.69(2C),43.56.
Embodiment 29:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } isoquinoline 99.9-1-methane amide (II-04)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material isoquinoline 99.9-1-formic acid, through column chromatography (sherwood oil: acetone=1: 2, gradient elution) purifying, obtains yellow oil 118mg, yield 74.5%.
ESI-MS(m/z):421.4[M+H]
+,433.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ9.58(dd,J=8.3,1.0Hz,1H,ArH),8.63(t,J=5.8Hz,1H,amide-H),8.48(d,J=5.5Hz,1H,ArH),7.87-7.77(m,2H,ArH),7.74-7.64(m,2H,ArH),7.03-6.83(m,4H,ArH),4.08-4.00(m,1H,-C
HOH),3.86(s,3H,-OCH3),3.78(ddd,J=13.8,6.2,3.7Hz,1H,NH-C
H 2CHOHCH
2-N),3.56-3.48(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.92-2.83(m,2H,piperazinyl-H),2.70-2.59(m,2H,piperazinyl-H),2.60-2.50(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ166.58,152.32,148.31,141.22,140.38,137.43,130.44,128.59,127.82,127.06,126.80,124.29,123.03,121.03,118.23,111.34,66.05,61.28,55.40,53.53(2C),50.75(2C),43.11.
Embodiment 30:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } quinoline-2-formamide (II-05)
Synthetic method, with reference to embodiment 26, substitutes raw material 1-naphthoic acid, through column chromatography (sherwood oil: acetone=1: 2) purifying, obtains white powder 113mg, yield 71.3%, fusing point 145-146 ℃ with raw material quinoline-2-formic acid.
ESI-MS(m/z):421.4[M+H]
+,433.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ8.69(t,J=5.9Hz,1H,amide-H),8.31(s,2H,ArH),8.13(d,J8.5Hz,1H,ArH),7.87(dd,J=8.2,0.8Hz,1H,ArH),7.78-7.72(m,1H,ArH),?7.64-7.58(m,1H,ArH),7.02-6.84(m,4H,ArH),4.09-3.99(m,1H,-C
HOH),3.85(s,3H,-OCH
3),3.79(ddd,J=13.9,6.2,3.7Hz,1H,NH-C
H 2CHOHCH
2-N),3.59-3.51(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.92-2.84(m,2H,piperazinyl-H),2.69-2.60(m,2H,piperazinyl-H),2.59-2.48(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ165.02,152.32,149.70,146.59,141.21,137.42,130.05,129.89,129.35,127.90,127.71,123.03,121.02,118.91,118.24,111.34,66.09,61.22,55.41,53.53(2C),50.75(2C),43.19.
Embodiment 31:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } quinoxaline-2-methane amide (II-06)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material quinoxaline-2-formic acid, through column chromatography (sherwood oil: acetone=1: 2-1: 1, gradient elution) purifying, obtains golden yellow powder 118mg, yield 74.3%, fusing point 136-137 ℃.
ESI-MS(m/z):422.4[M+H]
+,444.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ9.68(s,1H,ArH),8.45(t,J=5.8Hz,1H,amide-H),8.20-8.11(m,2H,ArH),7.89-7.78(m,2H,ArH),7.03-6.82(m,4H,ArH),4.08-4.00(m,1H,-C
HOH),3.85(s,3H,-OCH
3),3.80(ddd,J=13.8,6.2,3.6Hz,1H,NH-C
H 2CHOHCH
2-N),3.59-3.50(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.93-2.85(m,2H,piperazinyl-H),2.68-2.60(m,2H,piperazinyl-H),2.59-2.47(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ163.71,152.31,143.95,143.44,141.14,140.35,131.56,130.77,129.79,129.52,123.08,121.02,118.22,111.36,65.82,61.18,55.42,53.54(2C),50.73(2C),43.08.
Embodiment 32:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } quinoxaline-6-methane amide (II-07)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material quinoxaline-6-formic acid, through column chromatography (sherwood oil: acetone=1: 2-1: 1, gradient elution) purifying, obtains light yellow powder 104mg, yield 65.5%, fusing point 96-98 ℃.
ESI-MS(m/z):422.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.90(s,2H,ArH),8.52(d,J=1.7Hz,1H,ArH),8.27-8.16(m,2H,ArH),7.13(t,J=5.3Hz,1H,amide-H),7.03-6.83(m,4H,ArH),4.08-4.00(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.81(ddd,J=13.8,5.8,3.6Hz,1H,NH-C
H 2CHOHCH
2-N),3.53-3.45(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.94-2.85(m,2H,piperazinyl-H),2.70-2.62(m,2H,piperazinyl-H),2.57-2.50(m,2H,NH-CH
2CH-OHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ166.59,152.33,146.24,145.89,144.30,142.42,141.08,135.91,130.16,128.58,128.23,123.15,121.03,118.27,111.36,65.56,61.19,55.43,53.58(2C),50.68(2C),43.64.
Embodiment 33:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-3,4-methylene-dioxy benzamide (II-08)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material piperinic acid, through column chromatography (sherwood oil: acetone=1: 5-1: 4, gradient elution) purifying, obtains white oily matter 116mg, yield 74.4%.
ESI-MS(m/z):414.37[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ7.35-7.29(m,2H,ArH),7.03-6.96(m,1H,ArH),6.94-6.80(m,4H,ArH),6.68(t,J=5.4Hz,1H,amide-H),6.01(s,2H,?
),3.98-3.91(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.70(ddd,J=13.8,5.9,3.5Hz,1H,NH-C
H 2CHOHCH
2-N),3.42-3.34(m,1H,NH-C
H 2CHOHCH
2-N),3.08(brs,4H,pipera?zinyl-H),2.89-2.82(m,2H,piperazinyl-H),2.66-2.58(m,2H,piperazinyl-H),2.54-2.41(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ167.04,152.32,150.36,147.99,141.13,128.70,123.09,121.62,121.02,118.22,111.36,107.99,107.71,101.67,65.78,61.14,55.42,53.54(2C),50.71(2C),43.44.
Embodiment 34:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-Isosorbide-5-Nitrae-benzodioxan-6-methane amide (II-09)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material Isosorbide-5-Nitrae-benzodioxan-6-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 127mg, yield 78.8%, fusing point 57-58 ℃.
ESI-MS(m/z):428.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ7.36(d,J=2.1Hz,1H,ArH),7.33-7.27(m,1H,ArH),7.03-6.96(m,1H,ArH),6.95-6.83(m,4H,ArH),6.66(t,J=5.5Hz,1H,amide-H),4.31-4.24(m,4H,
),3.98-3.91(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.69(ddd,J=13.8,5.8,3.6Hz,1H,NH-C
H 2CHOHCH
2-N),3.44-3.36(m,1H,NH-C
H 2CHOHCH
2-N),3.09(brs,4H,piperazinyl-H),2.90-2.82(m,2H,piperazinyl-H),2.66-2.58(m,2H,piperazinyl-H),2.54-2.41(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ167.06,152.33,146.50,143.40,141.17,127.79,123.08,121.02,120.44,118.24,117.24,116.58,111.36,65.79,64.56,64.22,61.14,55.42,53.54(2C),50.72(2C),43.32.
Embodiment 35:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-Isosorbide-5-Nitrae-benzodioxan-2-methane amide (II-10)
Synthetic method, with reference to embodiment 26, substitutes raw material 1-naphthoic acid with raw material Isosorbide-5-Nitrae-benzodioxan-2-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtain white powder 92mg, yield 57.1%, fusing point 108-109 ℃.
ESI-MS(m/z):428.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ7.10-6.84(m,9H,ArH,amide-H),4.74-4.68(m,1H,?
),4.58-4.45(m,1H,
),4.33-4.15(m,1H,
),3.90-3.81(m,4H,-OCH
3,-C
HOH),3.55(ddd,J=14.4,5.7,3.7Hz,1H,NH-C
H 2CHOHCH
2-N),3.36-3.26(m,1H,NH-C
H 2CHOHCH
2-N),3.08(brs,4H,piperazinyl-H),2.88-2.77(m,2H,piperazinyl-H),2.65-2.47(m,2H,piperazinyl-H),2.44-2.15(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ167.62,152.31,143.39,141.68,141.12,123.10,122.40,122.02,121.03,118.23,117.64,117.29,111.36,73.43,65.47,61.01,55.42,53.51(2C),50.68(2C),42.59.
Embodiment 36:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } xanthene-9-methane amide (II-11)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material xanthene-9-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 102mg, yield 57.2%, fusing point 159-160 ℃.
ESI-MS(m/z):474.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ7.43-7.36(m,2H,ArH),7.34-7.27(m,2H,ArH),7.17-7.07(m,4H,ArH),7.02-6.96(m,1H,ArH),6.94-6.83(m,3H,ArH),5.80(t,J=5.5Hz,1H,amide-H),4.91(s,1H,
),3.85(s,3H,-OCH
3),3.73-3.65(m,1H,-C
HOH),3.31(ddd,J=13.9,5.3,3.8Hz,1H,NH-C
H 2CHOHCH
2-N),3.19(ddd,1H,J=13.9,6.2,5.3Hz,1H,NH-C
H 2CHOHCH
2-N),3.02(brs,4H,piperazinyl-H),2.74-2.65(m,2H,piperaz-inyl-H),2.49-2.38(m,2H,piperazinyl-H),2.24(dd,J=12.5,3.7Hz,1H,NH-CH
2CHOH-C
H 2-N),2.09(dd,J=12.5,10.3Hz,1H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ172.37,152.31,151.13,151.10,141.11,129.44,129.38,129.27,129.17,123.77,123.68,123.09,121.03,119.28,119.03,118.23,117.11,117.04,111.36,65.42,60.46,55.42,53.36(2C),50.60(2C),47.07,42.57.
Embodiment 37:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-4-benzopyrone-2-methane amide (II-12)
Synthetic method, with reference to embodiment 26, substitutes raw material 1-naphthoic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3 with raw material 4-benzopyrone-2-formic acid, gradient elution) purifying, obtain light yellow powder 96mg, yield 58.2%, fusing point 137-138 ℃.
ESI-MS(m/z):438.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.22(dd,J=8.0,1.5Hz,1H,ArH),7.72(ddd,J=8.7,7.2,1.5Hz,1H,ArH),7.54(dd,J=8.5,0.5Hz,1H,ArH),7.48-7.42(m,2H,ArH),7.17(s,1H,?
),7.03-6.98(m,1H,amide-H),6.94-6.85(m,3H,ArH),4.04-3.96(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.77(ddd,J=13.8,6.1,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.47-3.38(m,1H,NH-C
H 2CHOHCH
2-N),3.11(brs,4H,piperazinyl-H),2.93-2.85(m,2H,piperazinyl-H),2.69-2.61(m,2H,piperazinyl-H),2.57-2.43(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ178.15,159.58,155.31,154.65,152.32,141.04,134.53,126.14,125.97,124.40,123.17,121.03,118.22,118.19,112.32,111.40,65.33,60.99,55.44,53.52(2C),50.69(2C),43.25.
Embodiment 38:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } indoles-3-methane amide (II-13)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material indole-3-carboxylic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 88mg, yield 57.2%, fusing point 117-118 ℃.
ESI-MS(m/z):409.4[M+H]
+.
1H?NMR(400MHz,CDCl
3:δ9.24(s,1H,Indole-N
H),8.02(dd,J=8.4,4.4Hz,1H,ArH),7.75(d,J=2.6Hz,1H,ArH),7.43-7.38(m,1H,ArH),7.25-7.21(m,2H,ArH),7.03-6.97(m,1H,ArH),6.95-6.83(m,3H,ArH),6.64(t,J=5.7Hz,1H,amide-H),4.04-3.96(m,1H,-OCH
3),3.85(s,3H,-OCH
3),3.77(ddd,J=13.8,5.7,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.52-3.43(m,1H,NH-C
H 2CHOHCH
2-N),3.08(brs,4H,piperazinyl-H),2.89-2.79(m,2H,piperazinyl-H),2.64-2.59(m,2H,piperazin-yl-H),2.53-2.49(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ165.92,152.32,141.12,136.44,128.21,124.75,123.11,122.91,121.69,121.04,120.03,118.26,112.21,112.01,111.37,66.10,61.15,55.42,53.53(2C),50.67(2C),42.88.
Embodiment 39:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1-benzylindole-3-methane amide (II-14)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 1-benzylindole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 136mg, yield 72.4%, fusing point 156-157 ℃.
ESI-MS(m/z):499.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.06-8.01(m,1H,ArH),7.74(s,1H,ArH),7.35-7.21(m,7H,ArH),7.18-7.11(m,2H,ArH),7.02-6.95(m,1H,ArH),6.94-6.83(m,3H,ArH),6.56(t,J=5.7Hz,1H,amide-H),5.32(s,2H,-C
H 2Bn),4.04-3.97(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.78(ddd,J=13.9,5.7,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.51-3.45(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.92-2.85(m,2H,piperazinyl-H),2.70-2.60(m,2H,piperazinyl-H),2.58-2.49(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ165.51,152.32,141.11,136.88,136.12,131.70,128.97(2C),128.09,127.07(2C),125.68,123.09,122.74,121.70,121.03,120.43,118.25,111.36,110.57,66.08,61.10,55.42,53.56(2C),50.61(2C),42.74,29.71.
Embodiment 40:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-6-bromo indole-3-methane amide (II-15)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 6-bromo indole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 104mg, yield 56.6%, fusing point 117-118 ℃.
ESI-MS(m/z):487.3、489.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.68(s,1H,Indole-N
H),7.88(d,J=8.6Hz,1H,ArH),7.65(s,1H,ArH),7.50(d,J=1.6Hz,1H,ArH),7.30(dd,J=8.6,1.6Hz,1H?ArH),7.03-6.83(m,4H,ArH),6.63(t,J=5.7Hz,1H,amide-H),4.03-3.94(m,1H,-C
HOH),3.84(s,3H,-OCH
3),3.74(ddd,J=13.8,5.9,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.45-3.37(m,1H,NH-C
H 2CHOHCH
2-N),3.06(brs,4H,piperazinyl-H),2.86-2.78(m,2H,piperazinyl-H),2.64-2.55(m,2H,piperazinyl-H),2.50-2.42(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ165.60,152.30,141.05,137.22,128.25,124.86,123.92,123.16,121.52,121.07,118.27,116.42,114.95,112.13,111.38,66.03,61.21,55.42,53.54(2C),50.69(2C),43.08.
Embodiment 41:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } indazole-3-methane amide (II-16)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material indazole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 90mg, yield 58.3%, fusing point 89-90 ℃.
ESI-MS(m/z):432.3[M+Na]
+.
1H?NMR(40MHz,CDCl
3):δ12.07(s,1H,Indazole-N
H),8.49-8.40(m,2H,ArH),7.52(d,J=8.4Hz,1H),7.44-7.39(m,1H,ArH),7.32-7.27(m,1H,ArH),7.04-6.98(m,1H,amide-H),6.96-6.85(m,3H,ArH),4.19-4.13(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.77(ddd,J=14.2,6.0,2.9Hz,1H,NH-C
H 2CHOHCH
2-N),3.59-3.48(m,1H,NH-C
H 2CHOHCH
2-N),3.12(brs,4H,piperazinyl-H),2.98-2.87(m,2H,piperazinyl-H),2.71-2.66(m,2H,piperazinyl-H),2.66-2.53(m,2H,NH-CH
2CHOHC
H 2).
13C?NMR(100MHz,CDCl
3):δ163.53,152.34,141.26,141.08,139.12,127.18,123.16,122.72,122.26,121.05,118.27,111.38,110.03,66.68,60.93,55.43,53.47(2C),50.68(2C),42.26.
Embodiment 42:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1-methylindazole-3-methane amide (II-17)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 1-methyl-benzdiazole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 93mg, yield 58.3%, fusing point 60-61 ℃.
ESI-MS(m/z):424.3[M+H]
+,446.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ8.36(d,J=8.2Hz,1H,ArH),7.59-7.52(m,1H,ArH),7.43-7.33(m,2H,ArH),7.29-7.23(m,1H,ArH),7.01-6.95(m,1H,amide-H),6.93-6.82(m,ArH),4.05(s,3H,Indazole-C
H 3),4.04-3.97(m,1H,-CHOH),3.84(s,3H,-OCH
3),3.75(ddd,J=13.8,6.0,3.7Hz,1H,NH-C
H 2CHOHCH
2-N),3.56-3.45(m,1H,NH-C
H 2-CHOHCH
2-N),3.08(brs,4H,piperazinyl-H),2.90-2.80(m,2H,piperazinyl-H),2.69-2.59(m,2H,piperazinyl-H),2.57-2.49(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ163.04,152.29,141.24,141.20,137.04,126.74,122.99,122.85,122.78,122.53,120.99,118.18,111.34,109.07,66.11,61.28,55.39,53.54(2C),50.71(2C),42.57,35.95.
Embodiment 43:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-5-fluorine indazole-3-methane amide (II-18)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 5-fluorine indazole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains 95mg, yield 59.0%, fusing point 99-100 ℃.
ESI-MS(m/z):428.2[M+H]
+.
1H?NMR(400MHz,CDCl
3):δδ12.07(s,1H,Indazole-N
H),8.34-8.24(m,1H,ArH),7.93-7.85(m,1H,ArH),7.39(ddd,J=15.8,15.2,2.9Hz,1H,ArH),7.07-7.02(brs,1H,amide-H),6.87-6.65(m,4H,ArH),4.49-4.37(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.75(ddd,J=14.0,6.2,4.1Hz,1H,NH-C
H 2CHOHCH
2-N),3.57-3.43(m,1H,NH-C
H 2CHOHCH
2-N),3.03(brs,4H,piperazinyl-H),2.90-2.80(m,2H,piperazinyl-H),2.70-2.66(m,2H,piperazinyl-H),2.56-2.48(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ162.55,155.18,139.73,136.80,130.01,123.55,123.12,119.27,119.09,115.72,115.64,115.51,114.69,110.74,69.68,61.27,55.79,52.57(2C),50.67(2C),46.42.
Embodiment 44:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-5-bromo-indazole-3-methane amide (II-19)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 5-bromo-indazole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains 107mg, yield 58.1%, fusing point 178-180 ℃.
ESI-MS(m/z):488.3、490.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ12.10(s,1H,Indazole-N
H),8.37(d,J=2.8Hz,1H,ArH),8.24-8.17(m,1H,ArH),7.74-7.67(m,1H,ArH),7.04-7.00(brs,1H,amide-H),6.89-6.64(m,4H,ArH),4.34-4.23(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.73(ddd,J=14.0,6.0,2.8Hz,1H,NH-C
H 2CHOHCH
2-N),3.55-3.47(m,1H,NH-C
H 2CHOHCH
2-N),3.05(brs,4H,piperazinyl-H),2.88-2.79(m,2H,piperazinyl-H),2.68-2.60(m,2H,piperazinyl-H),2.55-2.47(m,2H,NH-CH
2CHOHC
H 2).
13C?NMR(100MHz,CDCl
3):δ162.55,156.79,139.73,138.05,131.98,130.01,123.55,123.32,122.43,119.27,119.09,115.81,115.26,114.69,69.98,61.17,56.83,52.57(2C),50.67(2C),46.42.
Embodiment 45:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-5-chloro-indole-2-methane amide (II-20)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 5-chloro-indole-2-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains 94mg, yield 56.3%, fusing point 115-116 ℃.
ESI-MS(m/z):443.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.85(s,1H,indoly-H),7.60(brs,1H,amide-H),7.35(d,J=8.7Hz,1H,ArH),7.22(dd,J=8.7,2.0Hz,1H,ArH),7.03-6.83(m,6H,ArH),4.05-3.97(m,1H,-C
HOH),3.86(s,3H,-OC
H 3),3.76(ddd,J=13.8,5.6,3.5Hz,1H,NH-C
H 2CHOHCH
2-N),3.51-3.42(m,1H,NH-C
H 2CHOHCH
2-N),3.10(s,4H,piperazinyl-H),2.91-2.84(m,2H,piperazinyl-H),2.68-2.60(m,2H,piperazinyl-H),2.56-2.45(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ161.70,152.32,141.03,134.73,131.88,128.62,126.27,124.97,123.19,121.18,121.06,118.25,113.09,111.38,101.96,65.63,61.02,55.42,53.53(2C),50.64(2C),43.05.
Embodiment 46:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-6-bromo indole-2-methane amide (II-21)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 6-bromo indole-2-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white solid 113mg, yield 61.5%, fusing point 171-172 ℃.
ESI-MS(m/z):487.3、489.3[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.95(s,1H,indoly-H),7.61(brs,1H,amide-H),7.49(d,J=8.5Hz,1H,ArH),7.23(dd,J=8.5,1.7Hz,1H,ArH),7.03-6.84(m,6H,ArH),4.05-3.97(m,1H,-CH
2OH),3.86(s,3H,-OCH
3),3.78(ddd,J=13.8,5.9,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.51-3.42(m,1H,NH-C
H 2CHOHCH
2-N),3.10(s,4H,piperazinyl-H),2.92-2.83(m,2H,piperazinyl-H),2.69-2.60(m,2H,piperazinyl-H),2.58-2.44(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δδ161.75,152.32,141.10,137.15,131.23,126.50,124.13,123.20,123.13,121.05,118.25,118.10,114.94,111.38,102.56,65.64,61.00,55.43,53.52(2C),50.72(2C),43.06.
Embodiment 47:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-7-azaindole-3-methane amide (II-22)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 7-azaindole-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains 83mg, yield 53.8%, fusing point 103-104 ℃.
ESI-MS(m/z):410.4[M+H]
+.
1H?NMR(500MHz,CDCl
3):δ11.30(s,1H,7-azaindolyl-N
H),8.43(dd,J=8.0,1.5Hz,1H,ArH),8.32(dd,J=4.8,1.5Hz,1H,ArH),7.91(s,1H,ArH),7.19(dd,J=7.9,4.8Hz,1H,ArH),7.02-6.97(m,1H,ArH),6.92-6.83(m,3H,ArH),6.74(t,J=5.7Hz,1H,amide-H),4.07-4.00(m,1H,-C
HOH),3.85(s,3H,-OCH
3),3.79(ddd,J=13.8,6.0,3.4Hz,1H,NH-C
H 2-CHOHCH
2-N),3.47-3.40(m,1H,NH-C
H 2CHOHCH
2-N),3.09(brs,4H,piperazinyl-H),2.91-2.84(m,2H,piperazinyl-H),2.68-2.60(m,2H,piperazinyl-H),2.59-2.50(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(125MHz,CDCl
3):δ164.98,152.31,148.60,143.54,141.06,129.74,127.69,123.13,121.03,118.39,118.22,117.54,111.36,110.75,66.07,61.19,55.42,53.57(2C),50.64(2C),42.89.
Embodiment 48:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } imidazo [1,2-a] pyridine-3-carboxamide (II-23)
Synthetic method, with reference to embodiment 26, substitutes raw material 1-naphthoic acid with raw material imidazo [1,2-a] Nicotinicum Acidum, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtain white powder 97mg, yield 62.9%, fusing point 98-99 ℃.
ESI-MS(m/z):410.4[M+H]
+.
1H?NMR(500MHz,CDCl
3):δ9.48(d,J=7.0Hz,1H,ArH),8.09(s,1H,ArH),7.68(d,J=9.0Hz,1H,ArH),7.38-7.32(m,1H,ArH),7.04-6.82(m,5H,ArH),6.71(t,J=5.4Hz,1H,amide-H),4.03-3.96(m,1H,-C
HOH),3.85(s,3H,-OCH
3),3.74(ddd,J=13.8,5.4,3.5Hz,1H,NH-C
H 2CHOHCH
2-N),3.48-3.41(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.92-2.84(m,2H,piperazinyl-H),2.70-2.61(m,2H,piperazinyl-H),2.57-2.46(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(125MHz,CDCl
3):δ161.00,152.31,147.91,141.07,136.02,128.14,126.98,123.13,121.05,118.27,117.64,113.77,111.35,65.78,61.12,55.42,53.56(2C),50.67(2C),42.61.
Embodiment 49:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1H-indenes-3-methane amide (II-24)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 1H-indenes-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains golden yellow oily matter 70mg, yield 45.6%.
ESI-MS(m/z):408.4[M+H]
+,430.3[M+Na]
+.
1H?NMR(400MHz,CDCl
3):δ7.92(d,J=7.6Hz,1H,ArH),7.48(d,J=7.4Hz,1H,ArH),7.37-7.32(m,1H,ArH),7.29-7.24(m,1H,ArH),7.04-6.96(m,2H,ArH),6.94-6.84(m,3H,ArH),6.63(t,J=5.8Hz,1H,amide-H),4.03-3.94(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.74(ddd,J=13.8,5.8,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.50(d,J=1.9Hz,2H,?
),3.45-3.37(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.93-2.85(m,2H,piperazinyl-H),2.68-2.61(m,2H,piperazinyl-H),2.55-2.47(m,2H,NH-CH
2-CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ165.27,152.33,143.63,141.32,141.10,140.29,136.51,126.69,125.62,123.90,123.12,121.91,121.03,118.23,111.37,65.75,61.08,55.43,53.54(2C),50.67(2C),42.71,38.25.
Embodiment 50:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group }-1-thionaphthene-3-methane amide (II-25)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material 1-thionaphthene-3-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white powder 84mg, yield 52.4%, fusing point 62-63 ℃.
ESI-MS(m/z):426.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ8.40(d,J=7.8Hz,1H,ArH),7.92(s,1H,ArH),7.89-7.84(m,1H,ArH),7.49-7.37(m,2H,ArH),7.04-6.97(m,1H,ArH),6.94-6.84(m,3H,ArH),6.70(t,J=5.5Hz,1H,amide-H),4.05-3.97(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.78(ddd,J=13.8,5.5,3.4Hz,1H,NH-C
H 2CHOHCH
2-N),3.48-3.39(m,1H,NH-C
H 2CHOHCH
2-N),3.09(brs,4H,piperazinyl-H),2.92-2.85(m,2H,piperazinyl-H),2.68-2.60(m,2H,piperazi-nyl-H),2.59-2.46(m,2H,NH-CH
2CHOHC
H 2-N).
13C
NMR(100MHz,CDCl
3):δ164.29,152.33,141.10,140.31,136.79,132.03,129.39,125.18,125.11,124.29,123.13,122.58,121.04,118.24,111.37,65.75,61.11,55.43,53.55(2C),50.68(2C),43.03.
Embodiment 51:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } benzamide (II-26)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with benzene feedstock formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains colorless oil 89mg, yield 63.9%.
ESI-MS(m/z):370.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ7.84-7.76(m,2H,ArH),7.53-7.39(m,3H,ArH),7.04-6.96(m,1H,ArH),6.95-6.83(m,3H,ArH),6.78(t,J=5.6Hz,1H,amide-H),4.01-3.93(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.74(ddd,J=13.8,5.9,3.5Hz,1H,NH-C
H 2CHOH?CH
2-N),3.47-3.38(m,1H,),3.09(brs,4H,piperazinyl-H),2.91-2.82(m,2H,piperazinyl-H),2.68-2.58(m,2H,piperazinyl-H),2.57-2.42(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ167.78,152.33,141.15,134.49,131.52,128.58(2C),127.01(2C),123.10,121.03,118.22,111.37,65.76,61.12,55.42,53.54(2C),50.73(2C),43.35.
Embodiment 52:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } niacinamide (II-27)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material nicotinic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains brown semi-solid 86mg, yield 61.6%, fusing point 85-86 ℃.
ESI-MS(m/z):371.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ9.04(d,J=1.7Hz,1H,ArH),8.72(dd,J=4.8,1.7Hz,1H,ArH),8.19-8.10(m,1H,ArH),7.43-7.34(m,1H,ArH),7.04-6.81(m,5H,ArH,amide-H),4.04-3.97(m,1H,-C
HOH),3.86(s,3H,-OCH
3),3.76(ddd,J=13.8,5.8,3.5Hz,1H,NH-C
H 2CHOHCH
2-N),3.46-3.37(m,1H,NH-C
H 2CHOHCH
2-N),3.11(brs,4H,piperazinyl-H),2.97-2.87(m,2H,piperazinyl-H),2.74-2.63(m,2H,piperazinyl-H),2.61-2.46(m,2H,NH-CH
2CHOHC
H 2-N).
13C?NMR(100MHz,CDCl
3):δ165.88,152.31,152.25,148.09,140.94,135.16,130.12,123.49,123.23,121.05,118.27,111.38,65.53,61.04,55.43,53.51(2C),50.45(2C),43.45.
Embodiment 53:N-{2-hydroxyl-3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl group } furans-2-methane amide (II-28)
Synthetic method is with reference to embodiment 26, and raw material 1-naphthoic acid is substituted with raw material furans-2-formic acid, through column chromatography (sherwood oil: acetone=1: 4-1: 3, gradient elution) purifying, obtains white oily matter 86mg, yield 63.5%.
ESI-MS(m/z):360.4[M+H]
+.
1H?NMR(400MHz,CDCl
3):δ7.43(dd,J=1.7,0.8Hz,1H,ArH),7.11(dd,J=3.5,0.8Hz,1H,ArH),7.04-6.84(m,5H,ArH,amide-H),6.49(dd,J=3.5,1.7Hz,1H,ArH),4.00-3.92(m,1H,C
HOH),3.86(s,3H,-OCH
3),3.71-3.63(m,1H,NH-C
H 2CHOHCH
2-N),3.45-3.37(m,1H,NH-C
H 2CHOHCH
2-N),3.10(brs,4H,piperazinyl-H),2.91-2.82(m,2H,piperazinyl-H),2.70-2.60(m,2H,piperazinyl-H),2.55-2.44(m,2H,NH-CH
2-CHOHC
H 2?-N).
13CNMR(100MHz,CDCl
3):δ158.76,152.31,147.96,143.97,141.11,123.10,121.03,118.20,114.27,112.10,111.37,65.75,61.19,55.41,53.54(2C),50.62(2C),42.65.
The embodiment of biological activity determination method:
Adopt luciferase reporter gene method, with Photinus pyralis LUC (Firefly luciferase), the α of renilla luciferase (Renilla luciferase) and G protein receptor conduction path
1receptor subtype medicament high flux screening model, filters out and has subtype-selective and act on α
1A-adrenoceptor and α
1Dthe piperazines micromolecular compound of-adrenoceptor.
Experimental technique:
HEK293 cell cultures, in cell bottle, is changed to liquid when cell degree of merging reaches 90% left and right, after 4 hours, carry out cell bed board (48 porocyte culture plate), carry out cell counting, make the cell number in every hole suitable.Bed board is complete, then adds a certain amount of substratum in cell bottle, is placed in thermostat container and cultivates standby after dilution.
After 4 hours, examine under a microscope the cell in cell hole, treat each hole totally degree of converging reach more than 90%, can carry out turning in wink.Mixed solution for cell transfecting needs interim preparation, A and B, consists of, and wherein, A is by plasmid α
1A, reporter gene CRE and SV40 and high glucose medium (DMEM) formulated, B is formulated by liposome and DMEM.Prepare respectively A liquid and B liquid, act on approximately 5 minutes, then A and B are mixed, after mixing, act on approximately 20 minutes.
Take out Tissue Culture Plate, discard waste liquid after cleaning 2 times with phosphate buffer soln (PBS), in every hole, add respectively 1640 substratum 220 μ L, after treating A+B effect, therefrom draw 80 μ L extremely in every hole, shake up, put into thermostat container and cultivate.
After transfection, hatch after 18 hours and take out Tissue Culture Plate, after cleaning 2 times with PBS, discard waste liquid, in each hole, add respectively 1640 substratum of corresponding calculated amount, add test-compound and dimethyl sulfoxide (DMSO) (DMSO), act on 30 minutes, then add agonist phyenlephrinium.Positive control medicine is Prazosin.After interpolation, rock and within 30 seconds, make enchylema composition be uniformly distributed, be then placed in thermostat container and cultivate.All compounds dissolve with cell grade DMSO, are mixed with the mother liquor that concentration is 10mmol/L, and redilution becomes 1mmol/L, tests.
Test-compound was hatched after 8 hours, took out culture plate, with PBS, cleaned after twice, added the lysate of 1 times, every hole 65 μ L.Tissue Culture Plate is placed in to the abundant cracking of decolorization swinging table 30 minutes.Be placed in-80 ℃ of environment and preserve (storage life is 2 weeks).
Utilize the ratio (RLU, relative light units) of fluoroscopic examination analyser (GloMaxTM96Microplate Luminometer (Promega company)) test Photinus pyralis LUC and renilla luciferase activity.The ratio [test compounds (RLU)/Prazosin (RLU)] of the RLU of test compounds and positive control Prazosin RLU numerical value, that is: this Compound Phase is strong and weak for the antagonistic activity of Prazosin, and the less expression antagonistic activity of numerical value is higher.According to above-mentioned same determination of experimental method test compounds to α
1B, α
1Dthe ratio of the RLU of acceptor and positive control Prazosin RLU numerical value.Table 1 is the RLU of test compounds and the ratio of positive control Prazosin RLU numerical value.
The demonstration of table 1 biological assessment result, most of test compounds have the α that is better than Prazosin
1Areceptor subtype antagonistic action, partial test compound is to α
1Dreceptor subtype antagonistic action is equal to or is better than Prazosin.Wherein test compounds I-05, I-15, I-16, I-18, II-01, II-25 have the α that is better than Prazosin simultaneously
1Aacceptor and α
1Dthe hypotype antagonistic action of acceptor, and to α
1Breceptor subtype antagonistic action will be weaker than Prazosin.They are potential α
1A/ α
1D-adrenoceptor antagonists, is expected to be used for the treatment of benign prostate hyperplasia, and is not easy to produce postural hypotension, the side effect such as tired, sleepy.
The ratio of the RLU of table 1 test compounds and positive control Prazosin RLU numerical value
Claims (3)
1. amides Phenylpiperazine derivatives, its structural formula is as shown in logical formula I or (II):
Wherein:
R
1be selected from 1-isoquinolyl, 2-quinolyl, 2-quinoxalinyl, 6-quinoxalinyl, 1,4-benzodioxan-2-base, indazole-3-base, 1-methylindazole-3-base, 5-fluorine indazole-3-base, 5-bromo-indazole-3-base, 7-azaindole-3-base, imidazo [1,2-a] pyridin-3-yl, 1H-indenes-3-base, thionaphthene-3-base, 2-chloropyridine-3-base, 6-5-flumethiazine-3-base, 2-methoxypyridine-3-base, 2,6-dichloropyridine-3-base, 2-methoxypyridine-4-base, pyridine-2-base;
R
2be selected from 1-naphthyl, 2-naphthyl, 9-anthryl, 1-isoquinolyl, 2-quinolyl, 2-quinoxalinyl, 6-quinoxalinyl, 3, 4-methylenedioxyphenyl, 1, 4-benzodioxan-6-base, 1, 4-benzodioxan-2-base, xanthene-9-base, 4-benzopyrone-2-base, indol-3-yl, 1-benzylindole-3-base, 6-bromo indole-3-base, indazole-3-base, 1-methylindazole-3-base, 5-fluorine indazole-3-base, 5-bromo-indazole-3-base, 5-chloro-indole-2-base, 6-bromo indole-2-base, 7-azaindole-3-base, imidazo [1, 2-a] pyridin-3-yl, 1H-indenes-3-base, thionaphthene-3-base, phenyl, pyridin-3-yl, furans-2-base.
2. the salt of amides Phenylpiperazine derivatives described in claim 1, it is characterized in that, described salt is amides Phenylpiperazine derivatives and the salt that is selected from following acid formation: hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid, methylsulfonic acid, phenylformic acid, Phenylsulfonic acid, tosic acid, formic acid, acetic acid, propionic acid, oxysuccinic acid, tartrate, oxalic acid, succsinic acid, fumaric acid, toxilic acid or amino acid.
3. amides Phenylpiperazine derivatives or its salt application in preparation treatment benign prostate hyperplasia medicine described in claim 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410175321.5A CN103980195A (en) | 2014-04-28 | 2014-04-28 | Amide-type phenylpiperazine derivative, and salt and application thereof in preparing medicine for treating benign prostatic hyperplasia |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410175321.5A CN103980195A (en) | 2014-04-28 | 2014-04-28 | Amide-type phenylpiperazine derivative, and salt and application thereof in preparing medicine for treating benign prostatic hyperplasia |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103980195A true CN103980195A (en) | 2014-08-13 |
Family
ID=51272392
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410175321.5A Pending CN103980195A (en) | 2014-04-28 | 2014-04-28 | Amide-type phenylpiperazine derivative, and salt and application thereof in preparing medicine for treating benign prostatic hyperplasia |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103980195A (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105061352A (en) * | 2015-07-29 | 2015-11-18 | 广州市广金投资管理有限公司 | Aryl piperazine derivatives (III), salt thereof, preparation method, and application |
CN105130921A (en) * | 2015-07-29 | 2015-12-09 | 广州市广金投资管理有限公司 | Aryl piperazine derivatives (I), salts, preparation method, and applications thereof |
CN105153145A (en) * | 2015-07-29 | 2015-12-16 | 广州市广金投资管理有限公司 | Arylpiperazine derivative II and salts thereof, and preparation method and application thereof |
CN108530391A (en) * | 2018-05-17 | 2018-09-14 | 袁牧 | A kind of amides aryl piperazine derivative and the preparation method and application thereof |
WO2022256382A1 (en) * | 2021-06-02 | 2022-12-08 | The University Of North Carolina At Chapel Hill | Rna-targeting ligands, compositions thereof, and methods of making and using the same |
CN116496234A (en) * | 2023-02-09 | 2023-07-28 | 江苏润安制药有限公司 | Preparation method of urapidil hydrochloride key intermediate |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1264300A (en) * | 1997-05-12 | 2000-08-23 | 奥索·麦克尼尔药品公司 | Arylsubstituted piperazines useful in the threatement of bening prostatic hyperlasia |
CN1291188A (en) * | 1998-02-20 | 2001-04-11 | 奥索-麦克尼尔药品公司 | Novel substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia |
CN102382032A (en) * | 2010-08-30 | 2012-03-21 | 广州医学院 | 1-(phenyl)-4-[3-(4-indoxyl)-2-hydroxypropyl]piperazine derivative and salts thereof as well as preparation method and application thereof |
CN103387531A (en) * | 2012-05-10 | 2013-11-13 | 广州医学院 | Amide arylpiperazine derivatives, their preparation method, and their application in benign prostatic hyperplasia resistance |
-
2014
- 2014-04-28 CN CN201410175321.5A patent/CN103980195A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1264300A (en) * | 1997-05-12 | 2000-08-23 | 奥索·麦克尼尔药品公司 | Arylsubstituted piperazines useful in the threatement of bening prostatic hyperlasia |
CN1291188A (en) * | 1998-02-20 | 2001-04-11 | 奥索-麦克尼尔药品公司 | Novel substituted pyridino arylpiperazines useful in the treatment of benign prostatic hyperplasia |
CN102382032A (en) * | 2010-08-30 | 2012-03-21 | 广州医学院 | 1-(phenyl)-4-[3-(4-indoxyl)-2-hydroxypropyl]piperazine derivative and salts thereof as well as preparation method and application thereof |
CN103387531A (en) * | 2012-05-10 | 2013-11-13 | 广州医学院 | Amide arylpiperazine derivatives, their preparation method, and their application in benign prostatic hyperplasia resistance |
Non-Patent Citations (2)
Title |
---|
GEE-HONG KUO等: "Design,Synthesis,and Structure-Activity Relationships of Phthalimide-Phenylpiperazines: A Novel Series of Potent and Selective -Adrenergic Receptor Antagonists", 《J.MED.CHEM.》, vol. 42, no. 11, 9 May 2000 (2000-05-09) * |
方浩等: "N-(取代苯基哌嗪基烷基)酰胺类α1-受体拮抗剂的设计、合成及生物活性研究", 《化学学报》, vol. 60, no. 4, 6 August 2004 (2004-08-06) * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105061352A (en) * | 2015-07-29 | 2015-11-18 | 广州市广金投资管理有限公司 | Aryl piperazine derivatives (III), salt thereof, preparation method, and application |
CN105130921A (en) * | 2015-07-29 | 2015-12-09 | 广州市广金投资管理有限公司 | Aryl piperazine derivatives (I), salts, preparation method, and applications thereof |
CN105153145A (en) * | 2015-07-29 | 2015-12-16 | 广州市广金投资管理有限公司 | Arylpiperazine derivative II and salts thereof, and preparation method and application thereof |
CN105153145B (en) * | 2015-07-29 | 2018-10-30 | 广州市广金投资管理有限公司 | Aryl piperazine derivative II and its salt, preparation method and purposes |
CN108530391A (en) * | 2018-05-17 | 2018-09-14 | 袁牧 | A kind of amides aryl piperazine derivative and the preparation method and application thereof |
CN108530391B (en) * | 2018-05-17 | 2022-05-17 | 袁牧 | Amide aryl piperazine derivative and preparation method and application thereof |
WO2022256382A1 (en) * | 2021-06-02 | 2022-12-08 | The University Of North Carolina At Chapel Hill | Rna-targeting ligands, compositions thereof, and methods of making and using the same |
CN116496234A (en) * | 2023-02-09 | 2023-07-28 | 江苏润安制药有限公司 | Preparation method of urapidil hydrochloride key intermediate |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103980195A (en) | Amide-type phenylpiperazine derivative, and salt and application thereof in preparing medicine for treating benign prostatic hyperplasia | |
CN101115718B (en) | N- (heteroaryl) -1h-indole-2-carb0xamide derivatives and their use as vanilloid TRPV1 receptor ligands | |
CN105793260B (en) | 1 (base of 5 tert-butyl group, 2 arylpyrazole 3) 3 [2 fluorine 4 [(base of 3 oxo 4H pyridos [2,3 B] pyrazine 8) epoxide] phenyl] urea derivative as the RAF inhibitor for treating cancer | |
CA2637333C (en) | Tricyclic n-heteroaryl-carboxamide derivatives containing a benzimidazole unit, method for preparing same and their therapeutic use | |
TWI388554B (en) | N-(amino-heteroaryl)-1h-indole-2-carboxamide derivatives, preparation thereof and therapeutic use thereof | |
TW589308B (en) | Novel cyclic diamine compounds and medicine containing the compound | |
ES2344666T3 (en) | DERIVATIVES OF INDOL ACTIVATORS OF THE PPAR. | |
CN104513213A (en) | Fxr agonist | |
CN104754941A (en) | Pro-neurogenic compounds | |
CN105968093B (en) | The preparation method of amber love song Ge Lieting | |
CN110291065A (en) | A kind of new isoindoline derivative, its pharmaceutical composition and application | |
BG108487A (en) | Triamide substituted indoles, benzofuranes and benzothiophenes as inhibitors of microsomal triglyceride transfer protein (mtp) and/or apolipoprotein b (apo b) secretion | |
PT1856057E (en) | Tetrahydroindolone and tetrahydroindazolone derivatives | |
CN103429571A (en) | Substituted pyridines as sodium channel blockers | |
CN103168033A (en) | Quinazoline compounds as sodium channel blockers | |
WO2006072458A2 (en) | Substituted oxindole derivatives, medicaments containing said derivatives and use thereof | |
CN110167937A (en) | Two rings pair-heteroaryl derivative as protein aggregation regulator | |
CN110198938A (en) | Double-heteroaryl derivative as protein aggregation regulator | |
CN106279167B (en) | Matrine compound derivative and its preparation method and application | |
CN101679370A (en) | Novel vanilloid receptor ligands and the use thereof for the production of pharmaceuticals | |
WO2012022121A1 (en) | Fused ring compound for use as mineralocorticoid receptor antagonist | |
WO2016124140A1 (en) | Heterocyclic-substituted n-sulfonylbenzamide derivatives, preparation method for derivatives, and pharmaceutical use of derivatives | |
CN102341373A (en) | Substituted 2-mercapto-3-aminopyridines as kcnq2/3 modulators | |
EP3412653A1 (en) | N-sulfonyl benzamide derivative with heterocyclic substituent, preparation method therefor and pharmaceutical application thereof | |
WO2020156312A1 (en) | Polycyclic derivative modulator, preparation method therefor and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140813 |