CN102775412B - Sedative and soporific compound, and preparation method and application thereof - Google Patents
Sedative and soporific compound, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a compound shown in a formula I. In the formula I, R is H, -SO2 or -Ar; and Ar is a C6-12 aromatic alkyl or substituted aromatic alkyl. The invention also provides a preparation method and application of the compound. The compound provided by the invention can obviously inhibit the spontaneous activity frequency of mice, and the comparison with a negative control group at each time point shows significant and highly-significant differences, so that the compound can be used as a medical active component of an anti-insomnia medicament to facilitate the development of a new medicament having a better effect, thereby achieving obvious social benefits and economic benefits. The method disclosed by the invention is very simple in process route, low in cost and high in product yield, and is suitable for requirements of industrialized and expanded production.
Description
Technical field
The present invention relates to compound of a kind of tranquilizing soporific and its production and use.
Background technology
Pyrazolo [1,5-a] pyrimidine is nitrogen heterocyclic ring important in organic chemistry and the pharmaceutical chemistry, is subject to for a long time extensive concern always.Owing to having simultaneously pyrazoles and the important activity unit of pyrimidine two classes in this molecule, thereby this compounds often has good biological activity, a large amount of compounds that contain the pyrazolopyrimidine structural unit have been applied to field of medicaments, its derivative can act on a plurality of important biological targets, demonstrate widely pharmacological activity, such as cell cycle deopendent protein kinase (CDKs) inhibitor, the Checkpoint Kinase inhibitor, hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, cyclooxygenase (COX-2) selective depressant, adenylic acid (AMP) phosphodiesterase inhibitor, serotonin 6 (5-HT6) receptor antagonist and tranquilizing soporific selectivity peripheral benzodiazepine receptor part isoreactivity.This compounds have these widely biological activity caused greatly interest of pharmaceutical chemists, impel the research of synthesizing pyrazole [1,5-a] pyrimidine novel method and new compound constantly to carry out, and obtaining new achievement.For example zaleplon, i.e. N-ethyl-N-3-[7-(the 3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide also is one of calm hypnotic drug of this class of pyrazolo [1,5-a] pyrimidine.The fugitive treatment that this medicine can be used for having a sleepless night.Different from traditional sedative hypnotic, its alternative acts on BZl(w1) acceptor, untoward reaction is less, and the transformation period is shorter, good effect, cumulative effect is not clearly yet.But also have many obvious side effects simultaneously, common as back of the body chest pain, migraine, constipation, dry, sacroiliitis, depression, anxiety and illusion generation etc. also affect and have restricted the clinical application of this medicine.
Along with the development of society, the increasing of people's survival pressure, the insomniac will get more and more, and the demand for sedative hypnotic also will increase year by year all over the world.Develop safer, effective, can cause physiological sleep and overcome the novel sedative hypnotic of existing adverse drug reaction, will be one of research direction of medicine scholars.Obviously, on the architecture basics of pyrazolo [1,5-a] pyrimidine, appropriate design with develop the new compound that more has the anti-insomnia activity extremely important and actual meaning arranged.
Summary of the invention
The object of the present invention is to provide a kind of new compound for tranquilizing soporific.Another object of the present invention is to provide preparation method and the purposes of compound.
The invention provides the compound shown in the formula I, its structural formula is as follows:
R be H ,-SO
2-Ar;
Wherein, the substituting group of the aryl radical of described replacement is halogen, nitro or alkyl.
Further, described Ar is phenyl or substituted-phenyl; Described alkyl is the alkyl of C1-5.
Wherein, described halogen is Cl or Br; Described alkyl is the alkyl of C1-3.
Further, described halogen is Br.
Further, described alkyl is methyl.
Further, described substituted-phenyl is the phenyl of para-orientation.
Further preferably, described compound is:
N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide;
7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-methylamine of N-ethanoyl-N-ethylamino-3-)
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl benzenesulfonamide,
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl brosyl amine,
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] the methyl para toluene sulfonamide or
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide.
Further, described compound is: and N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide.
The present invention also provides the preparation method of above-claimed cpd, and it comprises following operation steps:
(1) gets intermediate N ethyl-N-3-[7-(3-cyano pyrazole also [1,5a] pyrimidyl) phenyl] ethanamide, by sodium borohydride reduction reaction, prepare 7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-methylamine of N-ethanoyl-N-ethylamino-3-); (2) (phenyl [pyrazolo [1,5a] the pyrimidyl]-3-methylamine of N-ethanoyl-N-ethylamino-3-) is with Cl-SO to get the 7-of step (1) preparation
2-Ar namely gets formula 1 compound after amidate action occurs;
Wherein, Ar is the aryl radical of C6-12 or the aryl radical of replacement.
Further, its preparation method is: utilize intermediate N ethyl-N-3-[7-(the 3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl in solvent DMF] ethanamide and NaBH
4Under the Iron(III) chloride hexahydrate katalysis, obtain 7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-methylamine of N-ethanoyl-N-ethylamino-3-).Then the 7-that the utilize to generate (phenyl [pyrazolo [1 of N-ethanoyl-N-ethylamino-3-); 5a] pyrimidyl]-3-methylamine and substituted phenylsulfonyl chloride react under the NaH effect; obtain N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] the methyl substituted benzenesulfonamides.Its reaction formula is as follows:
In the above-mentioned reaction formula:
1N-ethyl-N-3-[7-(the 3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
27-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-methylamine of N-ethanoyl-N-ethylamino-3-)
3a: benzene sulfonyl chloride
4a:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl benzenesulfonamide
3b: p-bromobenzenesulfonyl chloride
4b:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl brosyl amine
3c: Tosyl chloride
4c:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] the methyl para toluene sulfonamide
3d: 4-Nitrobenzenesulfonyl chloride
4d:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide
Further, its preparation method is as follows:
(1) N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] preparation of ethanamide
Raw material: intermediate N ethyl-N-3-[7-(the 3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl] mol ratio of ethanamide and Iron(III) chloride hexahydrate and sodium borohydride is 1:2:10,
Intermediate N ethyl-N-3-[7-(the 3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide 10mmol, solvent: DMF:50mL
Processing step:
In the 100mL pear shape bottle, add the 10mL aqueous solution of 20mmol Iron(III) chloride hexahydrate and 10mmol N-ethyl-N-3-[7-(3-cyano pyrazole also [1,5a] pyrimidyl) phenyl] mixed solution of DMF solution of ethanamide, cool off 00C with frozen water, stir the lower 0.1mol sodium borohydride that adds several times, finish rear room temperature reaction 5h, follow the tracks of reaction with TLC.After the end, filter, extract several times with EA, water repeatedly washs, the organic layer anhydrous Na
2SO
4Drying is spin-dried for, and thick product gets the described N-ethyl of claim 1-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl through column chromatography purification] ethanamide, be the white powder solid.
(2) N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] preparation of methyl substituted benzsulfamide
Raw material: N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] mol ratio of ethanamide and substituted phenylsulfonyl chloride is 1:1.2.
Processing step:
In the 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stirred 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] the pyrimidyl phenyl] ethanamide, add the 0.12mmol substituted phenylsulfonyl chloride wait dissolving rear continuation, finish rear room temperature reaction 1h, after TLC follows the tracks of the reaction end, with the EA extraction, wash the organic layer anhydrous Na with water
2SO
4Drying is spin-dried for, and thick product is through column chromatography purification, get the described N-[7-of claim 1 (phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] the methyl substituted benzsulfamide.In the aforesaid method, described substituted phenylsulfonyl chloride is a kind of in benzene sulfonyl chloride, p-bromobenzenesulfonyl chloride, 4-Nitrobenzenesulfonyl chloride, the p-methyl benzene sulfonic chloride.
The present invention also provides the purposes of above-claimed cpd in the medicine of preparation Cure for insomnia.
Compound provided by the invention, the Assay of spontaneous activity that can obviously suppress mouse, each time point and negative control group relatively have significantly and utmost point difference, the active pharmaceutical ingredients that can be used as the anti-insomnia medicine is developed the better new drug of drug effect, simultaneously, because the structure such as nitrile group-containing not in this compounds, can reduce such medicine in vivo further metabolism produce the possibility of toxic side effect.Has obvious Social benefit and economic benefit.The method of the invention operational path is very simple, and cost is lower, and the yield of product is higher, can be suitable for the needs of industrialization and expanding production.
Embodiment
Embodiment 1N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] preparation of ethanamide (be called for short 2)
The processing step of the present embodiment is as follows:
In the 100mL pear shape bottle, add the 10mL aqueous solution of 20mmol Iron(III) chloride hexahydrate and 10mmol N-ethyl-N-3-[7-(3-cyano pyrazole also [1,5a] pyrimidyl) phenyl] mixed solution of DMF solution of ethanamide, cool off 00C with frozen water, stir the lower 0.1mol sodium borohydride that adds several times, finish rear room temperature reaction 5h, follow the tracks of reaction with TLC.After the end, filter, extract several times with EA, water repeatedly washs, the organic layer anhydrous Na
2SO
4Drying is spin-dried for, and thick product gets N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl through column chromatography purification] ethanamide, be the white powder solid, productive rate 58%, m.p.145-147 ℃;
1H?NMR(400MHz,CDCl
3)δ(ppm):
1.09(t,J=7.2Hz,3H),1.81(s,3H),2.20(m,1H),2.51(m,1H),3.23(m,2H),3.40(d,J=12.0Hz,3H),3.72(q,J=7.2Hz,2H)),5.51(t,J=4.0Hz,1H),6.23(s,1H),6.85(s,1H),7.01-7.51(m,4H,PhH).HRMS(ESI)m/z?calcd?for?C
17H
19N
5O(M+H
+)310.1666,found?310.1662.。
Embodiment 2:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] preparation of methyl benzenesulfonamide (being called for short 4a)
The processing step of the present embodiment is as follows: in the 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stirred 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] the pyrimidyl phenyl] ethanamide, add the 0.12mmol benzene sulfonyl chloride wait dissolving rear continuation, finish rear room temperature reaction 1h, after TLC follows the tracks of the reaction end, with the EA extraction, wash the organic layer anhydrous Na with water
2SO
4Drying is spin-dried for, and thick product is through column chromatography purification, get N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl benzenesulfonamide, be the white powder solid, productive rate 92%, m.p.160-161 ℃.
1H?NMR(400MHz,CDCl
3)δ(ppm):0.98(t,J=7.2Hz,3H),1.66(s,3H),1.89(m,1H),2.25(m,1H),3.59(q,J=7.2Hz,2H),3.74(m,1H),3.88(m,1H),5.26(t,J=6.8Hz,1H),6.43(s,1H),6.68-7.89(m,9H,PhH).HRMS(ESI)m/z?calcd?for?C
23H
23N
5O
3S(M+H
+)450.1602,found450.1594.
Embodiment 3:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] preparation of methyl brosyl amine (being called for short 4b)
The processing step of the present embodiment is as follows:
The processing step of the present embodiment is as follows: in the 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stirred 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] the pyrimidyl phenyl] ethanamide, add the 0.12mmol benzene sulfonyl chloride wait dissolving rear continuation, finish rear room temperature reaction 1h, after TLC follows the tracks of the reaction end, with the EA extraction, wash the organic layer anhydrous Na with water
2SO
4Drying is spin-dried for, and thick product is through column chromatography purification, get N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl brosyl amine, be white powder solid productive rate 89%, m.p.137-139 ℃.
1H?NMR(400MHz,CDCl
3)δ(ppm):1.08(t,J=7.2Hz,3H),1.75(s,3H),1.87(m,1H),2.13(m,1H),2.43(dd,J=13.6Hz,6.4Hz,3H),3.70(m,2H),3.82(m,2H),5.41(t,J=6.0Hz,1H),6.68(s,1H),6.70-7.87(m,8H,PhH).HRMS(ESI)m/zcalcd?for?C
23H
22N
5O
3SBr(M+H
+)528.0712,found?528.0699.
Embodiment 4:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] preparation of methyl para toluene sulfonamide (being called for short 4c)
The processing step of the present embodiment is as follows:
In the 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stirred 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] the pyrimidyl phenyl] ethanamide, add the 0.12mmol benzene sulfonyl chloride wait dissolving rear continuation, finish rear room temperature reaction 1h, after TLC follows the tracks of the reaction end, with the EA extraction, wash the organic layer anhydrous Na with water
2SO
4Drying is spin-dried for, and thick product is through column chromatography purification, get N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] the methyl para toluene sulfonamide, be the white powder solid, productive rate 89%, m.p.160-161 ℃.
1H?NMR(400MHz,CDCl
3)δ(ppm):0.97(t,J=6.8Hz,3H),1.66(s,3H),1.87(m,1H),2.22(m,1H),2.38(s,3H),3.59(m,2H),3.75(m,2H),5.28(t,J=6.4Hz,1H),6.57(s,1H),6.62-7.74(m,8H,PhH).HRMS(ESI)m/z?calcd?for?C
24H
25N
5O
3S(M+Na
+)486.1577,found486.1570.
Embodiment 5:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] preparation of methyl p-nitrophenyl sulphonamide (being called for short 4d)
The processing step of the present embodiment is as follows:
In the 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stirred 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] the pyrimidyl phenyl] ethanamide, add the 0.12mmol benzene sulfonyl chloride wait dissolving rear continuation, finish rear room temperature reaction 1h, after TLC follows the tracks of the reaction end, with the EA extraction, wash the organic layer anhydrous Na with water
2SO
4Drying is spin-dried for, and thick product is through column chromatography purification, get N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide, be yellow powder shape solid, productive rate 89%, m.p.69-71 ℃.
1H?NMR(400MHz,CDCl
3)δ(ppm):1.08(t,J=7.2Hz,3H),1.90(s,3H),2.22(m,1H),2.39(m,1H),2.72(dd,J=13.6Hz,6.4Hz,3H),3.74(m,2H),3.86(m,2H),5.54(t,J=6.0Hz,1H),6.89(s,1H),7.08-8.30(m,8H,PhH).HRMS(ESI)m/z?calcd?forC
23H
22SO
5N
6(M+Na
+)495.1441,found495.1445.
Below specify beneficial effect of the present invention by test example.
Test example 1 biological activity test
1, experimental drug
Be subjected to reagent:
(1) pyrazolo [1,5-a] pyrimidine derivatives: 2, the 4a of embodiment 1～embodiment 5 preparations ~ 4d.
(2) 2:N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide (embodiment 1 preparation)
4a:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl benzenesulfonamide (embodiment 2 preparations)
4b:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl brosyl amine (embodiment 3 preparations)
4c:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl para toluene sulfonamide (embodiment 4 preparations)
4d:N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide (embodiment 5 preparations)
2, laboratory animal
Kunming kind small white mouse, male and female half and half, body weight 18-22g is provided by the West China animal center.
3 instruments:
The free activation record instrument of YLS-1A Multifunctional mouse;
Sartorius electronic balance (0.0001g): Beijing Ao Duolisi balance company limited.
4, compounding medicine
(diazepam inj: with physiological saline be mixed with 0.05% concentration for.
2: accurately take by weighing compound 0.0278 gram on ten thousand/balance, add the 0.5%CMC(Xylo-Mucine) 4.0ml liquid is mixed with 140mg/kg concentration suspension for experiment;
4a: accurately take by weighing compound 0.0392 gram on ten thousand/balance, add the 0.5%CMC(Xylo-Mucine) 3.9ml liquid is mixed with 203mg/kg concentration suspension for experiment;
4b: accurately take by weighing compound 0.0477 gram on ten thousand/balance, add the 0.5%CMC(Xylo-Mucine) 4.0ml liquid is mixed with 239mg/kg concentration suspension for experiment;
4c: accurately take by weighing compound 0.0439 gram on ten thousand/balance, add the 0.5%CMC(Xylo-Mucine) 4.0ml liquid is mixed with 219mg/kg concentration suspension for experiment;
4d: accurately take by weighing compound 0.0374 gram on ten thousand/balance, add the 0.5%CMC(Xylo-Mucine) 3.8ml liquid is mixed with 195mg/kg concentration suspension for experiment;
5, experimental technique
Get 48 of healthy Kunming mouses, be divided at random 8 groups by sex, body weight, 6 every group, male and female half and half.Before the administration each group mouse is positioned over respectively in the box of spontaneous activity recording unit, makes its 5min that conforms, then begin writing time, the numeral that shows on observation and the record 5min charactron is as the control value of spontaneous activity in mice number of times before the administration.After all mouse assay is finished, the grouping administration.The every mouse gavage Xylo-Mucine 0.4ml/20g of negative group, stable group (positive controls) is injected 0.4ml/20g with 0.05% diazepam solution to mouse peritoneal, title compound is with the 0.4ml/20g gastric infusion, 30min, 60min, 90min and 120min after the administration, measure the Assay of spontaneous activity of respectively organizing mouse 5min with method, the data obtained carries out statistical treatment with spss.17.0 software, and the significant difference between comparative group.
4, the pharmacological results sees the following form 1
Table 1
Each time point compares with negative group
*P＜0.05
*P＜0.01
* *P＜0.001
Can find out from the data of table 1, in pyrazolo [1, the 5-a] pyrimidine derivatives of embodiment 1～embodiment 5 preparation 2,4a, 4b, 4d each time point of autonomic activities number of times, particularly 4d and the negative control group that all can obviously reduce mouse relatively have utmost point marked difference.
Experimental result shows, pyrazolo provided by the present invention [1,5-a] pyrimidine derivatives can further be developed the anti-insomnia medicine with better pharmacologically active that makes new advances.
Compound provided by the invention, the Assay of spontaneous activity that can obviously suppress mouse, each time point and negative control group relatively have significantly and utmost point difference, can be used as the active pharmaceutical ingredients of potential anti-insomnia medicine, further develop the less new drug still less of the better untoward reaction of drug effect, have obvious Social benefit and economic benefit.And the method for the invention operational path is very simple, and cost is lower, and the yield of product is higher, can be suitable for the needs of industrialization and expanding production.
Claims (1)
1. the compound shown in the formula I, its structural formula is as follows:
Ⅰ
R be H ,-SO
2-Ar;
Wherein, Ar is the aryl radical of C6-12 or the aryl radical of replacement; The substituting group of the aryl radical of described replacement is the alkyl of halogen, nitro or C1-10.
2, compound according to claim 1 is characterized in that: described Ar is phenyl or substituted-phenyl; Described alkyl is the alkyl of C1-5.
3, compound according to claim 1 and 2 is characterized in that: described halogen is Cl or Br; Described alkyl is the alkyl of C1-3.
4, compound according to claim 3 is characterized in that: described alkyl is methyl.
5, compound according to claim 2 is characterized in that: described substituted-phenyl is the phenyl of para-orientation.
6, compound according to claim 1 is characterized in that: described compound is:
N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide,
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl benzenesulfonamide,
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl brosyl amine,
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] the methyl para toluene sulfonamide or
N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide.
7, compound according to claim 1 is characterized in that: described compound is: and N-[7-(phenyl [pyrazolo [1,5a] the pyrimidyl]-3-of N-ethanoyl-N-ethylamino-3-)] methyl p-nitrophenyl sulphonamide.
8, the preparation method of the described compound of claim 1 is characterized in that: it comprises following operation steps:
(1) get N-ethyl-N-3-[7-(the 3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide, by the sodium borohydride reduction reaction, prepare N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide;
(2) get the N-ethyl of step (1) preparation-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, with Cl-SO
2-Ar namely gets formula I compound after amidate action occurs;
Wherein, Ar is the aryl radical of C6-12 or the aryl radical of replacement; The substituting group of the aryl radical of described replacement is the alkyl of halogen, nitro or C1-10.
9, the purposes of the described compound of claim 1-7 any one in the medicine of preparation Cure for insomnia.
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| US4626538A (en) * | 1983-06-23 | 1986-12-02 | American Cyanamid Company | [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines |
| CN1372561A (en) * | 1999-08-10 | 2002-10-02 | 纽罗克里恩生物科学有限公司 | Synthese of substitutd pyrazolopyrimidines |
| CN1507447A (en) * | 2001-03-14 | 2004-06-23 | Substituted pyrazolopyrimidines and thiazolopyrimidines used as analgesics |
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2012
- 2012-08-21 CN CN 201210298687 patent/CN102775412B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4626538A (en) * | 1983-06-23 | 1986-12-02 | American Cyanamid Company | [7-(3-disubstituted amino)phenyl]pyrazolo[1,5-a]pyrimidines |
| CN1372561A (en) * | 1999-08-10 | 2002-10-02 | 纽罗克里恩生物科学有限公司 | Synthese of substitutd pyrazolopyrimidines |
| CN1507447A (en) * | 2001-03-14 | 2004-06-23 | Substituted pyrazolopyrimidines and thiazolopyrimidines used as analgesics |
Non-Patent Citations (4)
| Title |
|---|
| Carlo Mustazza et al.,.Synthesis of Pyrazolo[1,5-a]-,1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines Related to Zaleplon, a new Drug for the Treatment of Insomnia.《J. Heterocyclic Chem.》.2001,第38卷第1119-1129页. |
| Ch. Bharathi et al.,.Impurity profile study of zaleplon.《Journal of Pharmaceutical and Biomedical Analysis》.2007,第44卷第101-109页. |
| Impurity profile study of zaleplon;Ch. Bharathi et al.,;《Journal of Pharmaceutical and Biomedical Analysis》;20070206;第44卷;第101-109页 * |
| Synthesis of Pyrazolo[1,5-a]-,1,2,4-Triazolo[1,5-a]- and Imidazo[1,2-a]pyrimidines Related to Zaleplon, a new Drug for the Treatment of Insomnia;Carlo Mustazza et al.,;《J. Heterocyclic Chem.》;20011031;第38卷;第1119-1129页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102775412A (en) | 2012-11-14 |
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