CN102807569B - Compound with clam and hypnosis functions, and preparation method and application thereof - Google Patents
Compound with clam and hypnosis functions, and preparation method and application thereof Download PDFInfo
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- CN102807569B CN102807569B CN201210298671.1A CN201210298671A CN102807569B CN 102807569 B CN102807569 B CN 102807569B CN 201210298671 A CN201210298671 A CN 201210298671A CN 102807569 B CN102807569 B CN 102807569B
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- YOQKUOXYFAEGFN-UHFFFAOYSA-N CCN(C(C)=O)c1cccc(C(CC=N2)C3C2=C(CC(CC(OCC)=C)=C)C=C3)c1 Chemical compound CCN(C(C)=O)c1cccc(C(CC=N2)C3C2=C(CC(CC(OCC)=C)=C)C=C3)c1 YOQKUOXYFAEGFN-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a compound expressed in a formula 1. The structural formula of the compound is shown in the description, wherein R is H, C1-10alkyl, -COOR1, -CH2-C6H4-R2, or a group shown in the description, wherein R1 is H or C1-10alkyl, R2 is H, halogen, nitro or C1-5alkyl, and R3 is C1-5alkyl, C6-12arene or substitutional C1-5alkyl. The invention also provides the application of the compound. The compound disclosed by the invention can obviously inhibit spontaneous movement times of a mouse, and the compound has a significance difference or an extreme significance difference by comparing each time point and a negative contrast group, so that the compound can be used as a medical active ingredient of a medicine preventing insomnia and further can be used for developing new medicines which are relatively good in medical effect and relatively small in untoward effect, thus having obvious social benefits and economic benefits. The method provided by the invention has the advantages that the method process line is very simple, the cost is relatively low, the yield of products is relatively high, and the requirements on industrial and large-scale production can be met.
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 structure important in pharmaceutical chemistry, enjoys the extensive concern of industry for a long time always.Owing to having pyrazoles and the important activity unit of pyrimidine two class in this molecule simultaneously, thus this compounds often has good biological activity, a large amount of compounds containing pyrazolopyrimidine structural unit is applied to field of medicaments, its derivative can act on multiple important biological targets, demonstrate pharmacological activity widely, as cyclin-depended kinase (CDKs) inhibitor, 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 cause the great interest of the world of medicine, impel the research of synthesizing pyrazole [1,5-a] pyrimidine novel method and new compound constantly to carry out, and obtaining new achievement.Such as zaleplon, i.e. N-ethyl-N-3-[7-(3-cyano pyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide are also that this class of pyrazolo [1,5-a] pyrimidine is calmed one of hypnotic drug.This medicine can be used for the fugitive treatment of 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, and cumulative effect is not clearly yet.But also there is 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 constrain the clinical application of this medicine.
Along with the development of society, the increasing of people's survival pressure, insomniac will get more and more, and the demand all over the world for sedative hypnotic also will increase year by year.Develop safer, effective, physiological can be caused to 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 more with anti-insomnia activity and have the extremely important and meaning of reality.
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 preparation method and purposes that compound is provided.
The invention provides the compound shown in formula I, its structural formula is as follows:
R is the alkyl ,-COOR of H, C1-10
1,-CH
2-C
6h
4-R
2or
Wherein, R
1for the alkyl of H or C1-5;
R
2for the alkyl of H, halogen, nitro or C1-5;
R
3for the alkyl of the C1-5 of the alkyl of C1-5, the aryl radical of C6-12 or replacement.
Further, R
3in, the substituting group of the alkyl of the C1-5 of described replacement is the aryl radical of halogen or C6-12.
Further, R
2in, described halogen is Cl or Br; R
3in, described halogen is F or Cl.
Wherein, R is the alkyl ,-COOR of C1-5
1,-CH
2-C
6h
4-R
2or-CO-R
3;
Further, R
1for the alkyl of C1-3;
R
2for the alkyl of H, Cl, nitro or C1-3;
R
3the alkyl of the C1-3 that the alkyl of the C1-3 replaced for the alkyl of C1-3, phenyl, phenyl or trifluoro replace.
Wherein, described R
3for alkyl, the phenyl ,-CH of C1-3
2-C
6h
5or-CH
2-CF
3.
Further preferably, described compound is:
N-ethyl-N-3-[7-(3-N-n-propylamine ylmethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-isopropylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-2 '-oxyethyl group-2 '-oxoethylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-is to nitrobenzylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-ethylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-is to methylbenzylamide methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-n-butyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-benzylamino-methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-Methylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-o-chlorobenzyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
N-ethyl-N-3-[7-(3-N-acetylamino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-phenylacetylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-benzamidomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide or
N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.
Further, described compound is:
N-ethyl-N-3-[7-(3-N-isopropylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-is to nitrobenzylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-is to methylbenzylamide methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-n-butyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-benzylamino-methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide,
N-ethyl-N-3-[7-(3-N-o-chlorobenzyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide or
N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.
Further preferably, described compound is: N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.
Present invention also offers the preparation method of above-claimed cpd, it comprises following operation steps:
It comprises following operation steps:
(1) N-ethyl-N-3-[7-(3-cyano pyrazole also [1 is got, 5a] pyrimidyl) phenyl] ethanamide, reacted by sodium borohydride reduction, prepare N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide;
(2) get N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide prepared by step (1), react under NaH effect with halohydrocarbon, obtain formula I; Or,
(3) N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide prepared by step (1) is got, with chloride compounds at Et
3the lower reaction of N effect, obtains formula I.
Its reaction formula is as follows:
In above-mentioned reaction formula:
1N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide
2a n-Propyl Bromide
4a:N-ethyl-N-3-[7-(3-N-n-propylamine ylmethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
2b: different N-PROPYLE BROMIDE
4b:N-ethyl-N-3-[7-(3-N-isopropylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
2c: ethyl bromoacetate
4c:N-ethyl-N-3-[7-(3-N-2 '-oxyethyl group-2 '-oxoethylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide
2d: to nitrobenzyl bromine
4d:N-ethyl-N-3-[7-(3-N-is to nitrobenzylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide
2e: monobromethane
4e:N-ethyl-N-3-[7-(3-N-ethylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
2f: to methyl benzyl bromine
4f:N-ethyl-N-3-[7-(3-N-is to methylbenzylamide methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide 2g: n-bromide butane
4g:N-ethyl-N-3-[7-(3-N-n-butyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
2h: benzyl bromine
4h:N-ethyl-N-3-[7-(3-N-benzylamino-methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
2i: methyl iodide
4i:N-ethyl-N-3-[7-(3-N-Methylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
2j: o-chloro benzyl chloride
4j:N-ethyl-N-3-[7-(3-N-o-chlorobenzyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
3a: Acetyl Chloride 98Min.
5a:N-ethyl-N-3-[7-(3-N-acetylamino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
3b: phenyllacetyl chloride
5b:N-ethyl-N-3-[7-(3-N-phenylacetylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
3c: Benzoyl chloride
5c:N-ethyl-N-3-[7-(3-N-benzamidomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
3d: trifluoroacetic anhydride
5d:N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
Further, concrete reactions steps is as follows:
(1) preparation of N-ethyl-N-3-[7-(3-N-substituted-amino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
Raw material and formula thereof: the mol ratio of N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide and acyl chlorides is 1:1.2.
Processing step:
1, in 25mL pear shape bottle, add 10mL THF, add 0.1mmolN-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue after to be dissolved to add 0.12mmol acyl chlorides under condition of ice bath, add 0.5m Et
3n, finishes rear room temperature reaction 2h, TLC and follows the tracks of after reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product, through column chromatography purification, obtains N-ethyl-N-3-described in claim 1 [7-(3-N-substituted-amino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.In aforesaid method, described replacement acyl chlorides is the one in Acetyl Chloride 98Min., phenyllacetyl chloride, Benzoyl chloride, trifluoroacetic anhydride.
Raw material and formula thereof: the mol ratio of N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide and halohydrocarbon is 1:1.2.
2, in 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue after to be dissolved to add 0.12mmol halohydrocarbon, finish rear room temperature reaction 2h, extract with EA, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product, through column chromatography purification, obtains N-ethyl-N-3-described in claim 1 [7-(3-N-substituted-amino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.In aforesaid method, halohydrocarbon be N-PROPYLE BROMIDE, different N-PROPYLE BROMIDE, ethyl bromoacetate, to nitrobenzyl bromine, monobromethane, to the one in methyl benzyl bromine, n-butyl bromide, benzyl bromine, o-chloro benzyl chloride, methyl iodide.
Present invention also offers the purposes of above-claimed cpd in the medicine preparing Cure for insomnia.
Compound provided by the invention, obviously can suppress the Assay of spontaneous activity of mouse, each time point compares with negative control group and has significantly and pole difference, the better new drug of drug effect can be developed as the active pharmaceutical ingredients of anti-insomnia medicine, simultaneously, due to the not structure such as nitrile group-containing in this compounds, can reduce such medicine in vivo further metabolism produce the possibility of toxic side effect.There is 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
The preparation of embodiment 1 N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide
The processing step of the present embodiment is as follows:
In 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, 00C is cooled with frozen water, 0.1mol sodium borohydride is added several times under stirring, finish rear room temperature reaction 5h, follow the tracks of reaction with TLC.After end, filter, extract several times with EA, repeatedly wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, is white powdery solids, productive rate 58%, m.p.145-147 DEG C;
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,found310.1662.。
The preparation of embodiment 2N-ethyl-N-3-[7-(3-N-n-propylamine ylmethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4a)
The processing step of the present embodiment is as follows:
The processing step of the present embodiment is as follows: in 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol n-Propyl Bromide, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-n-propylamine ylmethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 96%, m.p.111-116 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.00 (t, J=7.2Hz, 3H), 1.08 (t, J=7.0Hz, 3H), 1.73 (m, 2H), 1.79 (s, 3H), 2.23 (m, 1H), 2.55 (m, 1H), 3.20 (m, 2H), 3.47 (m, 1H), 3.64 (m, 1H), 3.69 (m, 2H), 5.48 (t, J=4.0Hz, 1H), 6.75 (s, 1H), 6.98-7.52 (m, 4H, PhH) .HRMS (ESI) m/z calcd for C
20h
25n
5o (M+Na
+) 366.2303, found366.2288.
The preparation of embodiment 3:N-ethyl-N-3-[7-(3-N-isopropylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide (being called for short 4b)
The processing step of the present embodiment is as follows: in 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add the different N-PROPYLE BROMIDE of 0.12mmol, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-isopropylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide, is white powdery solids, productive rate 92%, m.p.179-180 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.08 (t, J=7.2Hz, 3H), 1.26 (d, J=6.8Hz, 3H), 1.30 (d, J=6.4Hz, 3H), 1.79 (s, 3H), 2.23 (m, 1H), 2.49 (m, 1H), 3.00 (td, J=11.6Hz, 2.8Hz, 1H), 3.25 (dt, J=12Hz, 4Hz, 1H), 3.71 (m, 2H), 4.58 (m, 1H), 5.49 (t, J=4.0Hz, 1H), 6.74 (s, 1H), 6.99-7.52 (m, 4H, PhH) .HRMS (ESI) m/z calcd forC
20h
25n
5o (M+H
+) 352.2139, found352.2132.
The preparation of embodiment 4:N-ethyl-N-3-[7-(3-N-2 '-oxyethyl group-2 '-oxoethylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4c)
The processing step of the present embodiment is as follows:
The processing step of the present embodiment is as follows: in 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol ethyl bromoacetate, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-2 '-oxyethyl group-2 '-oxoethylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids.Productive rate 89%, m.p.120-122 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.00 (t, J=7.2Hz, 3H), 1.22 (t, J=7.2Hz, 3H), 1.72 (s, 3H), 2.14 (m, 1H), 2.58 (m, 1H), 3.08 (td, J=12.0Hz, 4.0Hz, 2H), 3.35 (td, J=12.0Hz, 2.8Hz, 2H), 3.66 (m, 2H), 3.98 (d, J=18.8Hz, 1H), 4.18 (m, 2H), 4.59 (d, J=18.8Hz, 1H), 5.49 (t, J=3.2Hz, 1H), 6.84 (s, 1H), 7.04-7.46 (m, 4H, PhH) .HRMS (ESI) m/z calcd for C
21h
25n
5o
3(M+H
+) 396.2035, found396.2030.
The preparation of embodiment 5:N-ethyl-N-3-[7-(3-N-is to nitrobenzylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4d)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol to nitrobenzyl bromine, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-is to nitrobenzylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 91%, m.p.125-127 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.07 (t, J=6.8Hz, 3H), 1.78 (s, 3H), 2.22 (m, 1H), 2.59 (m, 1H), 3.17 (m, 2H), 3.70 (q, J=7.2Hz, 2H), 4.92 (q, J=16.0Hz, 2H), 5.53 (t, J=4.4Hz, 1H), 6.80 (s, 1H), 6.93-8.24 (m, 8H, PhH) .HRMS (ESI) m/z calcd for C
24h
24n
6o
3(M+H
+) 352.1776, found352.1768.
The preparation of embodiment 6:N-ethyl-N-3-[7-(3-N-ethylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4e)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol monobromethane, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-ethylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 89%, m.p.73-74 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.08 (t, J=7.2Hz, 3H), 1.29 (t, J=7.2Hz, 3H), 1.79 (s, 3H), 2.26 (m, 1H), 2.57 (m, 1H), 3.20 (m, 2H), 3.57 (m, 1H), 3.74 (m, 2H), 5.49 (t, J=4.0Hz, 1H), 6.75 (s, 1H), 6.99-7.53 (m, 4H, PhH) .HRMS (ESI) m/z calcd for C
19h
23n
5o (M+H
+) 338.1981, found338.1985.
The preparation of embodiment 7:N-ethyl-N-3-[7-(3-N-is to methylbenzylamide methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4f)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol to methylbenzyl bromine, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-is to methylbenzylamide methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 86%, m.p.75-77 DEG C;
1hNMR (400MHz, CDCl
3) δ (ppm): 1.04 (t, J=7.2Hz, 3H), 1.72 (s, 3H), 2.14 (m, 1H), 2.34 (s, 3H), 2.50 (m, 1H), 3.07 (m, 2H), 3.66 (m, 2H), 4.65 (d, J=16.0Hz, 1H), 4.88 (d, J=16.0Hz, 1H), 5.47 (t, J=4.4Hz, 1H), 6.68 (s, 1H), 6.93-7.58 (m, 8H, PhH) .HRMS (ESI) m/zcalcd for C
25h
27n
5o (M+H
+) 414.2289, found414.2288.
The preparation of embodiment 8:N-ethyl-N-3-[7-(3-N-n-butyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4g)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol n-bromide butane, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-n-butyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 94%, m.p.87-88 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 0.98 (t, J=7.2Hz, 3H), 1.08 (t, J=6.8Hz, 3H), 1.40 (m, 2H), 1.68 (m, 2H), 1.79 (s, 3H), 2.22 (m, 1H), 2.55 (m, 1H), 3.19 (dd, J=4.0Hz, 8.0Hz, 2H), 3.49 (m, 3H), 3.70 (m, 3H), 5.48 (t, J=4.0Hz, 1H), 6.74 (s, 1H), 6.97-7.53 (m, 4H, PhH) .HRMS (ESI) m/z calcd forC
21h
27n
5o (M+H
+) 366.2303, found366.2288.
The preparation of embodiment 9:N-ethyl-N-3-[7-(3-N-benzylamino-methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4h)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol benzyl bromine, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-benzylamino-methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 90%, m.p.97-99 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.04 (t, J=7.2Hz, 3H), 1.72 (s, 3H), 2.16 (m, 1H), 2.51 (m, 1H), 3.10 (m, 2H), 3.66 (m, 2H), 4.69 (d, J=16.0Hz, 1H), 4.93 (d, J=16.0Hz, 1H), 5.48 (t, J=4.0Hz, 1H), 6.68 (s, 1H), 6.93-7.58 (m, 9H, PhH) .HRMS (ESI) m/z calcd for C
24h
25n
5o (M+H
+) 400.2133, found 400.2132.
The preparation of embodiment 10:N-ethyl-N-3-[7-(3-N-Methylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4i)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol methyl iodide, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-Methylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 98%, m.p.80-82 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.09 (t, J=7.2Hz, 3H), 1.79 (s, 3H), 2.24 (m, 1H), 2.59 (m, 1H), 3.18 (m, 2H), 3.30 (s, 3H), 3.72 (m, 2H), 5.46 (t, J=4.4Hz, 1H), 6.80 (s, 1H), 6.97-7.53 (m, 4H, PhH) .HRMS (ESI) m/z calcd for C
18h
21n
5o (M+H
+) 324.1825, found324.1819.
The preparation of embodiment 11:N-ethyl-N-3-[7-(3-N-o-chlorobenzyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 4j)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, under condition of ice bath, add 0.3mmol NaH, stir 5 minutes, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continues after to be dissolved to add 0.12mmol o-chloro benzyl chloride, finishes rear room temperature reaction 2h, after TLC tracking reaction terminates, with EA extraction, wash with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-[7-(3-N-o-chlorobenzyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide, is white powdery solids, productive rate 93%, m.p.123-124 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.07 (t, J=7.2Hz, 3H), 1.72 (s, 3H), 2.19 (m, 1H), 2.54 (m, 1H), 3.14 (m, 2H), 3.70 (q, J=7.2Hz, 2H), 4.96 (q, J=16.0Hz, 2H), 5.52 (t, J=4.0Hz, 1H), 6.76 (s, 1H), 6.99-7.59 (m, 8H, PhH) .HRMS (ESI) m/z calcd for C
24h
24n
5oCl (M+H
+) 434.1757, found434.1742.
The preparation of embodiment 12:N-ethyl-N-3-[7-(3-N-acetylamino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 5a)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue to add 0.12mmol Acetyl Chloride 98Min. under rear condition of ice bath to be dissolved, add 0.5ml Et
3n, finishes rear room temperature reaction 2h, with EA extraction, washes with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, obtaining N-ethyl-N-3-[7-(3-N-acetylamino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide described in claim 1, is white powdery solids, productive rate 92%, m.p.152-154 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.09 (t, J=7.2Hz, 3H), 1.79 (s, 3H), 2.30 (m, 1H), 2.41 (s, 3H), 2.62 (m, 1H), 3.71 (q, J=7.2Hz, 2H), 3.92 (s, 2H), 5.59 (t, J=6.0Hz, 1H), 6.81 (s, 1H), 6.84-7.78 (m, 4H, PhH) .HRMS (ESI) m/z calcd for C
19h
21n
5o
2(M+H
+) 352.1776, found352.1768.
The preparation of embodiment 13:N-ethyl-N-3-[7-(3-N-phenylacetylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide (being called for short 5b)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue to add 0.12mmol phenyllacetyl chloride under rear condition of ice bath to be dissolved, add 0.5ml Et
3n, finishes rear room temperature reaction 2h, with EA extraction, washes with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, and obtaining N-ethyl-N-3-described in claim 1 [7-(3-N-phenylacetylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide is white powdery solids.Productive rate 85%, m.p.179-180 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.06 (t, J=6.8Hz, 3H), 1.75 (s, 3H), 2.24 (m, 1H), 2.59 (m, 1H), 3.68 (q, J=7.2Hz, 2H), 3.75 (m, 1H), 4.05 (m, 2H), 5.43 (t, J=6.4Hz, 1H), 6.78 (m, 1H), 7.10-7.77 (m, 9H, PhH) .HRMS calcd for C
25h
25n
5o
2(M+H
+) 428.2084, found428.2081.
The preparation of embodiment 14:N-ethyl-N-3-[7-(3-N-benzamidomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide (being called for short 5c)
The processing step of the present embodiment is as follows:
In 25mL pear shape bottle, add 10mL THF, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue to add 0.12mmol Benzoyl chloride under rear condition of ice bath to be dissolved, add 0.5ml Et
3n, finishes rear room temperature reaction 2h, with EA extraction, washes with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, obtaining N-ethyl-N-3-[7-(3-N-benzamidomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide described in claim 1, is white powdery solids, productive rate 92%, m.p.179-180 DEG C;
1h NMR (400MHz, CDCl
3) δ (ppm): 1.09 (t, J=4.8Hz, 3H), 1.81 (s, 3H), 2.24 (m, 1H), 2.61 (m, 1H), 3.72 (q, J=7.2Hz, 2H)), 3.96 (m, 2H), 5.62 (t, J=6.0Hz, 1H), 6.90 (s, 1H), 7.04-8.05 (m, 9H, PhH) .HRMScalcd for C
24h
23n
5o
2(M+H
+) 414.1928, found414.1925.
The preparation of embodiment 15:N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide (being called for short 5d)
The processing step of the present embodiment is as follows: in 25mL pear shape bottle, add 10mL THF, add 0.1mmolN-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue to add 0.12mmol trifluoroacetic anhydride under rear condition of ice bath to be dissolved, add 0.5ml Et
3n, finishes rear room temperature reaction 2h, with EA extraction, washes with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product is through column chromatography purification, obtaining N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide described in claim 1, is red powder solid, productive rate 95%, m.p.67-69 DEG C;
1hNMR (400MHz, CDCl
3) δ (ppm): 1.18 (t, J=7.2Hz, 3H), 1.83 (s, 3H), 2.13 (m, 1H), 2.49 (m, 1H), 3.72 (q, J=7.2Hz, 2H), 3.94 (m, 1H), 4.32 (m, 1H), 5.48 (t, J=6.0Hz, 1H), 6.61 (s, 1H), 7.09-7.98 (m, 4H, PhH) .HRMS calcd for C
19h
18n
5o
2f
3(M+H
+) 406.1489found 406.1485.
Beneficial effect of the present invention is illustrated below by way of test example.
Test example 1 biological activity test
1, experimental drug
By reagent:
Pyrazolo [1,5a] pyrimidine derivatives prepared by embodiment 2 ~ embodiment 15: 4a ~ 4j, 5a ~ 4d.
4a:N-ethyl-N-3-[7-(3-N-n-propylamine ylmethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
4b:N-ethyl-N-3-[7-(3-N-isopropylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
4c:N-ethyl-N-3-[7-(3-N-2 '-oxyethyl group-2 '-oxoethylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide
4d:N-ethyl-N-3-[7-(3-N-is to nitrobenzylamino methylpyrazole also [1,5a] pyrimidyl) phenyl] ethanamide
4e:N-ethyl-N-3-[7-(3-N-ethylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
4f:N-ethyl-N-3-[7-(3-N-is to methylbenzylamide methylpyrazole also [1,5a] pyrimidyl) phenyl] second
Acid amides 4g:N-ethyl-N-3-[7-(3-N-n-butyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
4h:N-ethyl-N-3-[7-(3-N-benzylamino-methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
4i:N-ethyl-N-3-[7-(3-N-Methylaminomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
4j:N-ethyl-N-3-[7-(3-N-o-chlorobenzyl amino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
5a:N-ethyl-N-3-[7-(3-N-acetylamino methyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
5b:N-ethyl-N-3-[7-(3-N-phenylacetylamino methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
5c:N-ethyl-N-3-[7-(3-N-benzamidomethyl pyrazolo [1,5a] pyrimidyl) phenyl] ethanamide
5d:N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide
2, laboratory animal
Kun Ming mice, male and female half and half, body weight 18-22g, is provided by West China animal center.
3 instruments:
The free activity recorder of YLS-1A Multifunctional mouse;
Sartorius electronic balance (0.0001g): Beijing Ao Duolisi balance company limited.
4, compounding medicine 4, compounding medicine
(1) diazepam inj: become 0.05% concentration to be for experiment with normal saline.
(2) by pyrazolo [1,5a] pyridine derivatives 4a ~ 4j prepared by embodiment 1 ~ embodiment 12, it is 0.02mmol/mL suspension that 5a ~ 5d 0.5%CMC is mixed with concentration.
5, experimental technique
Get healthy Kunming mouse 112, be divided into 17 groups at random by sex, body weight, often organize 6, male and female half and half.Before administration, each group of mouse is positioned in the box of spontaneous activity recording unit respectively, makes its 5min that conforms, then start writing time, observe and record the numeral that 5min charactron shows, as the control value of spontaneous activity in mice number of times before administration.After whole mouse assay completes, grouping administration.The every mouse gavage Xylo-Mucine 0.4ml/20g of negative group, stable group (positive controls) injects 0.4ml/20g with 0.05% diazepam solution to mouse peritoneal, the pyrazolo [1 of new synthesis, 5a] pyrimidine compound is with 0.4ml/20g gastric infusion, 30min, 60min, 90min and 120min after administration, be measured in the same method the Assay of spontaneous activity of each group of mouse 5min, the data obtained spss.17.0 software carries out statistical treatment, and the significant difference between comparative group.
4, experimental result is in table 1
Table 1
Each time point compares with negative group
*p<0.05
*p<0.01
* *p<0.001
As can be seen from the data of table 1, pyrazolo [1 prepared by embodiment 1 ~ embodiment 14,5a] 4b, 4d, 4f, 4g, 4h, 4j, 5d all significantly can reduce mouse in pyridine derivatives each time point of autonomic activities number of times, particularly 5d compares with negative control group and has pole marked difference.
Experimental result shows, what pyrazolo provided by the present invention [1,5a] pyrimidine derivatives may be made new advances by further exploitation has the less less anti-insomnia medicine of the better untoward reaction of pharmacologically active.
Compound provided by the invention, obviously can suppress the Assay of spontaneous activity of mouse, each time point compares with negative control group and has significantly and pole difference, the less less new drug of the better untoward reaction of drug effect can be developed as the active pharmaceutical ingredients of anti-insomnia medicine, there is 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.
Claims (3)
1. compound as follows: N-ethyl-N-3-[7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.
2. the preparation method of compound described in claim 1, is characterized in that: it comprises following operation steps:
In 25mL pear shape bottle, add 10mL THF, add 0.1mmol N-ethyl-N-3-[7-amino methyl pyrazolo [1,5a] pyrimidyl phenyl] ethanamide, continue to add 0.12mmol trifluoroacetic anhydride under rear condition of ice bath to be dissolved, add 0.5ml Et
3n, finishes rear room temperature reaction 2h, with EA extraction, washes with water, organic over anhydrous Na
2sO
4drying, is spin-dried for, and thick product, through column chromatography purification, obtains N-ethyl-N-3-described in claim 1 [7-(3-N-trifluoroacetamido methylpyrazole is [1,5a] pyrimidyl also) phenyl] ethanamide.
3. the purposes of compound according to claim 1 in the medicine preparing 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 |
| CN1829719A (en) * | 2003-07-24 | 2006-09-06 | 菲尔若国际公司 | N-[3-(3-substituted-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-sulfonamides, and compositions, and methods related thereto |
| CN101641359A (en) * | 2006-08-04 | 2010-02-03 | 菲尔若国际公司 | Pyrazolo [1,5-a] miazines, method, purposes and composition |
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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 |
| CN1829719A (en) * | 2003-07-24 | 2006-09-06 | 菲尔若国际公司 | N-[3-(3-substituted-pyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-sulfonamides, and compositions, and methods related thereto |
| CN101641359A (en) * | 2006-08-04 | 2010-02-03 | 菲尔若国际公司 | Pyrazolo [1,5-a] miazines, method, purposes and composition |
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