CN108148004A - The compound of a kind of hydrazine containing propionyl and pyrimidine structure, preparation method and its usage - Google Patents
The compound of a kind of hydrazine containing propionyl and pyrimidine structure, preparation method and its usage Download PDFInfo
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- CN108148004A CN108148004A CN201711496310.7A CN201711496310A CN108148004A CN 108148004 A CN108148004 A CN 108148004A CN 201711496310 A CN201711496310 A CN 201711496310A CN 108148004 A CN108148004 A CN 108148004A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 49
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 title description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 title description 4
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 7
- 201000000980 schizophrenia Diseases 0.000 claims description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims description 4
- 230000036571 hydration Effects 0.000 claims description 4
- 238000006703 hydration reaction Methods 0.000 claims description 4
- -1 pyrimidine compound Chemical class 0.000 claims description 4
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 150000008282 halocarbons Chemical class 0.000 claims description 2
- 238000006698 hydrazinolysis reaction Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 23
- 108020002739 Catechol O-methyltransferase Proteins 0.000 description 19
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- 230000000694 effects Effects 0.000 description 14
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- 229960003638 dopamine Drugs 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 10
- 208000024891 symptom Diseases 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 210000002442 prefrontal cortex Anatomy 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
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- 102000004190 Enzymes Human genes 0.000 description 5
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- 201000010099 disease Diseases 0.000 description 5
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- 238000004458 analytical method Methods 0.000 description 4
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- 238000001514 detection method Methods 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 125000005909 ethyl alcohol group Chemical group 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 3
- 102000006441 Dopamine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010044266 Dopamine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- 102000008092 Norepinephrine Plasma Membrane Transport Proteins Human genes 0.000 description 3
- 108010049586 Norepinephrine Plasma Membrane Transport Proteins Proteins 0.000 description 3
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 3
- 229960001570 ademetionine Drugs 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 description 3
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- CFFZDZCDUFSOFZ-UHFFFAOYSA-N 3,4-Dihydroxy-phenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C(O)=C1 CFFZDZCDUFSOFZ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
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- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
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- RODXRVNMMDRFIK-UHFFFAOYSA-N scopoletin Chemical compound C1=CC(=O)OC2=C1C=C(OC)C(O)=C2 RODXRVNMMDRFIK-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
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- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 1
- DIVQKHQLANKJQO-UHFFFAOYSA-N 3-methoxytyramine Chemical compound COC1=CC(CCN)=CC=C1O DIVQKHQLANKJQO-UHFFFAOYSA-N 0.000 description 1
- 201000010000 Agranulocytosis Diseases 0.000 description 1
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 1
- 101100459319 Arabidopsis thaliana VIII-2 gene Proteins 0.000 description 1
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 description 1
- XEHFSYYAGCUKEN-UHFFFAOYSA-N Dihydroscopoletin Natural products C1CC(=O)OC2=C1C=C(OC)C(O)=C2 XEHFSYYAGCUKEN-UHFFFAOYSA-N 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
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- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 1
- 229960004170 clozapine Drugs 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- MHUWZNTUIIFHAS-CLFAGFIQSA-N dioleoyl phosphatidic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(O)=O)OC(=O)CCCCCCC\C=C/CCCCCCCC MHUWZNTUIIFHAS-CLFAGFIQSA-N 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000009585 enzyme analysis Methods 0.000 description 1
- ILEDWLMCKZNDJK-UHFFFAOYSA-N esculetin Chemical class C1=CC(=O)OC2=C1C=C(O)C(O)=C2 ILEDWLMCKZNDJK-UHFFFAOYSA-N 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000012921 fluorescence analysis Methods 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002974 pharmacogenomic effect Effects 0.000 description 1
- 235000017807 phytochemicals Nutrition 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940097325 prolactin Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- FWYIBGHGBOVPNL-UHFFFAOYSA-N scopoletin Natural products COC=1C=C2C=CC(OC2=C(C1)O)=O FWYIBGHGBOVPNL-UHFFFAOYSA-N 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000000954 titration curve Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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- 230000004584 weight gain Effects 0.000 description 1
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- 229940039925 zyprexa Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology fields.Specifically, the present invention relates to a kind of compound for containing the third hydrazide structure, Its Preparation Method And Uses.
Description
Technical field
The invention belongs to pharmaceutical technology fields.In particular it relates to a kind of change of hydrazine containing propionyl and pyrimidine structure
Close object, preparation method and its application in terms for the treatment of mental disease drug is prepared.
Background technology
Schizoid symptom generally falls into three classes：The positive, negative and cognition.Positive symptom include illusion, illusion and
Chaotic behavior, and negative symptoms have the feature for lacking happy sense and/or the interest to life.Cognitive defect is included to idea
Tissue and to the difficulty in terms of the priorization of task.Patient with bipolar disorders is usually shown from serious depressed to tight
The periodic emotional change feature of mental disease (with or without) of the mania of weight.Schizophrenia and bipolar disorders belong to
Cause the phrenoblabia of the most serious type of the cognitive defect of overlapping and the disease is intended to be chronic/progressive.
Compared with positive symptom, schizoid negative and cognition symptom is considered to long-term disability, treats consequence and function is extensive
There is the influence of bigger again.To treatment be not full of due to lack efficiency or can not endure and unacceptable side effect caused by
's.It has been found that the adverse events in terms of the side effect and important metabolism, extrapyramidal system, prolactin and heart are related
(referring to Lieberman et al., N.Engl.J.Med.2005,353:1209-1223).
It is considered being related to leading to negative and cognition symptom schizoid pathogenesis, but more in spite of a plurality of access
More concerns has concentrated on the reduction that dopamine neuronal transmits in prefrontal cortex.Dopamine neuronal transmits in prefrontal cortex
The regional cerebral blood flow amount in schizophreniac that the evidence of reduction obtained reduces or the activity of tergolateral prefrontal cortex
The support of decline.Before having been found that the relevant prefrontal lobe defect of schizophrenia (unrelated with treatment or psychotic state) and evaluating
Frontal lobe participates in execution functional task (such as the n-back or Wisconsin Card of (prefrontal engagement)
Sorting Test) in bad luck performance it is related.In addition to the defects of control function is performed, dopamine god in prefrontal cortex
Reduction through transmission is related with several cerebration, including note that the activity of enjoyment, instinct feedback (natural
) and biological action (such as cellular signal transduction) rewards.Therefore, the DOPA inside Selective long-range DEPT prefrontal cortex
The compound of amine neurotransmission may have the acology potential for the treatment of cognition and negative symptoms.
Dopamine level in brain is by biosynthesis and release and its diffusion rate, and reuptake and degradation are determined
's.Catechol O-methyltransferase (COMT) is to involve the important enzyme that dopamine decomposes in cortex.COMT is by Dopamine Turnover
Homovanillic acid (HVA) is converted into 3-methoxytyramine and by Dopamine metabolites dihydroxyphenyl acetic acid (DOPAC).In fact,
COMT acts on the catecholamines of various biological sources and catechol estrogen class, diet phytochemicals and ascorbic acid.
In infracortical structure (such as corpus straitum), dopaminergic signal mainly (is passed through by dopamine from the elimination in synaptic cleft
The quick intake of Dopamine Transporter (DAT) and/or norepinephrine transporter (NET)) adjusting.In prefrontal cortex
Dopamine transmit adjusting be dramatically different.DAT is expressed in prefrontal cortex with relatively low density and (passes through in this dopamine
The intake of NET, diffusion or the metabolism of COMT and monoamine oxidase and eliminate) in cynapse in.Therefore, COMT inhibitor will
Selectively increase cortex dopaminergic signal can be expected and improve cognitive function whereby.
COMT genes are located in Chromosome 22q11 .21 regions, it has been found that the region and schizophrenia, bipolar disorders,
ADHD is related with substance depilatory.There are the COMT of two kinds of predominant isoforms, the COMT (MB-COMT) that film combines is involved in human brain
Principal mode (Lachman the et al., Pharmacogenetics, 1996,6 (3) of the degradation of cynapse frontal lobe dopamine:243-
250).Another form is soluble COMT (S-COMT), is from different from the promoter transcription of MB-COMT and except this
Except it is identical with subtracting the people MB-COMT of 50 amino acid in the N- ends of albumen.In people, COMT activity by
The adjusting of single nucleotide polymorphism at Val158Met (MB-COMT).Since the thermal stability of enzyme has differences, homozygous Met
Carrier has relatively low COMT activity, and heterozygote shows that the Val carriers of medium activity and homozygosis have stronger enzymatic activity.To the greatest extent
The difference that pipe is observed in the activity based on genotype, pass only appropriate between Val158Met genotype and cognitive performance
System is shown by the meta-analysis (meta-analysis) in normal individual, and is not seen in schizophrenia
Observe effect.Based on the U-shaped relationship for being considered as the existing reversing between dopamine receptor activation and the function of prefrontal cortex
(inverted-U relationship), these have found that it is likely that consistent with following facts：Morbid state and a variety of environment and
The factor of heredity together contributes to the efficiency of forehead and dopamine level.
Although Clozapine, Zyprexa, Risperidal and other antipsychotic drugs have been used to treatment schizophrenia and two-phase
The positive and negative (remaining dispute) symptom of obstacle, these drugs still without departing from side effect, such as group agranulocytosis,
Calmness, weight gain, hyperlipidemia and hyperglycemia, all these side effects limit their application.Therefore, it still deposits
In the demand to such drug, negative symptoms and cognitive defect are effectively treated, without serious side effect, and in essence
In the treatment of refreshing Split disease, bipolar disorders, depression, substance depilatory and ADD/ADHD etc. effectively.When it is as another essence
The part that refreshing disease learns syndrome exists or when it occurs with nerve problems, and such drug can be used for
Reduce the symptom.
The invention discloses a kind of hydrazine containing propionyl and the COMT inhibitor of pyrimidine structure, these compounds can be used for preparing essence
The medicine of refreshing Split disease etc..
Invention content
It is an object of the present invention to provide a kind of COMT inhibitor with Formulas I；Another object of the present invention is to carry
Method for preparing the compound with Formulas I；It is also another object of the present invention to provide the compound containing Formulas I in treatment spirit
The application of Split disease etc..The content of present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the invention with formula (I) is with following structural formula：
Formula (I) compound of the present invention can be synthesized by following route：
Cyclopentadiene II reacts in the presence of KOH with halogenated hydrocarbon compound III, obtains compound IV；Compound IV is in KOH
In the presence of reacted with compound V, obtain compound VI；Compound VI obtains compound VII with hydration hydrazine reaction, hydrazinolysis；Chemical combination
Object VII is reacted with pyrimidine compound VIII, obtains compound I；Wherein described X is selected from Cl, Br and I.
Compound of formula I of the present invention has COMT inhibiting effect, can be used as an active ingredient in the preparation of schizophrenia
Medicine.The activity of compound of formula I of the present invention is by the way that COMT experiments is inhibited to be verified in vitro.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.General technical staff's training centre according to the present invention in the art is made various
Variation should all be within the protection domain required by the application claim.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step 1. compound VI-1
Compound II (1.32g, 20mmol) is dissolved in 20mL DMSO, is stirred at room temperature, addition KOH solids (2.24g,
40mmol), continue stirring 1 hour at room temperature.MeI (III-1,2.84g, 20mmol) is added, continues to be stirred at room temperature
Night.Tert-butyl acrylate V-1 (2.56g, 20mmol) is then added, continues stirring 12 hours, TLC detections find to have reacted
Into.
Reaction mixture is carefully poured into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, uses
5% salt water washings of 100mL, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated on a rotary evaporator, residue
It is purified using silica gel column chromatography, obtains compound VI-I, 2.96g (merging yield 71%).ESI-MS, m/z=209 ([M+H
]+)。
The synthesis of step 2. compound VII-1
Compound VI-1 (2.08g, 10mmol) is dissolved in 20mL absolute ethyl alcohols, is stirred at room temperature, adds in 80% hydration
Hydrazine (5mL) then stirs 3 hours at room temperature, and TLC detections find that reaction is completed.
Reaction mixture is directly evaporated on a rotary evaporator, and residue is purified using short silica gel column chromatography, obtains chemical combination
Object VII-I, 1.40g (yield 84%).ESI-MS, m/z=167 ([M+H]+)。
The synthesis of step 3. compound I-1
Compound VII-1 (0.83g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and ice-water bath cooling is lower to stir, and adds in three second
Pyrimidine compound VIII-1 (0.93g, 5mmol) is then slowly added portionwise in amine (2.02g, 20mmol) again, reacts mixed after adding
Closing object, stirring was continued at room temperature overnight, and the reaction of TLC displays at this time is completed.
Reaction mixture is directly evaporated on a rotary evaporator, and residue is purified using short silica gel column chromatography, obtains chemical combination
Object I-I, 1.06g (yield 78%).ESI-MS, m/z=273 ([M+H]+)。
The synthesis of 2 compound I-2 of embodiment
The synthesis of step 1. compound VI-2
Compound II (1.32g, 20mmol) is dissolved in 20mL DMSO, is stirred at room temperature, addition KOH solids (2.24g,
40mmol), continue stirring 1 hour at room temperature.Again plus compound III-1 (2.84g, 20mmol), continue to be stirred at room temperature
Night.20mmol compound V-2 are then added, continue stirring 12 hours, TLC detections find that reaction is completed.Reaction mixture is small
The heart is poured into 200mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges extraction phase, with 5% salt water washings of 100mL, nothing
Aqueous sodium persulfate is dried.It filtering and removes drier, filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography,
Obtain compound VI-2.ESI-MS, m/z=223 ([M+H]+)。
The synthesis of step 2. compound VII-2
Compound VI-2 (2.22g, 10mmol) is dissolved in 20mL absolute ethyl alcohols, is stirred at room temperature, adds in 80% hydration
Hydrazine (5mL) then stirs 3 hours at room temperature, and TLC detections find that reaction is completed.Reaction mixture is directly on a rotary evaporator
It is evaporated, residue is purified using short silica gel column chromatography, obtains compound VII-2.ESI-MS, m/z=181 ([M+H]+)。
The synthesis of step 3. compound I-2
Compound VII-2 (0.90g, 5mmol) is dissolved in 10mL absolute ethyl alcohols, and ice-water bath cooling is lower to stir, and adds in three second
Pyrimidine compound VIII-2 (1.19g, 5mmol) is then slowly added portionwise in amine (2.02g, 20mmol) again, reacts mixed after adding
Closing object, stirring was continued at room temperature overnight, and the reaction of TLC displays at this time is completed.Reaction mixture directly steams on a rotary evaporator
Dry, residue is purified using short silica gel column chromatography, obtains compound I-2, ESI-MS, m/z=339 ([M+H]+) white solid.
3 Compound ira vitro of embodiment inhibits COMT analyses
The COMT inhibitory activity of the compound of the present invention is determined using experimental method described below.The fluorescence analysis
It is to be methylated by COMT with the product (7- hydroxyl -6- methoxyl groups for generating high fluorescent based on substrate (6,7- dihydroxycoumarins)
Cumarin).The reaction needs the presence of magnesium ion and methyl donor [being in this case s-adenosylmethionine (SAM)].It adopts
It is prepared 10: 3 times of dilution series with storing solution of the 10mM compounds in DMSO and is positioned over the 1 μ L dilutions being suitble to minute
Analyse hole (the 96 hole round bottom polystyrene board of black from Costar；Catalog number (Cat.No.) 3792) in.Recombinase is diluted in analysis buffering
Liquid (100mM Na2HPO4PH 7.4,1mM DTT, 0.005%Tween-20) in and 35 μ L are added in comprising 1 μ L compounds
It analyzes in hole.The preculture 2 hours of COMT enzymes and compound is carried out in room temperature.40 μM of SAM (USB catalog number (Cat.No.)s are included with 5 μ L
US10601), 4 μM of Esculetins (substrate) and 40mM MgCl2Mixture start enzyme analysis.Use Tecan
By fluorescence, (excitation 340nm emits 460nm to 2 microplate reader of Safire (plate reader), non-delay, when 100 μ s are integrated
Between, 5 flickers, top set is read) formation of monitoring product (scopoletin) at any time.At any time to this point
Analysis monitoring, until generating 4:1 signal:Background ratio.Titration curve and IC are calculated using standard method50Value.In short, data are pressed
According to " (average of instrument connection)-(average of no enzyme control)/(average of total enzyme control)-(average of no enzyme control) "
To calculate, be then expressed as percentage and the suppression percentage to obtain COMT activity subtracted from 100.
Test result see the table below.
| Compound | IC50(nM) |
| Compound I-1 | 271.6 |
| Compound I-2 | 35.2 |
Can be seen that the compound of the present invention from upper table result has very strong inhibiting effect to COMT, can be used as system
Medicines are waited for schizoid.
Claims (3)
1. the compound with logical formula (I) structure,
2. synthesize the method for claim 1 compound：
Cyclopentadiene II reacts in the presence of KOH with halogenated hydrocarbon compound III, obtains compound IV；Compound IV exists in KOH
It is lower to be reacted with compound V, obtain compound VI；Compound VI obtains compound VII with hydration hydrazine reaction, hydrazinolysis；Compound VII
It is reacted with pyrimidine compound VIII, obtains compound I；Wherein described X is selected from Cl, Br and I.
3. application of claim 1 compound in terms for the treatment of schizophrenia drug is prepared.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050080087A1 (en) * | 2003-10-10 | 2005-04-14 | Annapurna Pendri | Pyrazole derivatives as cannabinoid receptor modulators |
| US20050137162A1 (en) * | 2003-12-19 | 2005-06-23 | Francois Diederich | New COMT inhibitors for the treatment of depression and impaired cognition |
| WO2005103055A1 (en) * | 2004-04-21 | 2005-11-03 | Schering Corporation | PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO-[1,5-c]-PYRIMIDINE ADENOSINE A2A RECEPTOR ANTAGONISTS |
| CN101248064A (en) * | 2005-07-26 | 2008-08-20 | 坡特拉有限公司 | Nitrocatechol derivatives as COMT inhibitors |
-
2017
- 2017-12-31 CN CN201711496310.7A patent/CN108148004A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050080087A1 (en) * | 2003-10-10 | 2005-04-14 | Annapurna Pendri | Pyrazole derivatives as cannabinoid receptor modulators |
| US20050137162A1 (en) * | 2003-12-19 | 2005-06-23 | Francois Diederich | New COMT inhibitors for the treatment of depression and impaired cognition |
| WO2005103055A1 (en) * | 2004-04-21 | 2005-11-03 | Schering Corporation | PYRAZOLO-[4,3-e]-1,2,4-TRIAZOLO-[1,5-c]-PYRIMIDINE ADENOSINE A2A RECEPTOR ANTAGONISTS |
| CN101248064A (en) * | 2005-07-26 | 2008-08-20 | 坡特拉有限公司 | Nitrocatechol derivatives as COMT inhibitors |
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