CN109666055A - Adjust the compound and application thereof of nervous centralis treatment depression - Google Patents
Adjust the compound and application thereof of nervous centralis treatment depression Download PDFInfo
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- CN109666055A CN109666055A CN201710956304.9A CN201710956304A CN109666055A CN 109666055 A CN109666055 A CN 109666055A CN 201710956304 A CN201710956304 A CN 201710956304A CN 109666055 A CN109666055 A CN 109666055A
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- tautomer
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- QFVRLYRYKCLRMD-UHFFFAOYSA-N cyclodecane-1,6-diol Chemical compound OC1CCCCC(O)CCCC1 QFVRLYRYKCLRMD-UHFFFAOYSA-N 0.000 claims 1
- -1 following compounds Chemical class 0.000 claims 1
- 210000003169 central nervous system Anatomy 0.000 abstract description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 17
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 15
- 201000009916 Postpartum depression Diseases 0.000 description 11
- 230000000694 effects Effects 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 208000020401 Depressive disease Diseases 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 2
- 102000005915 GABA Receptors Human genes 0.000 description 2
- 108010005551 GABA Receptors Proteins 0.000 description 2
- 102000027484 GABAA receptors Human genes 0.000 description 2
- 108091008681 GABAA receptors Proteins 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000000049 anti-anxiety effect Effects 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- AURFZBICLPNKBZ-SYBPFIFISA-N brexanolone Chemical compound C([C@@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-SYBPFIFISA-N 0.000 description 2
- 230000000994 depressogenic effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- HARRKNSQXBRBGZ-GVKWWOCJSA-N zuranolone Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@H]4CC[C@@](C)(O)C[C@H]4CC3)CC[C@@]21C)CN1C=C(C#N)C=N1 HARRKNSQXBRBGZ-GVKWWOCJSA-N 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- VTBHBNXGFPTBJL-UHFFFAOYSA-N 4-tert-butyl-1-sulfanylidene-2,6,7-trioxa-1$l^{5}-phosphabicyclo[2.2.2]octane Chemical compound C1OP2(=S)OCC1(C(C)(C)C)CO2 VTBHBNXGFPTBJL-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 206010010144 Completed suicide Diseases 0.000 description 1
- 206010057315 Daydreaming Diseases 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 208000000091 Maternal Death Diseases 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 210000004227 basal ganglia Anatomy 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000002996 emotional effect Effects 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 230000002102 hyperpolarization Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 229960001785 mirtazapine Drugs 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960004644 moclobemide Drugs 0.000 description 1
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 229960002296 paroxetine Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
- C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
The present invention provides formula (I) compound, and stereoisomer, tautomer or pharmaceutically acceptable salt, as central nervous system is adjusted, treatment has depression, is with a wide range of applications.
Description
Technical field
The present invention relates to novel structure formula (I) compound or pharmaceutically acceptable salt thereof, tautomer or in vivo it is hydrolyzable
Precursor, their compositions and their application method.These novel compounds and its purposes medically.
Background technique
Post-natal depression is type most commonly seen in women phrenoblabia, is after women produces, due to sex hormone, society
Can role and psychology change brought by a series of variations such as body, mood, psychology, symptom include significant functional disorder,
Depressed and, appetite stimulator cold and detached to newborn, have difficulty in going to sleep, be absent minded, is out of strength, it is handicapped and lose from
Numerous depression related symptoms such as letter.Typical post-natal depression was occurred in 6 weeks postpartum, in sustainable entire puerperium, was had
Even continue to child before going to school.The disease incidence of post-natal depression is 15%~30%.Post-natal depression is usually sent out within 6 weeks
Disease can voluntarily be restored at 3~6 months, but serious also sustainable 1~2 year, and gestation then has 20%~30% recurrence again
Rate.
Some women post-natal depression is in a bad way, or even deteriorates into and can't take care of oneself or emotional flooding, needs to be hospitalized
Treatment realizes rehabilitation in the environment of safety and stability.In modern society, suicide is one of the first cause of maternal death after childbirth.
The features such as selective serotonin reuptake inhibits, has toxic side effect small, take simplicity can be selected.For now very
The fiest-tire medication of more developed country's treatment depressions.Representing drug has Prozac, Paxil, Sertraline, Fluvoxamine, western phthalein general
It is blue.Or the novel antidepressant of other mediator mechanism is taken in selection: Trazodone: being weak antidepressants, to major depression effect phase
Difference.Light modest depression to antianxiety, insomnia is optimal adaptation card.Duloxetine, Venlafaxine: it is suitable for various depressed shapes
State, rapid-action, without special contraindication, but liver kidney patient is used with caution.Mirtazapine: the tolerance of this medicine is good, few side effects, is a kind of new
Type antidepressant.Moclobemide: it can treat various types of depressions, also preferable to anxiety-depression admixture effect.
It is counted according to U.S.'s Disease Control and Prevention Center (CDC), the U.S. about 4,000,000 newborns in 2014,
In 10%~15% puerpera meet with post-natal depression puzzlement, some patientss, which seriously arrive, needs hospitalization.It there is no at present specially
Door is granted for the drug of post-natal depression, and the therapeutic choice of severe patients with postpartum depression is very limited, for treating the disease
The pharmaceutical requirements of disease are very urgent.
γ-aminobutyric acid (abbreviation GABA) is a kind of naturally occurring nonprotein amino acid, is mammalian central mind
Substance is conveyed through inhibiting nerve important in system, about 30% nervous centralis synapses are using GABA as mediator.In human body
It plays an important role in cerebral cortex, hippocampus, thalamus, basal ganglion and cerebellum, and has to adjust to the multiple functions of body and make
With.Research finds (Neuron.2008；59 (2): 207-13), the source P nerve steroidal being significantly increased during gestation and in point
The rapid decline in puerperium can produce bigger effect intracerebral GABA (A) R so as to cause depressive symptom generation.
The A receptor of GABA, also referred to as γ-aminobutyric acid A receptor are a kind of ionotropic receptors, and are a kind of ligands
Door-control type ion channel.The endogenic ligand in this channel is a kind of neurotransmitter for being referred to as GABA.GABA is central nervous system
A kind of main mediator in system, although that GABA generates during the release of neurotransmitter is inhibition effect, GABA
Itself is not a kind of inhibition but a kind of irritation mediator, because of the opening of GABA activation GABA receptor.In GABAA receptor quilt
After activation, the property of can choose allows Cl- to pass through, and causes the hyperpolarization of neuron.
Drug causes GABAA receptor patient can be made to eliminate Anxiety the moderate inhibition of neuron activity, and (antianxiety is made
With), and stronger inhibiting effect can then generate general anesthesia.The serious excess of drug rarely has appearance, and the reaction generated is to prolong
Long anesthesia duration, or even occur dead.[1] benzodiazepine and benzodiazepine receptors combine, can be enhanced GABA with
The affinity of GABA receptor increases stream in cl ion, thus can increase the depression effect that GABA can be neural.
At present the A receptor modulators of the GABA for postpartum depression of clinical stage only there are two, SAGE
The SAGE-547 and SAGE-217 of Therapeutics, is respectively at Ph3 the and Ph2 stage.SAGE-547 in postpartum depression two
Phase clinic shows significant therapy, but its bioavilability is low, can only Parenteral administration.SAGE-217 treats postpartum depression
Clinical data is open not yet.
It is badly in need of the A receptor modulators of safe and effective, convenient drug administration the novel GABA of exploitation.
Summary of the invention
The present invention provides a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,
Wherein, R1For C1~C6 carbonic acyl radical；
R2Selected from alkyl, alkoxy, aryl, naphthenic base, heteroaryl, heterocycle, heterocyclylalkyl group.
Formula (I) compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt,
In include following compounds,
Compound of the present invention, stereoisomer, tautomer or pharmaceutically acceptable salt, as drug or
Pharmaceutical composition, the application in treating depression.
Specific embodiment:
The present invention is further illustrated with embodiment below, but the present invention is not intended to be limited thereto.
Embodiment 1:
The present invention provides similar testing program according to document WO2016134301, is prepared into compound 4, ESI-MS:m/z:
359.6[M+H]+。
Biological test result: the biological test scheme provided according to document WO2016134301, TBPS combination experimental test
The result shows that the activity of compound 4 is 0.1nM (IC50 value).
Claims (3)
1. a kind of formula (I) compound, stereoisomer, tautomer or pharmaceutically acceptable salt,
Wherein, R1For C1~C6 carbonic acyl radical；
R2Selected from alkyl, alkoxy, aryl, naphthenic base, heteroaryl, heterocycle, heterocyclylalkyl group.
2. formula (I) compound as described in claim 1, stereoisomer, tautomer or pharmaceutically acceptable salt,
Including following compounds,
3. the compound as described in any one of claims 1 to 2, stereoisomer, tautomer or pharmaceutically acceptable
Salt, the application as drug or pharmaceutical composition, in treating depression.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710956304.9A CN109666055A (en) | 2017-10-16 | 2017-10-16 | Adjust the compound and application thereof of nervous centralis treatment depression |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710956304.9A CN109666055A (en) | 2017-10-16 | 2017-10-16 | Adjust the compound and application thereof of nervous centralis treatment depression |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109666055A true CN109666055A (en) | 2019-04-23 |
Family
ID=66139444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710956304.9A Pending CN109666055A (en) | 2017-10-16 | 2017-10-16 | Adjust the compound and application thereof of nervous centralis treatment depression |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109666055A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019211668A3 (en) * | 2018-05-04 | 2019-12-12 | Acerus Pharmaceuticals Corporation | Neurosteroid derivatives and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005000869A1 (en) * | 2003-05-29 | 2005-01-06 | Washington University | Neuroactive 13,24-cyclo-18,21-dinorcholanes and structurally-related pentacyclic steroids |
| WO2016134301A2 (en) * | 2015-02-20 | 2016-08-25 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
-
2017
- 2017-10-16 CN CN201710956304.9A patent/CN109666055A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005000869A1 (en) * | 2003-05-29 | 2005-01-06 | Washington University | Neuroactive 13,24-cyclo-18,21-dinorcholanes and structurally-related pentacyclic steroids |
| WO2016134301A2 (en) * | 2015-02-20 | 2016-08-25 | Sage Therapeutics, Inc. | Neuroactive steroids, compositions, and uses thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019211668A3 (en) * | 2018-05-04 | 2019-12-12 | Acerus Pharmaceuticals Corporation | Neurosteroid derivatives and uses thereof |
| CN112823164A (en) * | 2018-05-04 | 2021-05-18 | 阿克罗斯制药公司 | Neurosteroid derivatives and uses thereof |
| JP2021523938A (en) * | 2018-05-04 | 2021-09-09 | アセラス ファーマシュウティカルズ コーポレーション | Neurosteroid derivatives and their use |
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| WD01 | Invention patent application deemed withdrawn after publication | ||
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Application publication date: 20190423 |