CN114426494A - Substituted methylamine derivative acting on TAAR agonist - Google Patents
Substituted methylamine derivative acting on TAAR agonist Download PDFInfo
- Publication number
- CN114426494A CN114426494A CN202210038963.5A CN202210038963A CN114426494A CN 114426494 A CN114426494 A CN 114426494A CN 202210038963 A CN202210038963 A CN 202210038963A CN 114426494 A CN114426494 A CN 114426494A
- Authority
- CN
- China
- Prior art keywords
- substituted
- methyl
- derivative
- structural formula
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/76—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/14—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a substituted methylamine derivative acting on TAAR agonist, the structural formula of the derivative is as follows: r1 is selected from hydrogen, methyl; r2 is selected from methyl, ethyl, benzyl; r3 is selected from hydroxy and methoxy; when n1 is 1, R4 is selected from carbon and oxygen; ar is an aromatic group selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivative is positioned at para position and is selected from any one substituent of F, methyl and methoxy; when n1 is 0, the amino group is ortho to the aromatic ring of formula; n1 is 1, and when R4 is carbon, the amino group is at the ortho, meta, or para positions of the aromatic ring in the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring in the structural formula. The compound provided by the invention is a trace amine receptor agonist with a novel structure, has nanomolar molecular level agonistic activity, has better effective dose compared with SEP-363856, and can be further prepared into a drug for treating schizophrenia.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a substituted methylamine derivative acting on a TAAR agonist.
Background
Schizophrenia is a serious chronic psychiatric disease with a lifetime prevalence of about 1%. The main clinical features of schizophrenia include positive symptoms such as hallucinations, delusions, disorganized thought; negative symptoms, such as apathy, social withdrawal; and impairment of cognitive functions such as memory and decision making. In the 50 s of the 20 th century, 1 st-generation antipsychotics represented by chlorpromazine were developed, which exert curative effects mainly by antagonizing dopamine 2 receptors, but have limited curative effects on negative symptoms and cognitive impairment, and are prone to extrapyramidal adverse reactions and tardive dyskinesia; the 2 nd generation antipsychotics antagonize both the D2 receptor and the 5-hydroxytryptamine 2A receptor, EPS occurs less frequently than the 1 st generation antipsychotics, but the therapeutic effect on negative symptoms and cognitive impairment is still not satisfactory for clinical treatment and leads to an increased risk of metabolic syndrome. Therefore, the development of new target therapeutic drugs for improving the diagnosis and treatment of schizophrenia is an urgent need at present.
The trace amine is a compound similar to a classical monoamine neurotransmitter in structure, mainly comprises beta-phenylethylamine, p-tyramine, deoxyepinephrine, octopamine, tryptamine and the like, has a lower concentration in the brain of a mammal, is more than 1000 times lower than the classical catechol amine neurotransmitter, has extremely high intracerebral metabolic rate and cannot be stored in vesicles like the classical monoamine neurotransmitter, and can freely diffuse into body fluid through a plasma membrane without a transporter, and the diffusion half-life is 15s or shorter. Trace amine and its receptor play a regulating role in monoamine transmitter system and neuron activity, can regulate and control the action of neurotransmitter released in synaptic cleft, for example, animal research shows that octopamine can enhance the reactivity of frontal cortex neuron to norepinephrine, etc. Recent research evidence suggests that trace amine levels are altered in a variety of diseases such as schizophrenia, depression, anxiety states, parkinson's disease and attention deficit hyperactivity disorder, for example, increased beta-phenylethylamine in the urine of schizophrenic patients, altered metabolism of tyramine and tryptamine, and the like.
There are 6 functional subtypes of trace amine associated receptors in human body, of which TAAR1 has been studied most extensively, and TAAR1 is mainly distributed in neurons, glial cells and peripheral tissue cells, and is an excitatory G protein-coupled receptor. TAAR1 expression was confirmed in amygdala, basal ganglia, limbic zones, prefrontal cortex, raphe nucleus, substantia nigra compacta and ventral tegmental areas in rodents and primates. The function research of TAAR1 is mainly realized by TAAR1 knock-out mice, and recent research suggests that the TAAR1 knock-out mice have significant prepulse inhibition defect compared with wild-type mice, which is a phenotype closely related to schizophrenia, and a specific mechanism is probably related to the interaction between TAAR1 and a D2 receptor. In the striatum of a mouse knocked out by TAAR1, the expression of a postsynaptic D2 receptor is increased, and in vitro experiments show that TAAR1 in a neuron can transfer to a cell membrane to form a heterodimer with a D2 receptor on the cell membrane, so that the activation of a downstream beta-arrestin signal channel by a D2 receptor is inhibited, the activation of a downstream glycogen synthase kinase 3 beta of a D2 receptor is reduced, and the related nerve activity of a dopamine transmitter system is regulated, thereby providing a substituted methylamine derivative acting on a TAAR agonist.
Disclosure of Invention
The present invention aims to solve the above problems of the background art by providing a substituted methylamine derivative acting on TAAR agonist.
In order to achieve the purpose, the invention provides the following technical scheme: a substituted methylamine derivative acting on TAAR agonist, the structural formula of the derivative is:
in the formula:
r1 is selected from hydrogen, methyl;
r2 is selected from methyl, ethyl, benzyl;
r3 is selected from hydroxy and methoxy;
when n1 is 1, R4 is selected from carbon and oxygen;
ar is an aromatic group selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivative is positioned at para position and is selected from any one substituent of F, methyl and methoxy;
when n1 is 0, the amino group is ortho to the aromatic ring of the formula; n1 is 1, and when R4 is carbon, the amino group is at the ortho, meta, or para positions of the aromatic ring in the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring in the structural formula.
In a preferred embodiment of the present invention, when the structural formula is a compound or a pharmaceutically acceptable salt thereof, R1 is hydrogen, R4 is carbon, n1 is 1, Ar is a p-F substituted phenyl group, R2 is benzyl, and R3 is hydroxy.
In a preferred embodiment of the present invention, when the structural formula is a compound or a pharmaceutically acceptable salt thereof, R1 is hydrogen, R4 is carbon, n1 is 1, Ar is a p-F substituted phenyl group, R2 is ethyl, and R3 is hydroxy.
As a preferable technical scheme of the invention, the structural formula is a compound, pharmaceutically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical composition.
As a preferable technical scheme of the invention, the structural formula is a compound, pharmaceutically acceptable salts thereof and application of the compound and the pharmaceutically acceptable pharmaceutical composition thereof.
As a preferable technical scheme of the invention, the structural formula is the compound, the pharmaceutically acceptable salt thereof and the application of the compound and the pharmaceutically acceptable pharmaceutical composition thereof in the preparation of medicines for treating schizophrenia.
Has the advantages that: the compound provided by the invention is a trace amine receptor agonist with a novel structure, has nanomolar molecular level agonistic activity, has a better effective dose compared with SEP-363856, has good potential and application prospect, and can be further prepared into a drug for treating schizophrenia.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention and to clearly define the scope of the invention.
The invention provides a technical scheme that: a substituted methylamine derivative acting on TAAR agonist, the structural formula of the derivative is:
in the formula:
r1 is selected from hydrogen, methyl;
r2 is selected from methyl, ethyl, benzyl;
r3 is selected from hydroxy and methoxy;
when n1 is 1, R4 is selected from carbon and oxygen;
ar is an aromatic group selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivative is positioned at para position and is selected from any one substituent of F, methyl and methoxy;
when n1 is 0, the amino group is ortho to the aromatic ring of formula; n1 is 1, and when R4 is carbon, the amino group is at the ortho, meta, or para positions of the aromatic ring in the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring in the structural formula.
In the invention, when R1 is hydrogen, R4 is carbon, n1 is 1, Ar is phenyl substituted by F para position, R2 is benzyl, and R3 is hydroxyl;
in the invention, when R1 is hydrogen, R4 is carbon, n1 is 1, Ar is phenyl substituted by F para position, R2 is ethyl, and R3 is hydroxyl;
in the present invention, compounds No. 1 to No. 20 can be further described:
table 1 shows the structural formulas of the compounds numbered 1 to 20;
TABLE 1
In the invention, part of compounds contain basic groups such as amino groups and the like which can form salts with acid, and salts of derivatives can be formed by adopting common means. Including organic acid salts such as acetate, citrate, fumarate, maleate, oxalate, malate, citrate, succinate, tartrate, lactate, camphorsulfonate, benzenesulfonate, p-toluenesulfonate, methanesulfonate, trifluoroacetate, trifluoromethanesulfonate, etc.; inorganic acid salts such as hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid), sulfate, phosphate, nitrate, and the like. Or with amino acids such as glutamic acid or aspartic acid to form glutamate or aspartate.
The invention also discloses a composition of the medicine, which comprises tablets and capsules, wherein the medicine carrier comprises conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the field of pharmacy, and flavoring agents, sweetening agents and the like can be added if necessary.
The invention also provides application of substituted methylamine derivatives acting on TAAR agonists in preparation of trace amine receptor agonists, wherein the invention adopts a radioligand binding experiment of TAAR1 in vitro, examines the binding capacity of a compound to a receptor and the receptor selectivity by an isotope labeling method, calculates the EC50 of each compound by a logit method, and obtains the Kd value and Bmax of each radioligand by Scatchard mapping;
the invention also carried out in vitro hERG channel research experiment, data by HEKA EPC-10Quatro amplifier collected and stored in PatchMaster software.
Radioligand binding experiments based on in vitro TAAR1 show that the substituted methylamine derivatives shown in the structural formula have nanomolar trace amine receptor agonistic activity, are effective components for agonizing trace amine receptors, and have EC of compound 2050Significantly lower than SEP-363856; research experiments on the hERG channel in vitro show that the hERG inhibition activity of the compound 20 is lower than that of SEP-363856; the radioligand binding assay of TAAR1 in vitro and the study of the hERG channel in vitro show that the agonistic activity of the compounds on the trace amine receptors is shown in Table 1.
The invention further aims to provide the application of the substituted methylamine derivatives and salts thereof shown in the structural formula in treating schizophrenia, and the compound 20 has the anti-schizophrenia activity through an MK-801 high activity model test and a mouse catalepsy test; acute toxicity studies were also conducted in the present invention, and half of the lethal dose of compound 20 was determined, with the results shown in table 2;
the experiment proves that compared with the TAAR1 receptor agonist SEP-363856, the compound 20 disclosed by the invention has obviously higher agonistic activity on TAAR1 than SEP-363856. Compared with a model group, the compound 20 disclosed by the invention can obviously improve MK-801 induced high activity, does not cause EPS under an effective dose, and shows that the compound has obvious anti-schizophrenia effect, and the effective dose of the compound 20 is obviously superior to that of a positive drug SEP-363856. The compounds of the present invention differ in structure from SEP-363856.
Example 1:
preparation of 2- ((dimethylamino) methyl) -1-phenylcyclohexane-1-ol (1)
Adding tetrahydrofuran (40ml) and magnesium chips (4.0g, 165mmol) into a 250ml reaction bottle, stirring and heating to reflux, dropwise adding a tetrahydrofuran solution (40ml) of bromobenzene (1.6g, 10mmol), completing the process within 1h, continuing to react for 2h to obtain a phenylmagnesium bromide solution, cooling to 40 ℃, dropwise adding a THF solution (40ml) of 2- (dimethylamino) cyclohexane-1-ketone (1.4g, 10mmol), continuing to react for 6h, stopping the reaction by TLC detecting the disappearance of a raw material point, concentrating under reduced pressure to remove tetrahydrofuran, and separating by silica gel column chromatography (eluent: dichloromethane: methanol: 20: 1) to obtain 0.8g of a white solid product with the yield of 36.5%.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,C DCl3)δ7.31-7.29(m, 2H),7.14-7.03(m,3H),2.45-2.41(m,1H),2.24(s,6H),1.94-1.44(m,5H), 1.35-1.30(m,6H).MS(ESI)m/z 220.2([M+H]+)。
example 2:
preparation of 2- ((methylamino) methyl) -1-phenylcyclohexane-1-ol (2)
To a 50ml round bottom flask was added product 1(0.5g, 2.3mmol), dissolved in dichloromethane (20ml), added ethyl chloroformate, added zinc powder, reacted for 1h, filtered, spin dried, column chromatographed (eluent: dichloromethane: methanol 10: 1) to give 0.2g of white product in 42.3% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows: 1H NMR (500MHz, CDCl3) delta 7.32-7.28(M, 2H),7.13-7.02(M,3H),3.25(s,3H),2.45-2.41(M,1H),1.94-1.44(M,5H), 1.32-1.30(M,6H). MS (ESI) M/z 206.2([ M + H ] +).
Example 3:
2- ((methylamino) methyl) -1- (4-methylphenyl) cyclohexan-1-ol (3)
Preparation of 2- ((dimethylamino) methyl) -1- (4-methylphenyl) cyclohexan-1-ol
Adding tetrahydrofuran (40ml) and magnesium chips (4.0g, 165mmol) into a 250ml reaction bottle, stirring and heating to reflux, dropwise adding a tetrahydrofuran solution (40ml) of bromotoluene (1.7g, 10mmol), completing the process within 1h, continuing to react for 2h to obtain a toluene magnesium bromide solution, cooling to 40 ℃, dropwise adding a THF solution (40ml) of 2- (dimethylamino) cyclohexane-1-one (1.4g, 10mmol), continuing to react for 6h, stopping the reaction by TLC detecting the disappearance of a raw material point, concentrating under reduced pressure to remove tetrahydrofuran, and separating by silica gel column chromatography (eluent: dichloromethane: methanol: 10: 1) to obtain 1g of a product, wherein the yield is 42.9%.
Preparation of 2- ((methylamino) methyl) -1- (4-methylphenyl) cyclohexan-1-ol (3)
And thirdly, performing the operation of the device.
To a 50ml round bottom flask was added 2- ((dimethylamino) methyl) -1- (4-methylphenyl) cyclohexan-1-ol (1g, 4.3mmol), dissolved in dichloromethane (20ml), added ethyl chloroformate, added zinc powder, reacted for 1h, filtered, spun dried, and column chromatographed (eluent: dichloromethane: methanol: 10: 1) to give 0.7g of a white solid in 74.2% yield, 31.8% overall yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.33-7.29(m, 2H),7.12-7.01(m,2H),3.25(s,3H)，2.46-2.41(m,1H),2.35(s,3H), 1.95-1.42(m,5H),1.34-1.31(m,6H).MS(ESI)m/z 220.2([M+H]+)。
example 4:
2- ((methylamino) methyl) -1- (4-methoxyphenyl) cyclohexan-1-ol (4)
The procedure of example 4 was the same as in example 3 except that p-bromobenzene in the first reaction of example 3 was changed to p-methoxybenzene, and the product was a white solid with a yield of 38.8%.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows: 1H NMR (500MHz, CDCl3) delta 7.35-7.30(M, 2H),7.14-7.02(M,2H),3.55(s,3H),3.25(s,3H),2.48-2.42(M,1H), 1.93-1.48(M,5H),1.37-1.33(M,6H). MS (ESI) M/z 236.2([ M + H ] +).
Example 5:
2- ((methylamino) methyl) -1- (4-fluorophenyl) cyclohexan-1-ol (5)
Example 5 the procedure of example 3 was followed to replace p-bromotoluene in the first reaction of example 3 with 1-bromo-4-fluorobenzene to give the product as a pale yellow solid in 35.6% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 2H),7.15-7.05(m,2H),3.25(s,3H),2.48-2.42(m,1H),1.93-1.49(m,5H), 1.37-1.32(m,6H).MS(ESI)m/z 224.3([M+H]+)。
example 6:
2- ((methylamino) methyl) -1- (thien-2-yl) cyclohexan-1-ol (6)
Example 6 was prepared as in example 3, substituting p-bromotoluene from reaction one of example 3 for 2-bromothiophene to give the product as a gray brown solid in 40% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.46-7.41(m, 1H),7.11-7.04(m,2H),3.25(s,3H),2.48-2.42(m,1H),1.93-1.43(m,5H), 1.36-1.31(m,6H).MS(ESI)m/z 212.2([M+H]+)。
example 7:
2- ((methylamino) methyl) -1-phenylcyclopentane-1-ol (7)
Example 7 was prepared as in example 3, substituting 2- (dimethylamino) cyclohexan-1-one from reaction one of example 3 for 2- (dimethylamino) cyclopentan-1-one as a colorless oil in 31.2% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.33-7.29(m, 2H),7.13-7.02(m,3H),3.25(s,3H),2.45-2.42(m,1H),1.89-1.44(m,5H), 1.32-1.30(m,4H).MS(ESI)m/z 192.2([M+H]+)。
example 8:
2- ((methylamino) methyl) -1- (4-methylphenyl) cyclopentan-1-ol (8)
Example 8 was prepared as in example 7, substituting bromobenzene in the first reaction of example 7 for p-bromotoluene to give the product as a colorless oil in 32.4% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.33-7.29(m, 2H),7.12-7.01(m,2H),3.25(s,3H),2.46-2.41(m,1H),2.35(s,3H), 1.95-1.42(m,5H),1.34-1.31(m,4H).MS(ESI)m/z 206.2([M+H]+)。
example 9:
2- ((methylamino) methyl) -1- (4-methoxyphenyl) cyclopentan-1-ol (9)
Example 9 the procedure of example 7 was followed to replace bromobenzene in the first reaction of example 7 with p-methoxybenzene to give the product as a colorless oil in 44.6% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.35-7.30(m, 2H),7.14-7.02(m,2H),3.55(s,3H),3.25(s,3H),2.48-2.42(m,1H), 1.93-1.48(m,5H),1.37-1.33(m,4H).MS(ESI)m/z 250.2([M+H]+)。
example 10:
2- ((methylamino) methyl) -1- (4-fluorophenyl) cyclopentan-1-ol (10)
EXAMPLE 10 following example 7, bromobenzene in the reaction one of example 7 was replaced by 1-bromo-4-fluorobenzene to give a pale yellow oil in 42.3% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 2H),7.15-7.05(m,2H),3.25(s,3H),2.48-2.42(m,1H),1.93-1.49(m,5H), 1.37-1.32(m,4H).MS(ESI)m/z 210.3([M+H]+)。
example 11:
3- ((methylamino) methyl) -4-phenyl-tetrahydro-2H-pyran-4-ol (11)
Example 11 was prepared as in example 3, substituting 2- (dimethylamino) cyclohexan-1-one from reaction one of example 3 for 3- (dimethylamino) tetrahydro-4H-pyran-4-one, the product being a colorless oil in 33.2% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 3H),7.15-7.05(m,2H),3.78-3.52(m,4H),3.25(s,3H),3.12-3.08 (m,1H)，2.17-1.94(m,2H).MS(ESI)m/z 208.2([M+H]+)。
example 12:
3- ((methylamino) methyl) -4- (4-fluorophenyl) -tetrahydro-2H-pyran-4-ol (12)
EXAMPLE 12 following example 11, the bromobenzene in the reaction one of example 11 was changed to 1-bromo-4-fluorobenzene to give a pale yellow solid in 38.5% yield
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 2H),7.15-7.07(m,2H),3.78-3.57(m,4H),3.26(s,3H),3.12-3.08 (m,1H)，2.17-1.94(m,2H).MS(ESI)m/z 226.2([M+H]+)。
example 13:
2- ((dimethylamino) methyl) -4-methyl-1-phenylcyclohexane-1-ol (13)
Example 13 was prepared as in example 3 by replacing 2- (dimethylamino) cyclohexan-1-one from reaction one of example 3 with 3- (dimethylamino) cyclohexan-1-one to give the product as a white solid in 29.5% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.32-7.29(m, 2H),7.13-7.02(m,3H),3.24(s,3H),2.45-2.40(m,1H),1.87-1.32(m,11H). MS(ESI)m/z 206.2([M+H]+)。
example 14:
2- ((dimethylamino) methyl) -4- (4-fluorophenyl) -1-phenylcyclohexane-1-ol (14)
EXAMPLE 14 the procedure of example 13 was followed to replace the starting bromobenzene in example 13 with 1-bromo-4-fluorobenzene to give the product as a pale yellow solid in 30.1% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.32-7.29(m,2H), 7.13-7.02(m,3H),3.24(s,3H),2.45-2.40(m,1H),1.87-1.32(m,11H). MS(ESI)m/z 224.2([M+H]+)。
example 15;
4- ((dimethylamino) methyl) -4- (4-fluorophenyl) -1-phenylcyclohexane-1-ol (15)
Example 15 was prepared as in example 14, substituting 2- (dimethylamino) cyclohexan-1-one from reaction one of example 14 for 4- (dimethylamino) cyclohexan-1-one, the product being a gray solid in 33.5% yield.
Of the present embodimentThe nuclear magnetic hydrogen spectrum result is as follows:1H NMR(500MHz,CDCl3)δ7.32-7.29(m, 2H),7.13-7.03(m,3H),3.26(s,3H),2.45-2.42(m,1H),1.89-1.31(m,11H). MS(ESI)m/z 224.2([M+H]+)。
example 16:
2- (4-methylphenyl) -2-methoxy-N-methyl-cyclohexan-1-amine (16)
Firstly, preparing 2- (dimethylamino) -1- (4-fluorophenyl) cyclohexane-1-alcohol
Adding tetrahydrofuran (40ml) and magnesium chips (4.0g, 165mmol) into a 250ml reaction bottle, stirring and heating to reflux, dropwise adding a tetrahydrofuran solution (40ml) of 1-bromo-4-fluorobenzene (1.75g, 10mmol), continuing to react for 2h to obtain a Grignard reagent, cooling to 40 ℃, dropwise adding a THF solution (40ml) of 2- (dimethylamino) cyclohexane-1-ketone (1.4g, 10mmol), continuing to react for 6h, stopping the reaction by TLC detection of material point disappearance, concentrating under reduced pressure to remove tetrahydrofuran, and separating by silica gel column chromatography (eluent: dichloromethane: methanol: 10: 1) to obtain 1.1g of a light yellow oily product with a yield of 46.4%.
Preparation of 2- (4-fluorophenyl) -2-methoxy-N, N-dimethylcyclohexan-1-amine
2- (dimethylamino) -1- (4-fluorophenyl) cyclohexan-1-ol (1.1g, 4.6mmol) and sodium carbonate (0.72g, 6.9mmol) were added to a 250ml two-necked flask, the flask was purged with nitrogen three times, then DMF (10ml) and iodomethane (0.98g, 6.9mmol) were added, the reaction was allowed to proceed at 60 ℃ for 6 hours, TLC (TLC) detected disappearance of starting material spot, the reaction was quenched with water and extracted with dichloromethane (15ml silica gel column 3), the combined organics were dried and concentrated, and then chromatographed (eluent: dichloromethane: methanol ═ 30: 1) to give 0.6g of a pale yellow oily product in 46.4% yield.
Preparation of 2- (4-methylphenyl) -2-methoxy-N-methyl-cyclohexan-1-amine (16)
To a 50ml round bottom flask was added 2- (4-fluorophenyl) -2-methoxy-N, N-dimethylcyclohexane-1-amine (0.6g, 2.4mmol), dissolved in dichloromethane (20ml), added ethyl chloroformate (0.32g, 7.2mmol), added zinc powder (1.2g), reacted for 1.5h, filtered, spun dry, and column chromatographed (eluent: dichloromethane: methanol ═ 30: 1) to give 0.3g of product as a pale yellow oil in 52.7% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.34-7.29(m, 2H),7.13-7.05(m,3H),3.65(s,3H)，3.27(s,3H),2.48-2.41(m,1H), 1.89-1.35(m,11H).MS(ESI)m/z 238.2([M+H]+)。
example 17:
2- ((ethylamino) methyl) -1- (4-fluorophenyl) cyclohexan-1-ol (17)
Example 17 was prepared as in example 5, substituting 2- (dimethylamino) cyclohexan-1-one from reaction one of example 5 for 2- (ethyl (methyl) amino) cyclohexan-1-one to give an off-white solid in 33.7% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 2H),7.15-7.05(m,2H),3.25-3.21(m,2H),2.48-2.42(m,1H),1.93-1.49 (m,5H),1.37-1.27(m,9H).MS(ESI)m/z 238.3([M+H]+)。
example 18:
2- ((benzylamino) methyl) -1- (4-fluorophenyl) cyclohexan-1-ol (18)
Example 18 was prepared as in example 5, substituting 2- (dimethylamino) cyclohexan-1-one from reaction one of example 5 for 2- (benzyl (methyl) amino) cyclohexan-1-one as a white solid in 35.6% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 5H),7.15-7.06(m,4H),3.56(s,2H),2.48-2.42(m,1H),1.93-1.49(m,5H), 1.37-1.27(m,9H).MS(ESI)m/z300.2([M+H]+)。
example 19:
(2R) -2- ((dimethylamino) methyl) -1- (4-fluorophenyl) cyclohexan-1-ol (19)
To a 100ml round bottom flask was added 2- ((dimethylamino) methyl) -1- (4-fluorophenyl) cyclohexan-1-ol (2.2g, 10mmol) and dichloromethane (20ml), L-tartaric acid (3g, 20mmol) was added with stirring at 40 ℃ for 0.5h, cooled to room temperature and crystallized with stirring for 3h, filtered, and the filtrate was washed with saturated brine and concentrated to give 1g of a white solid in 45.5% yield.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 2H),7.15-7.05(m,2H),3.25(s,3H),2.48-2.42(m,1H),1.93-1.49(m,5H), 1.37-1.32(m,6H).MS(ESI)m/z 224.3([M+H]+)。
example 20:
(2S) -2- ((dimethylamino) methyl) -1- (4-fluorophenyl) cyclohexan-1-ol (20)
The filter cake obtained in example 19 was dissolved in water, pH adjusted to 8 with saturated sodium bicarbonate solution, extracted with dichloromethane (15ml x 3), concentrated and dried under vacuum to yield 0.9g, 40.9% of white solid product.
The nuclear magnetic hydrogen spectrum result of the embodiment is as follows:1H NMR(500MHz,CDCl3)δ7.36-7.31(m, 2H),7.15-7.05(m,2H),3.25(s,3H),2.48-2.42(m,1H),1.93-1.49(m,5H), 1.37-1.32(m,6H).MS(ESI)m/z 224.2([M+H]+)。
example 21:
in vitro TAAR1 radioligand binding assays for compounds of the invention;
an isotope labeling method is adopted to examine the binding capacity of the compound to a receptor and the receptor selectivity, and the specific operation steps are as follows:
preparation of acceptor membrane:
HEK-293 cells stably expressing mouse TAAR1 were then maintained in DMEM high glucose medium with fetal bovine serum (10%, heat-inactivated at 58 ℃ for 30min), penicillin/streptomycin (1%) and 375ug/mL geneticin (Gibco) at 37 ℃ and 5% CO 2. Cells were released from culture flasks using trypsin/EDTA, harvested, washed 2 times with ice cold PBS (without Ca2+ and Mg2+), pelleted at 4 ℃ for 5 minutes at 1000rpm, frozen and stored at-80 ℃ the frozen pellet was suspended in 20mL HEPES-NaOH (20mM, pH7.4) containing 1mM EDTA and homogenized with Polytron (PT6000, Kinematica) at 14000rpm for 20 s. The homogenate was centrifuged at 48000g at 4 ℃ for 30 min. Thereafter, the supernatant was removed and the pellet was resuspended in HEPES-NaOH (20mM, pH7.4) containing 0.1mM EDTA using Polytron (14000rpm, 20s), the procedure was repeated and the final pellet was resuspended in HEPES-NaOH (20mM, pH7.4) containing 0.1mM EDTA and homogenized using Polytron, stored at-80 ℃ until use.
TAAR1 affinity assay:
the prepared membrane is uniformly dispersed by a homogenizer by using a proper amount of homogenate (20mM, pH7.4) for standby. Each reaction tube was filled with 100. mu.L of the membrane preparation. mu.L of the homogenate (20mM, pH7.4) was added to the total binding Tube (TB), 100. mu.L of (S) -4- [ (ethyl-phenyl-amino) -methyl-4, 5-dihydro-oxazol-2-ylamine (final concentration 5mM) was added to the non-specific binding tube (NB), and 100. mu.L of the test compound (final concentration 10-5M) was added to each test compound specific binding tube (SB); the radioligand 3[ H ] - (S) -4- [ (ethyl-phenyl-amino) -methyl-4, 5-dihydro-oxazol-2-ylamine (10. mu.L each reaction tube was equipped with 2 parallel tubes, each tube was placed on ice when loading). Incubating each reaction tube at 4 ℃ for 120min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing the ligand by using ice-cold test buffer solution, taking out the filter disc, putting the filter disc into a 2mL scintillation cup, adding 1mL of toluene scintillation solution, and uniformly mixing; and (5) putting the scintillation vial into a liquid scintillation counter for counting.
The main reagents of the test are as follows:
penicillin (Aladdin), streptomycin (Aladdin), geneticin, trypsin/EDTA, PBS (Sigma-Aldrich), hepes (Aladdin), (S) -4- [ (ethyl-phenyl-amino) -methyl-4, 5-dihydro-oxazol-2-ylamine (Sigma-Aldrich), 3[ H ] - (S) -4- [ (ethyl-phenyl-amino) -methyl-4, 5-dihydro-oxazol-2-ylamine (Sigma-Aldrich), toluene;
data processing and statistical analysis:
inhibition (I%) (TB-SB)/(TB-NB) × 100%
TB: a summary and constants;
NB: a non-specific binding constant;
SB: the binding constant of the compound;
calculating the EC5 of each compound by a logit method;
table 2 shows the Kd and Bmax of the respective radioligands by Scatchard plot.
Example 22:
research experiments on the in vitro hERG channel of the compound of the invention;
the HEK293 cell line stably expressed by the hERG potassium channel is cultured in a DMEM medium containing 10% fetal bovine serum and 1.2mg/mL G418, and the specific operation steps are as follows:
cell collection:
removing the old culture medium, washing with PBS once, adding 2mL of Accutase solution, and incubating at 37 ℃ for 5 min; adding 9mL of serum-containing culture medium, and carrying out mild blowing and sucking; centrifuging at 100g for 2min, and discarding supernatant; the cells were resuspended in extracellular fluid to a final cell density of 1X106 to 5X 107 cells/mL.
The experimental steps are as follows:
placing the collected cell suspension in a cell pool, and blowing and sucking the cells once every 30 s; the mechanical arm automatically injects intracellular fluid and extracellular fluid and injects cell suspension into the sealing chip; the cells are randomly attached to the holes under the attraction of negative pressure, and then the membrane attached to the holes is broken through suction to form a whole-cell recording mode; whole cell patch clamp recordings were made as Nanion
Finishing the established standard program; dosing was started 5 minutes after the whole cell recording was stable, 5 minutes per drug concentration recording, 3 repeated doses during the recording period; the method for recording the whole cell hERG potassium current by using the whole cell patch clamp comprises the following steps: clamping the membrane potential at-90 mV for 500 ms, clamping the voltage at-80 mV for 500 ms to measure the leakage current, then depolarizing to +30mV for 1000 ms, rapidly maintaining at-50 mV for 500 ms, recording the tail current, and finallyGo back to-90 mV and repeat data acquisition every 20 seconds. Data were collected by HEKA EPC-10Quatro amplifier and stored in PatchMaster software.
The main reagents of the experiment are as follows: PBS (Sigma-aldrich), Accutase;
table 2, agonist activity and hERG inhibitory activity of compound formula to TAAR 1;
TABLE 2
Example 23:
the MK-801 high activity model of the compound;
the experimental steps are as follows: KM mice, which are divided into 8-10 mice per group randomly after being layered according to body weight; after administration (or control), mice were acclimated in an autonomous activity box for 0.5h, and injected intraperitoneally with MK-801; after MK-801 is injected into the abdominal cavity, the mouse is placed into an autonomous activity box for video recording, the video recording time is 90 minutes, data analysis is carried out after the video recording is finished, and the autonomous activity condition of the mouse is evaluated.
Example 24:
testing of compounds of the invention for catalepsy in mice;
the experimental steps are as follows:
KM mice are randomly divided into a negative control group, a model group, positive drugs and compound dose groups, and each group comprises 10 mice; and (3) feeding purified water with corresponding solvent into the negative control group and the model group by intragastric administration, feeding corresponding positive medicine into the positive medicine group by intragastric administration, and feeding corresponding compound into each compound dosage group by intragastric administration, wherein the intragastric administration volume is 0.1mL/10 g. When the medicine is administrated by gavage for 30min, 60min and 90min, the two forepaws of the mouse are softly placed on a small rod which is 20cm long, 0.3cm in diameter and 5.5cm higher than a workbench, the hind limbs of the animal are softly placed on the bottom surface of the box, the duration time of the posture of the two forepaws of the mouse on the rod is recorded, and 30s of rigor and stillness is taken as a positive reaction; if the mouse forepaw is not put down all the time, the observation is stopped at 60 s; the number of positive-reacting animals in each compound dose group was counted.
Example 25:
acute toxicity testing of compounds of the invention;
the experimental steps are as follows:
the KM mice are taken in a limit experiment of a sequential method, and male and female halves are randomly divided into a plurality of groups, wherein each group comprises 2-5 mice, and the groups respectively comprise different dose groups and solvent groups of each compound. Animals were observed for mortality within 3 days. (if 3 or more than 3 animals survive within three days and the life state is not obviously abnormal, the observation is continued until the experiment is ended after 7 days, and if 3 or more than 3 animals die within three days, the LD50 is measured by a median lethality method)
Table 3. results of acute animal experiments;
TABLE 3
The experimental conclusion is that:
compared with a model group SEP-363856, the compound 20 can obviously improve MK-801 induced high activity, does not cause EPS under effective dose, and shows that the compound has obvious anti-schizophrenia effect, and the effective dose of the compound 20 is obviously superior to that of a positive drug.
The main reagents of the experiment are as follows: MK-801 (Sigma-aldrich);
composition examples:
example 26:
preparation of tablets containing compounds 1-20:
the experimental steps are as follows:
sieving raw materials with a 80-mesh sieve for later use, weighing active ingredients, microcrystalline cellulose, lactose and povidone K30 according to the formula amount, adding into a high-speed mixing preparation machine, stirring and mixing uniformly at low speed, adding a proper amount of purified water, stirring at low speed, cutting and granulating at high speed, drying wet granules for 3h at 60 ℃, granulating with a 24-mesh sieve, adding carboxymethyl starch sodium, silicon dioxide and magnesium stearate according to the formula amount, mixing totally, and tabletting by a rotary tablet press.
Example 27:
preparing a capsule containing compounds 1-20;
the experimental steps are as follows:
sieving raw materials with a 80-mesh sieve for later use, weighing the active ingredients, lactose, starch and polyvidone K30 according to the formula amount, adding into a high-speed mixing preparation machine, stirring and mixing uniformly at low speed, adding a proper amount of purified water, stirring at low speed, cutting and granulating at high speed, drying wet granules at 60 ℃ for 3h, sieving with a 24-mesh sieve for granulating, adding silicon dioxide and magnesium stearate according to the formula amount, mixing totally, and filling into capsules by a capsule filling machine.
The main reagents of the experiment are as follows: microcrystalline cellulose, lactose, povidone K30(Sigma-aldrich), carboxymethyl starch sodium, silicon dioxide, magnesium stearate, starch.
The above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.
Claims (6)
1. A substituted methylamine derivative having an action on TAAR agonist characterized in that: the structural formula of the derivative is as follows:
in the formula:
r1 is selected from hydrogen, methyl;
r2 is selected from methyl, ethyl, benzyl;
r3 is selected from hydroxy and methoxy;
when n1 is 1, R4 is selected from carbon and oxygen;
ar is an aromatic group selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivative is positioned at para position and is selected from any one substituent of F, methyl and methoxy;
when n1 is 0, the amino group is ortho to the aromatic ring of formula; n1 is 1, and when R4 is carbon, the amino group is at the ortho, meta, or para positions of the aromatic ring in the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring of the structural formula.
2. The derivative of substituted methylamines as claimed in claim 1, having an effect on TAAR agonists, wherein: when the structural formula is a compound or pharmaceutically acceptable salt thereof, R1 is hydrogen, R4 is carbon, n1 is 1, Ar is F para-substituted phenyl, R2 is benzyl, and R3 is hydroxyl.
3. The derivative of substituted methylamines as claimed in claim 1, having an effect on TAAR agonists, wherein: when the structural formula is a compound or pharmaceutically acceptable salt thereof, R1 is hydrogen, R4 is carbon, n1 is 1, Ar is F para-substituted phenyl, R2 is ethyl, and R3 is hydroxyl.
4. The derivative of substituted methylamines as claimed in claim 1, having an effect on TAAR agonists, wherein: the structural formula is a compound, pharmaceutically acceptable salt thereof and a pharmaceutically acceptable pharmaceutical composition.
5. The derivative of substituted methylamine as claimed in claim 1, wherein said derivative has the function of acting on TAAR agonist, and is characterized in that: the structural formula is a compound, pharmaceutically acceptable salt thereof and application of the compound and a pharmaceutically acceptable pharmaceutical composition.
6. The derivative of substituted methylamines as claimed in claim 1, having an effect on TAAR agonists, wherein: the structural formula is the compound, the pharmaceutically acceptable salt thereof and the application of the compound and the pharmaceutically acceptable pharmaceutical composition thereof in the drugs for treating schizophrenia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210038963.5A CN114426494B (en) | 2022-01-13 | 2022-01-13 | Substituted methylamine derivatives acting on TAAR agonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210038963.5A CN114426494B (en) | 2022-01-13 | 2022-01-13 | Substituted methylamine derivatives acting on TAAR agonist |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114426494A true CN114426494A (en) | 2022-05-03 |
| CN114426494B CN114426494B (en) | 2023-09-15 |
Family
ID=81310588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210038963.5A Active CN114426494B (en) | 2022-01-13 | 2022-01-13 | Substituted methylamine derivatives acting on TAAR agonist |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114426494B (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060276655A1 (en) * | 2005-06-06 | 2006-12-07 | Blackaby Wesley P | Cyclohexanesulfonyl derivatives as GlyT1 inhibitors to treat schizophrenia |
| US20070082927A1 (en) * | 2003-09-25 | 2007-04-12 | Shionogi & Co., Ltd. | Piperidine derivative having nmda receptor antagonistic activity |
| US20090029962A1 (en) * | 2007-07-27 | 2009-01-29 | Guido Galley | 2-azetidinemethaneamines and 2-pyrrolidinemethaneamines as taar-ligands |
| US20090036452A1 (en) * | 2007-08-03 | 2009-02-05 | Guido Galley | Taar1 ligands |
| CN104024250A (en) * | 2012-01-12 | 2014-09-03 | 霍夫曼-拉罗奇有限公司 | Heterocyclic derivatives as trace amine associated receptors (taars) |
| US9283196B1 (en) * | 2013-01-30 | 2016-03-15 | MediSynergics, LLC | Cycloalkyl-diamines for CNS disorders |
| CN110240559A (en) * | 2018-03-07 | 2019-09-17 | 泰州医药城国科化物生物医药科技有限公司 | 2-(2,2- diarylethene base) Cycloamine derivative and preparation method thereof |
-
2022
- 2022-01-13 CN CN202210038963.5A patent/CN114426494B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070082927A1 (en) * | 2003-09-25 | 2007-04-12 | Shionogi & Co., Ltd. | Piperidine derivative having nmda receptor antagonistic activity |
| US20060276655A1 (en) * | 2005-06-06 | 2006-12-07 | Blackaby Wesley P | Cyclohexanesulfonyl derivatives as GlyT1 inhibitors to treat schizophrenia |
| US20090029962A1 (en) * | 2007-07-27 | 2009-01-29 | Guido Galley | 2-azetidinemethaneamines and 2-pyrrolidinemethaneamines as taar-ligands |
| CN101765587A (en) * | 2007-07-27 | 2010-06-30 | 弗·哈夫曼-拉罗切有限公司 | 2-azetidinemethaneamines and 2-pyrrolidinemethaneamines as TAAR-ligands |
| US20090036452A1 (en) * | 2007-08-03 | 2009-02-05 | Guido Galley | Taar1 ligands |
| CN104024250A (en) * | 2012-01-12 | 2014-09-03 | 霍夫曼-拉罗奇有限公司 | Heterocyclic derivatives as trace amine associated receptors (taars) |
| US9283196B1 (en) * | 2013-01-30 | 2016-03-15 | MediSynergics, LLC | Cycloalkyl-diamines for CNS disorders |
| CN110240559A (en) * | 2018-03-07 | 2019-09-17 | 泰州医药城国科化物生物医药科技有限公司 | 2-(2,2- diarylethene base) Cycloamine derivative and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| ENAMINE LLC等提供的产品目录: "STN检索报告", 《数据库REGISTRY（在线）》, pages 1 - 8 * |
| TORIZO TAKAHASHI ET AL.: "Syntheses of analgesics. IX. Aminocyclohexane derivatives. 5", 《YAKUGAKU ZASSHI》, vol. 76, pages 56 - 60 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114426494B (en) | 2023-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4960217B2 (en) | Azabicyclo (3.1.0) hexane derivatives useful as modulators of dopamine D3 receptors | |
| HRP950460A2 (en) | Therapeutical agents | |
| WO2018226846A1 (en) | Compounds and methods for kinase modulation | |
| CN115884971B (en) | Substituted piperidine compounds and uses thereof | |
| RU2477269C2 (en) | Solid forms containing (-)-o-desmethylvenlafaxine and use thereof | |
| EA015745B1 (en) | Compounds expressing activity to cb | |
| EP1512679B1 (en) | Novel adamantane derivatives with neuroprotective, antidepressant and anti-ischaemic activities, and process for preparing them | |
| CN114426494A (en) | Substituted methylamine derivative acting on TAAR agonist | |
| EA016456B1 (en) | 8-sulfonyl-1,3,4,8-tetrahydro-2h-[1,4]oxazepino[6,7-e]indole derivatives and their use as 5-htreceptor ligands | |
| BG65161B1 (en) | Polymorphic salt | |
| CN109563072B (en) | Crystal of cyclic amine derivative and medical use thereof | |
| CN102869647A (en) | Sulfone compounds as 5-ht6 receptor ligands | |
| US10188758B2 (en) | Organic compounds | |
| HRP20050523A2 (en) | Morpholine derivatives for use as dopamine agonists in the treatment of i.a. sexual dysfunction | |
| CN110511174B (en) | Indolylalkyl piperazine compound and application thereof | |
| CN104995180A (en) | Crystalline forms of neurotrophin mimetic compounds and their salts | |
| JP5384487B2 (en) | New method | |
| WO2015007191A1 (en) | Paliperidone amino acids derivates and use thereof | |
| US11224667B2 (en) | 11C-labeled catechol derivative, pet probe of phosphorylated tau aggregation inhibitor using the same, and production method of the same | |
| CN113861185B (en) | Salts of 2- (substituted pyrimidinyl) thiazolecarboxamide compounds, compositions and uses thereof | |
| US20240140941A1 (en) | Derivative of 2,5-diketopiperazine compound, and preparation method therefor, pharmaceutical composition thereof and use thereof | |
| CN112851642B (en) | Salt of phenylpyrimidine piperazine compound and use thereof | |
| US20240083870A1 (en) | Salts of pyridinylmethylenepiperidine derivatives and uses thereof | |
| CN107586269B (en) | One kind is for treating the noval chemical compound of the nervous system disease | |
| WO2023033680A1 (en) | Substituted 2,3,4,5-tetrahydrobenzo[ f][1,4]oxazepines as modulators of trace amine-associated receptor 1 (taar1) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |