CN114426494B - Substituted methylamine derivatives acting on TAAR agonist - Google Patents
Substituted methylamine derivatives acting on TAAR agonist Download PDFInfo
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- CN114426494B CN114426494B CN202210038963.5A CN202210038963A CN114426494B CN 114426494 B CN114426494 B CN 114426494B CN 202210038963 A CN202210038963 A CN 202210038963A CN 114426494 B CN114426494 B CN 114426494B
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The invention discloses a substituted methylamine derivative acting on a TAAR agonist, which has the structural formula: r1 is selected from hydrogen, methyl; r2 is selected from methyl, ethyl and benzyl; r3 is selected from hydroxy and methoxy; when n1 is 1, R4 is selected from carbon and oxygen; ar is an aromatic group, and is selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivatives is positioned at the para position, and is selected from any 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 is in the ortho position, meta position and para position of the aromatic ring of the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring of the formula. The compound provided by the invention is a trace amine receptor agonist with novel structure, has nanomolar molecular level agonism activity, has better effective dose compared with SEP-363856, and can be further prepared into medicines for treating schizophrenia.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a substituted methylamine derivative acting on a TAAR agonist.
Background
Schizophrenia is a severe chronic mental disorder with a life-long prevalence of about 1%. The main clinical features of schizophrenia include positive symptoms such as hallucinations, delusions, and confusion in thinking; 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 have been developed, which exert efficacy mainly by antagonizing dopamine 2-type receptors, but have limited efficacy against negative symptoms and cognitive impairment, and are prone to extrapyramidal adverse reactions and tardive dyskinesias; the generation 2 antipsychotics can simultaneously antagonize the D2 receptor and the 5-hydroxytryptamine 2A receptor, the occurrence rate of EPS is lower than that of the generation 1 antipsychotics, but the treatment effect on negative symptoms and cognitive impairment still cannot meet the clinical treatment requirements, and the risk of metabolic syndrome is increased. Therefore, development of new target therapeutic drugs to improve the diagnosis and treatment conditions of schizophrenia is an urgent need at present.
Trace amines are a class of compounds structurally similar to classical monoamine neurotransmitters, mainly including beta-phenylethylamine, p-tyramine, phenylephrine, octopamine, tryptamine, etc., at lower concentrations in the brain of mammals, 1000 fold lower than classical catecholamine neurotransmitters, at extremely fast rates of metabolism in the brain and not as stored in vesicles as classical monoamine transmitters, and without a transporter, trace amines diffuse freely through the plasma membrane into body fluids with a diffusion half-life of 15s or less. Trace amine and its receptor play a role in regulating monoamine transmitter system and neuron activity, and can regulate neurotransmitter released in synaptic cleft, for example, animal research shows that octopamine can strengthen the reactivity of parietal cortex neuron to norepinephrine, etc. Recent research evidence suggests that trace amine content is altered in various diseases such as schizophrenia, depression, anxiety states, parkinson's disease, and attention deficit hyperactivity disorder, for example, beta-phenylethylamine is increased in urine of patients with schizophrenia, and metabolism of tyramine and tryptamine is also altered, etc.
Among the 6 functional subtypes of trace amine associated receptors in humans, TAAR1 has been most widely studied, and TAAR1 is a class of excitatory G protein-coupled receptors that is primarily distributed in neurons, glial cells and peripheral tissue cells. Expression of TAAR1 was demonstrated in amygdala, basal ganglia, limbic, prefrontal cortex, midstitch nucleus, substantia nigra compacta, and ventral tegmental areas of rodents and primates. The functional studies of TAAR1 are mainly carried out by TAAR1 knockout mice, and recent studies suggest that TAAR1 knockout mice have significant defects in prepulse inhibition compared to wild-type mice, a phenotype closely associated with schizophrenia, and that specific mechanisms may be associated with the existence of interactions between TAAR1 and D2 receptors. In the striatum of TAAR1 knockout mice, the expression of postsynaptic D2 receptor is increased, and in vitro experiments show that TAAR1 in neurons can be transferred to cell membranes to form heterodimers with the D2 receptor on the cell membranes, inhibit the activation of beta-arestin signaling pathway downstream of the D2 receptor, reduce the activation of glycogen synthase kinase 3 beta downstream of the D2 receptor, and regulate and control the neural activity related to a dopamine transmitter system, so that the substituted methylamine derivative with the function of TAAR agonist is provided.
Disclosure of Invention
The present invention aims to solve the above-mentioned problems of the prior art by providing a substituted methylamine derivative acting on a TAAR agonist.
In order to achieve the above purpose, the present invention provides the following technical solutions: a substituted methylamine derivative having a structural formula which acts on a TAAR agonist, the derivative having the formula:
wherein:
r1 is selected from hydrogen, methyl;
r2 is selected from methyl, ethyl and benzyl;
r3 is selected from hydroxy and methoxy;
when n1 is 1, R4 is selected from carbon and oxygen;
ar is an aromatic group, and is selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivatives is positioned at the para position, and is selected from any 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 is in the ortho position, meta position and para position of the aromatic ring of the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring of the formula.
As a preferable technical scheme of the invention, 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.
As a preferable technical scheme of the invention, 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.
As a preferable technical scheme of the invention, the structural formula is a compound, pharmaceutically acceptable salt and a medical acceptable pharmaceutical composition.
As a preferred technical scheme of the invention, the structural formula is a compound, pharmaceutically acceptable salt thereof and application of the compound and a pharmaceutical composition acceptable in medicine.
As a preferable technical scheme of the invention, the structural formula is a compound, pharmaceutically acceptable salt thereof and application of the compound and a pharmaceutical composition acceptable in medicine in treating schizophrenia.
The beneficial effects are that: the compound provided by the invention is a trace amine receptor agonist with novel structure, has nanomolar molecular level agonism activity, has better effective dose compared with SEP-363856, has good potential and application prospect, and can be further prepared into medicines for treating schizophrenia.
Detailed Description
The following detailed description of the preferred embodiments of the invention will provide those skilled in the art with a better understanding of the invention with its advantages and features, and thus define the scope of the invention more clearly and clearly.
The invention provides a technical scheme that: a substituted methylamine derivative having a structural formula which acts on a TAAR agonist, the derivative having the formula:
wherein:
r1 is selected from hydrogen, methyl;
r2 is selected from methyl, ethyl and benzyl;
r3 is selected from hydroxy and methoxy;
when n1 is 1, R4 is selected from carbon and oxygen;
ar is an aromatic group, and is selected from alpha-substituted thiophene, phenyl and substituted derivatives of phenyl, wherein the substituent of the substituted derivatives is positioned at the para position, and is selected from any 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 is in the ortho position, meta position and para position of the aromatic ring of the structural formula; when n1 is 1 and R4 is oxygen, the amino group is ortho to the aromatic ring of the formula.
In the invention, when R1 is hydrogen, R4 is carbon, n1 is 1, ar is F para-substituted phenyl, R2 is benzyl, and R3 is hydroxy;
in the invention, when R1 is hydrogen, R4 is carbon, n1 is 1, ar is F para-substituted phenyl, R2 is ethyl, and R3 is hydroxy;
in the present invention, compounds numbered 1 to 20 may be further described as:
table 1 shows the structural formulas of the compounds numbered 1 to 20;
TABLE 1
Some compounds of the present invention contain basic groups such as amine groups and the like which can form salts with acids, and salts of derivatives can be formed by ordinary means. Including organic acid salts such as acetates, citrates, fumarates, maleates, oxalates, malates, citrates, succinates, tartrates, lactates, camphorsulfonates, benzenesulfonates, p-toluenesulfonates, methanesulfonates, trifluoroacetates, trifluoromethanesulfonates, and the like; inorganic acid salts such as hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid) salts, sulfates, phosphates, nitrates, and the like. Or may form glutamate or aspartate with amino acids such as glutamate or aspartate.
The invention also discloses a composition of the medicine, which comprises a tablet and a capsule, wherein the medicine carrier comprises a conventional diluent, an excipient, a filler, an adhesive, a wetting agent, a disintegrating agent, an absorption promoter, a surfactant, an adsorption carrier, a lubricant and the like in the pharmaceutical field, and a flavoring agent, a sweetener and the like can be added if necessary.
A second object of the present invention is to provide the use of substituted methylamine derivatives with an effect on TAAR agonists for the preparation of trace amine receptor agonists, the present invention uses in vitro TAAR1 radioligand binding experiments to examine the binding capacity of compounds to the receptor and the receptor selectivity by the isotopic labelling method, calculates each compound EC50 by the logic method, and maps each radioligand Kd value and Bmax by Scatchard;
the invention also carries out research experiments of in vitro hERG channel, and data are collected by HEKA EPC-10 Quatto amplifier 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 are EC of compound 20 50 Significantly lower than SEP-363856; research experiments of in vitro hERG channel show that the hERG inhibition activity of the compound 20 is lower than that of SEP-363856; radioligand binding assay of TAAR1 in vitro and study assay of hERG channel in vitro, the agonistic activity of compounds on trace amine receptors is shown in table 1.
The invention further aims at the application of the substituted methylamine derivatives shown in the structural formula and the salts thereof in the treatment of schizophrenia, and the MK-801-based high activity model test and the mouse catalepsy test show that the compound 20 has the anti-schizophrenia activity; the present invention also conducted acute toxicity studies, and the median lethal dose of compound 20 was determined, and the results are shown in table 2;
experiments prove that compared with a TAAR1 receptor agonist SEP-363856, the compound 20 disclosed by the invention has significantly 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 at an effective dose, and shows that the compound 20 has obvious anti-schizophrenia effect, and the effective dose of the compound 20 is obviously better than that of a positive medicine 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)
Tetrahydrofuran (40 ml) and magnesium turnings (4.0 g,165 mmol) are added into a 250ml reaction bottle, stirring and heating are carried out until bromobenzene (1.6 g,10 mmol) tetrahydrofuran solution (40 ml) is added dropwise, the process is completed in 1h, after continuing to react for 2h, a magnesium phenylbromide solution is obtained, the temperature is reduced to 40 ℃, 2- (dimethylamino) cyclohexane-1-one (1.4 g,10 mmol) THF solution (40 ml) is added dropwise, the reaction is continued for 6h, TLC detects the disappearance of the raw material point, the reaction is stopped, tetrahydrofuran is removed by decompression concentration, and silica gel column chromatography separation (eluent: dichloromethane: methanol=20:1) is carried out, thus obtaining white solid product of 0.8g with the yield of 36.5%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,C DCl 3 )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 (0.5 g,2.3 mmol), dissolved in dichloromethane (20 ml), ethyl chloroformate was added, zinc powder was added, reacted for 1h, filtered, dried by spin, and column-passed (eluent: dichloromethane: methanol=10:1) to give 0.2g of a white product in 42.3% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1H NMR (500 MHz, CDCl 3) 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) cyclohexane-1-ol (3)
Preparation of 2- ((dimethylamino) methyl) -1- (4-methylphenyl) cyclohexane-1-ol
Tetrahydrofuran (40 ml) and magnesium turnings (4.0 g,165 mmol) are added into a 250ml reaction bottle, the mixture is stirred and heated until bromotoluene (1.7 g,10 mmol) and tetrahydrofuran solution (40 ml) are added dropwise, the process is completed in 1h, after the reaction is continued for 2h, toluene magnesium bromide solution is obtained, the temperature is reduced to 40 ℃, 2- (dimethylamino) cyclohexane-1-one (1.4 g,10 mmol) and THF solution (40 ml) are added dropwise, the reaction is continued for 6h, the TLC detects the disappearance of the raw material point, the reaction is stopped, the tetrahydrofuran is removed by decompression concentration, and the silica gel column chromatography separation (eluent: dichloromethane: methanol=10:1) is carried out, thus obtaining 1g of the product with the yield of 42.9%.
Preparation of 2- ((methylamino) methyl) -1- (4-methylphenyl) cyclohexane-1-ol (3)
Thirdly, the third step is to provide a third step.
To a 50ml round bottom flask was added 2- ((dimethylamino) methyl) -1- (4-methylphenyl) cyclohexane-1-ol (1 g,4.3 mmol), dissolved in dichloromethane (20 ml), ethyl chloroformate was added, zinc powder was added, reacted for 1h, filtered, spin-dried and column-passed (eluent: dichloromethane: methanol=10:1) to give 0.7g of a white solid in a yield of 74.2% and a total yield of 31.8%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclohexane-1-ol (4)
The procedure for the preparation of example 4 was as in example 3, substituting p-bromotoluene for p-methoxybenzene in reaction one of example 3, and the product was a white solid with a yield of 38.8%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1H NMR (500 MHz, CDCl 3) 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) cyclohexane-1-ol (5)
The procedure for the preparation of example 5 was as in example 3, substituting p-bromotoluene in reaction one of example 3 for 1-bromo-4-fluorobenzene, and the product was a pale yellow solid with a yield of 35.6%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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- (thiophen-2-yl) cyclohexan-1-ol (6)
The procedure for the preparation of example 6 was as in example 3, substituting p-bromotoluene in reaction one of example 3 for 2-bromothiophene, and gave a grey-brown solid in 40% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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)
The procedure for the preparation of example 7 was as in example 3, substituting 2- (dimethylamino) cyclohexane-1-one from reaction one of example 3 into 2- (dimethylamino) cyclopentane-1-one, and the product was a colorless oil in 31.2% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclopentane-1-ol (8)
The procedure for the preparation of example 8 was as in example 7, substituting bromobenzene for bromotoluene in reaction one of example 7, and the product was a colorless oil in 32.4% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclopentane-1-ol (9)
The procedure for the preparation of example 9 was as in example 7, substituting bromobenzene for p-methoxybenzene in reaction one of example 7, and gave a colorless oil in 44.6% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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)
The procedure for the preparation of example 10 was as in example 7, substituting bromobenzene in reaction one of example 7 for 1-bromo-4-fluorobenzene to give a pale yellow oil in 42.3% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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 by substituting 2- (dimethylamino) cyclohexane-1-one from reaction one of example 3 into 3- (dimethylamino) tetrahydro-4H-pyran-4-one in a colorless oil, with a yield of 33.2%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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 was prepared in the same manner as in example 11, substituting bromobenzene in reaction one of example 11 into 1-bromo-4-fluorobenzene to give a pale yellow solid with a yield of 38.5%
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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 in the same manner as in example 3 by substituting 2- (dimethylamino) cyclohexane-1-one from reaction one of example 3 into 3- (dimethylamino) cyclohexane-1-one, and the product was a white solid in 29.5% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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 was prepared in the same manner as in example 13, substituting bromobenzene as raw material in example 13 into 1-bromo-4-fluorobenzene, and obtaining a pale yellow solid with a yield of 30.1%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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 in the same manner as in example 14, substituting 2- (dimethylamino) cyclohexane-1-one from reaction one of example 14 into 4- (dimethylamino) cyclohexane-1-one, and the product was a gray solid in 33.5% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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-cyclohexane-1-amine (16)
1. Preparation of 2- (dimethylamino) -1- (4-fluorophenyl) cyclohexane-1-ol
Tetrahydrofuran (40 ml) and magnesium turnings (4.0 g,165 mmol) are added into a 250ml reaction bottle, stirring and heating are carried out until a tetrahydrofuran solution (40 ml) of 1-bromo-4-fluorobenzene (1.75 g,10 mmol) is added dropwise, the process is completed in 1.5h, after the reaction is continued for 2h, a Grignard reagent is obtained, the temperature is reduced to 40 ℃, a THF solution (40 ml) of 2- (dimethylamino) cyclohexane-1-one (1.4 g,10 mmol) is added dropwise, the reaction is continued for 6h, the TLC detects the disappearance of the starting point and stops reacting, tetrahydrofuran is removed by decompression concentration, and silica gel column chromatography separation (eluent: dichloromethane: methanol=10:1) is carried out to obtain 1.1g of pale yellow oily product with the yield of 46.4%.
2. Preparation of 2- (4-fluorophenyl) -2-methoxy-N, N-dimethylcyclohexane-1-amine
2- (dimethylamino) -1- (4-fluorophenyl) cyclohexane-1-ol (1.1 g, 4.6 mmol) and sodium carbonate (0.72 g,6.9 mmol) were added to a 250ml two-port flask, after three nitrogen substitutions in the flask, DMF (10 ml) and methyl iodide (0.98 g,6.9 mmol) were added, the reaction was stopped by detecting the disappearance of the starting material spot by TLC at 60℃and quenched with water and extracted with dichloromethane (15 ml x 3), the combined organic phases were dried and concentrated, and then chromatographed on silica gel (eluent: dichloromethane: methanol=30:1) to give 0.6g of the product as a pale yellow oil in 46.4% yield.
3. Preparation of 2- (4-methylphenyl) -2-methoxy-N-methyl-cyclohexane-1-amine (16)
To a 50ml round bottom flask was added 2- (4-fluorophenyl) -2-methoxy-N, N-dimethylcyclohexane-1-amine (0.6 g,2.4 mmol), dissolved in dichloromethane (20 ml), ethyl chloroformate (0.32 g, 7.2 mmol) was added, zinc powder (1.2 g) was added, reacted for 1.5h, filtered, spin-dried and column-passed (eluent: dichloromethane: methanol=30:1) to give 0.3g of the product as a pale yellow oil in 52.7% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclohexane-1-ol (17)
The procedure for the preparation of example 17 was as in example 5, substituting 2- (dimethylamino) cyclohexane-1-one from reaction one of example 5 into 2- (ethyl (methyl) amino) cyclohexane-1-one, and gave an off-white solid in 33.7% yield.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclohexane-1-ol (18)
Example 18 was prepared in the same manner as in example 5, substituting 2- (dimethylamino) cyclohexane-1-one from reaction one of example 5 into 2- (benzyl (methyl) amino) cyclohexane-1-one, and the product was a white solid with a yield of 35.6%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclohexane-1-ol (19)
To a 100ml round bottom flask was added 2- ((dimethylamino) methyl) -1- (4-fluorophenyl) cyclohexane-1-ol (2.2 g,10 mmol) and dichloromethane (20 ml), L-tartaric acid (3 g,20 mmol) was added under stirring at 40℃and the process continued for 0.5h, cooled to room temperature and stirred for crystallization 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 spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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) cyclohexane-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 (15 ml x 3), concentrated and dried in vacuo to give the product as a white solid, 0.9g,40.9%.
The nuclear magnetic hydrogen spectrogram of this example shows the following results: 1 H NMR(500MHz,CDCl 3 )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 experiments with compounds of the invention;
the isotope labeling method is adopted to examine the binding capacity of the compound to the 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 maintained in DMEM high glucose medium containing fetal bovine serum (10%, further heat-inactivated at 58 ℃ C. For 30 min), penicillin/streptomycin (1%) and 375ug/mL geneticin (Gibco) at 37 ℃ C. And 5% CO 2. Cells were released from the flask using trypsin/EDTA, harvested, washed 2 times with ice-cold PBS (without Ca2+ and Mg2+) and precipitated at 1000rpm for 5 minutes at 4 ℃, frozen and stored at-80℃the frozen pellet was suspended in 20mL HEPES-NaOH (20 mM, pH 7.4) containing 1mM EDTA and homogenized with Polytron (PT 6000, kinematica) at 14000rpm for 20s. The homogenate was centrifuged at 48000g at 4℃for 30min. Thereafter, the supernatant was removed and the pellet was resuspended in HEPES-NaOH (20 mM, pH 7.4) containing 0.1mM EDTA using a Polytron (14000 rpm,20 s), the procedure was repeated and the final pellet was resuspended in HEPES-NaOH (20 mM, pH 7.4) containing 0.1mM EDTA and homogenized using a Polytron and stored at-80℃for later use.
TAAR1 affinity experiments:
the prepared film was uniformly dispersed with a homogenizer by using an appropriate amount of homogenate (20 mM, pH 7.4) for use. Each reaction tube was charged with 100. Mu.L of the membrane preparation. 100. Mu.L of homogenate (20 mM, pH 7.4) was added to the total binding Tube (TB), 100. Mu.L (final concentration 5 mM) of (S) -4- [ (ethyl-phenyl-amino) -methyl-4, 5-dihydro-oxazol-2-ylamine was added to the non-specific binding tube (NB), and 100. Mu.L (final concentration 10-5M) of test compound 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 was added to each reaction tube (2 parallel tubes were used for each reaction tube) and each tube was placed on ice during sample addition. Incubating each reaction tube at 4 ℃ for 120min, after the reaction is finished, rapidly filtering the combined ligand through decompression, fully washing with ice-cold test buffer solution, taking out a filter disc, putting the filter disc into a 2mL scintillation cup, adding 1mL toluene scintillation solution, and uniformly mixing; the scintillation vial was placed into a liquid scintillation counter for counting.
The main reagent for the test:
penicillin (Aladin), streptomycin (Aladin), 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 ratio (I%) = (TB-SB)/(TB-NB) ×100%
TB: summary and constant;
NB: a non-specific binding constant;
SB: binding constant of the compound;
the logit method calculates each compound EC5;
table 2 shows the Kd values and Bmax of the respective radioligands by Scatchard plot.
Example 22:
research experiments on in vitro hERG channels of the compounds of the invention;
HEK293 cell line with stable expression of hERG potassium channel is cultured in DMEM medium containing 10% fetal bovine serum and 1.2mg/mL G418, and the specific operation steps are as follows:
cell collection:
the old medium was removed and washed once with PBS, then 2mL of Actutase solution was added and incubated for 5 min at 37 ℃; adding 9mL of serum-containing culture medium, and performing mild blowing and sucking; centrifuging at 100g for 2min, and discarding supernatant; the cells were resuspended with extracellular fluid to a final cell density of 1X106 to 5X 107cells/mL.
The experimental steps are as follows:
placing the collected cell suspension in a cell pool, and blowing and sucking cells every 30 s; the mechanical arm automatically injects the intracellular fluid, extracellular fluid and cell suspension into the sealing chip; cells are randomly attached to the holes under the suction of negative pressure, and then the membranes attached to the holes are ruptured by suction to form a whole cell recording mode; whole cell patch clamp recordings were performed as described by NanionFinishing the established standard program; dosing was started after 5 minutes of whole cell recording, 5 minutes for each drug concentration, and 3 replicates during the recording period; the whole cell patch clamp recording whole cell hERG potassium current recording method is as follows: the membrane potential was clamped at-90 mV for 500 ms, the leakage current was measured at-80 mV for 500 ms, then the voltage was removed to +30mV for 1000 ms, rapidly held at-50 mV for 500 ms, tail current was recorded, and finally back to-90 mV, and data were collected repeatedly every 20 seconds. Data were collected by HEKA EPC-10 Quatto amplifier and stored in PatchMaster software.
The main reagent of the experiment: PBS (Sigma-aldrich), acceutase;
table 2, compound formula on TAAR1 agonistic activity and hERG inhibitory activity;
TABLE 2
Example 23:
a model of high activity caused by the compound MK-801;
the experimental steps are as follows: KM mice, wherein the mice are randomly grouped after being layered according to weight, and 8-10 mice are in each group; after administration (or control), mice were placed in an autonomous mobility box for 0.5h, and injected intraperitoneally with MK-801; after MK-801 is injected into the abdominal cavity, the mice are placed into an autonomous activity box for video recording, the video recording time is 90 minutes, data analysis is carried out after video recording is finished, and the autonomous activity condition of the mice is evaluated.
Example 24:
testing of compounds of the invention for catalepsy in mice;
the experimental steps are as follows:
KM mice were randomly divided into a negative control group, a model group, a positive drug and a compound, each dose group, 10 mice per group; the negative control group and the model group are irrigated with corresponding solvent purified water, the positive medicine group is irrigated with corresponding positive medicine, each dose group of the compound is irrigated with corresponding dose compound, and the volume of the irrigated stomach is 0.1mL/10g. When the medicine is administrated by stomach irrigation for 30min, 60min and 90min, the two front paws of the mouse are gently placed on a small rod with the length of 20cm and the diameter of 0.3cm and 5.5cm higher than a workbench, then the hind limbs of the animal are gently placed on the bottom surface of the box, the duration of the posture of the two front paws of the mouse on the rod is recorded, and the positive reaction is carried out by 30s of rigidity; if the front paw of the mouse is not put down all the time, stopping observing at 60 s; the number of positive animals per compound dose group was counted.
Example 25:
acute toxicity test of the compounds of the present invention;
the experimental steps are as follows:
the limited experiment of the sequential method is to take KM mice, wherein the male and female mice are divided into a plurality of groups randomly, each group comprises 2-5 compounds, and the groups are respectively different in dosage and solvent. Animals were observed for death within 3 days. ( If 3 or more animals survive in three days, continuing to observe until the experiment is finished after 7 days when the life state is not obviously abnormal; if the animal dies 3 or more within three days, its LD50 is determined using a half-lethal dose method. )
Table 3. Acute toxicity animal experiment results;
TABLE 3 Table 3
Conclusion of experiment:
compared with the model SEP-363856, the compound 20 can obviously improve high activity induced by MK-801, does not cause EPS at 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 medicine.
The main reagent of the experiment: MK-801 (Sigma-aldrich);
composition examples:
example 26:
tablets comprising compounds 1-20 were prepared:
the experimental steps are as follows:
sieving the raw materials with 80 mesh sieve for use, weighing the active ingredients with the prescription amount, microcrystalline cellulose, lactose and povidone K30, adding into a high-speed mixing machine, stirring at low speed, mixing uniformly, adding a proper amount of purified water, stirring at low speed, cutting at high speed, granulating, drying wet granules at 60 ℃ for 3h, sieving with 24 mesh sieve, granulating, adding the prescription amount of carboxymethyl starch sodium, silicon dioxide and magnesium stearate, mixing, and tabletting with a rotary tablet press.
Example 27:
preparing a capsule comprising compounds 1-20;
the experimental steps are as follows:
sieving raw materials with 80 mesh sieve, weighing the active ingredient, lactose, starch and povidone K30, adding into a high-speed mixing machine, stirring at low speed, mixing, adding appropriate amount of purified water, stirring at low speed, cutting at high speed, granulating, drying wet granule at 60deg.C for 3h, sieving with 24 mesh sieve, adding the silica and magnesium stearate, mixing, and filling into capsule.
The main reagent of the experiment: microcrystalline cellulose, lactose, povidone K30 (Sigma-aldrich), sodium carboxymethyl starch, silicon dioxide, magnesium stearate, starch.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.
Claims (6)
1. A substituted methylamine derivative as a TAAR1 agonist, characterized in that: the structural formula of the derivative is as follows:
wherein:
R 1 selected from hydrogen, methyl;
R 2 selected from methyl, ethyl, benzyl;
R 3 selected from hydroxy and methoxy;
n 1 when 1, R is 4 Selected from-CH 2 -oxygen;
ar is an aromatic group, is a substituted derivative selected from phenyl, wherein the substituent of the substituted derivative is positioned at the para position and is selected from any 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, R 4 is-CH 2 -when the amino group is ortho-or meta-to the aromatic ring of formula; n1 is 1, R 4 In the case of oxygen, the amino group is ortho to the aromatic ring of the structural formula, ar is selected from phenyl and p-fluorophenyl;
and R is 1 Selected from hydrogen, R 2 Selected from methyl, R 3 Selected from hydroxy, n1 is 1 and R 4 Selected from-CH 2 When the amino group is in the meta position of the aromatic ring of the formula, ar is not p-F-substituted phenyl or p-methyl-substituted phenyl.
2. A substituted methylamine derivative as claimed in claim 1, which is a TAAR1 agonist, wherein: r is R 1 Is hydrogen, R 4 is-CH 2 -, n1 is 1, ar is F para-substituted phenyl, R 2 Is benzyl, R 3 Is hydroxyl.
3. A substituted methylamine derivative as claimed in claim 1, which is a TAAR1 agonist, wherein: r is R 1 Is hydrogen, R 4 is-CH 2 -, n1 is 1, ar is F para-substituted phenyl, R 2 Is ethyl, R 3 Is hydroxyl.
4. A pharmaceutically acceptable salt of a substituted methylamine derivative as claimed in claim 1 as an agonist of TAAR 1.
5. A pharmaceutically acceptable pharmaceutical composition comprising a substituted methylamine derivative as claimed in claim 1 as a TAAR1 agonist.
6. Use of a substituted methylamine derivative as claimed in claim 1, a pharmaceutically acceptable salt as claimed in claim 4 and a pharmaceutical composition as claimed in claim 5 in the manufacture of a medicament for the treatment of schizophrenia.
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